A comprehensive review on herbal approaches for treatment of urinary tract infections: Scope and challenges

Abstract

Urinary tract infections (UTIs) have become a major health concern globally, necessitating effective treatments for mitigating discomfort and avert complications. The uropathogens commonly associated with UTIs in humans such as Bacillus species, Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Escherichia coli (E. coli) are progressively developing resistance to current treatments and medications. The ancient wisdom of Ayurvedic medicines and its holistic approach can contribute to UTI treatment due to its lower toxicity, effectiveness against pathogens, and cost efficiency making it a viable option to complement or replace conventional treatments. This review delineates the key probable interactions between the bioactive components of antibacterial herbal drugs and UTI pathogens. Herbal drugs are rich in antioxidants such as flavonoids and polyphenols which can effectively neutralize free radicals and inhibit the formation of bacterial biofilms. These actions help alleviate oxidative stress and contribute to their anti-inflammatory effects. Certain specific herbs traditionally identified for their anti-inflammatory and antibacterial activity have been evaluated for their efficacy towards treatment of UTIs. Finally, the review addresses the challenges associated with herbal treatments of UTIs including issues related to standardization, dosage, and potential interactions with conventional medications that need to be overcome for broader acceptance and application.

Graphical abstract

Highlights

• •UTIs are a global health concern, requiring effective treatments to manage discomfort and prevent complications.
• •Herbal treatments can be a safer, cost-effective complement or alternative to conventional UTI antibiotics.
• •Flavonoids and polyphenols in herbal drugs help neutralize free radicals and inhibit bacterial biofilms.
• •Specific herbs with antibacterial and anti-inflammatory properties show promise for UTI relief.
• •Overcoming challenges with herbal treatments is crucial for their wider use in UTI management.

1. Introduction

The urinary tract is a crucial physiological system in the human body responsible for eliminating waste products and maintaining the balance of body fluids [1]. The major components of this system include kidneys, ureters, bladder, and urethra, all of which are quite important for preserving good health and homeostasis [2]. The malfunctioning of urinary tract, often due to urinary tract infections (UTIs), can result in substantial discomfort and complications. A thorough understanding of the urinary tract's anatomy and physiology, along with its causative agents (Fig. 1), is essential for grasping the etiology and effective management of UTIs.

Fig. 1.

Anatomy of the urinary tract, which includes organs along with their connections, causative agents, and infected areas. UTI: urinary tract infection; E. coli: Escherichia coli.

The kidneys, located in the retroperitoneal space, filter the waste and excess fluids from the blood to create urine. This urine then passes through the ureters, which connect the kidneys to the bladder. The urine is deposited in the bladder and finally ejected through the urethra during micturition [1]. Various factors such as bacterial infections, urinary obstructions, or underlying medical conditions can disrupt the equilibrium of urinary system, leading to UTIs. These infections can cause inflammation in various sections of the urinary tract, which include the kidneys (pyelonephritis), urethra (urethritis), and bladder (cystitis). The major symptoms of UTIs often include urgency, frequent urination, pain during urination, and blood in the urine, which can significantly impair quality of life if it is not promptly addressed [3].

Nowadays, various distinctive methods are employed for the prevention and treatment of recurrent and chronic UTIs, which are significantly produced by bacteria, they are mostly treated with antibiotics. The overuse and misuse of antibiotics have supported the emergence of Multi-Drug Resistance pathogens. Moreover, antibiotic remedy is frequently associated with adverse effects, including gastrointestinal tract (GIT) disturbances, allergic reactions, and disruption of vaginal microbiota, potentially increasing susceptibility to secondary infections such as vaginal candidiasis. Herbal drugs hold potential to overcome these limitations by offering alternative, non-antibiotic therapies and contributing to the development of precise diagnostic approaches. The bioactive compounds present in herbal formulations can provide antimicrobial properties without contributing to the rise of antimicrobial resistance, addressing a critical gap in current treatment strategies [[4], [5], [6]].

According to the World Health Organization (WHO), sixty percent of the global population rely on herbal medicine, with around eighty percent of people in underdeveloped nations depending almost entirely on it for their initial health care needs. Phytocompounds and their chemical analogs extracted from medicinal plants have yielded numerous clinically effective medicines for the therapy of both chronic and acute diseases. The herbal industry is currently valued at approximately USD 100 billion and is guessed to grow at an annual rate of 15% until 2030, potentially reaching USD 230.55 billion [7]. In comparison, the global market for UTI drugs is approximated to be priced at USD 9.39 billion in 2024 and is predicted to raise at a compound annual growth rate (CAGR) of 3%, reaching about USD 11.58 billion by 2031. The UTI drug market is distributed across the Middle East, Africa, Asia Pacific, Europe, North America, and Latin America [8]. In this review, a thorough analysis of some commonly used remedial plants, their extracts, and biologically active compounds has been done to identify effective natural remedies for treating UTIs. The review attempts to understand the origin of UTIs, herbal treatment, and their efficacy by providing a comprehensive overview of how herbal strategies can enhance UTI management while recognizing the barriers that must be addressed for broader acceptance and implementation.

This review utilizes data from multiple databases, including Nature, ACS, RSC, Web of Science, PubMed, and Scopus emphasizing clinical trials, meta-analyses systematic reviews, and peer-reviewed articles published between 1998 and 2024 (Fig. 2).

Fig. 2.

Flow chart of methodology utilized to select appropriate articles.

Various search terms include “urinary tract infections”, “herbal remedies”, “phototherapy”, and “natural products”. We analyzed studies and publications that explored the antifungal, anti-inflammatory, and antimicrobial properties of various herbal treatment approaches for UTIs and vaginal infections. Data from various sources, including herbal medicinal texts, Ayurveda, and ethnopharmacological literature, focusing on the anti-inflammatory and antimicrobial properties of different plant extracts has also been included in the current study.

2. Etiology of UTIs

2.1. Urinary tract microbiome and immunity

The urinary microbiome (urobiome) refers to the diverse community of microorganisms (bacteria, fungi, viruses, and other microbes) present in the urinary system. The lower urinary tract particularly serves as a major reservoir for a variety of bacteria such as Lactobacillus, Streptococcus, and bacterial vaginosis-associated species (Gardnerella, Prevotella, and Bacteroides). These microorganisms play a crucial role in preserving urinary tract health and modulating the immune response and are influenced by numerous factors such as age, menopausal status, estrogen levels, and preceding UTIs [9]. The alterations or an imbalance in the microbiome can contribute to recurrent UTI development [10]. A lesser diversity of the urinary microbiome is related to a higher susceptibility to UTI when visible to bacterial pathogens [11].

The immune signaling pathway is a highly intricate network that governs immune responses, with distinct roles in homeostasis and disease progression. While equally adaptive and innate immune responses contribute to pathogen defense, their mechanisms differ significantly. The innate immune system primarily relies on pattern recognition receptors (PRRs) to damage-associated molecular patterns (DAMPs) and perceive pathogen-associated molecular patterns (PAMPs), triggering rapid immune activation. In contrast, adaptive immunity is modulated by regulatory elements such as Forkhead Box P3 (FOXP3)-expressing regulatory T cells (Tregs) and microRNAs (miR-146a and miR-155), which influence immune homeostasis and UTI susceptibility [12,13]. Among innate immune components, toll-like receptors (TLRs) are pivotal in pathogen recognition and immune activation [14].

TLRs, as immunoregulatory glycoproteins, initiate signaling cascades that regulate pro-inflammatory mediators, contributing to cytokine storms but also promoting infection defense and tissue repair. These receptors, which are expressed on various immune and epithelial cells, are essential for recognizing PAMPs and DAMPs that are present on infectious agents or damaged host cells. By recognizing these signals, TLRs initiate immune responses to prevent the spread of infection [15]. When the pathogens enter the urinary tract, TLRs on epithelial cells and immune cells detect them and trigger immune responses to eliminate the infection. For example, TLR4, which recognizes lipopolysaccharides (LPS) on the outward Gram-negative bacteria, plays a significant role in detecting Escherichia coli (E. coli) during UTIs, leading to the activation of pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which help recruit macrophages and neutrophils to the site of infection. Dysregulated TLR signaling can result in an overactive immune response, directing persistent inflammation, increased sensitivity of the bladder, and recurring infections. Hence, a balanced TLR response is essential for effective immune defense and tissue protection and prevention of chronic inflammation and recurrent infections [[16], [17], [18], [19]].

2.2. Uropathogens pan-genome and their arsenal

The pan-genome of uropathogens encompasses the entire set of genetic material found within bacterial species that are responsible for UTIs. Uropathogens, such as Klebsiella pneumoniae (K. pneumoniae), E. coli, and Proteus mirabilis (P. mirabilis), exhibit a diverse and dynamic genome, which includes both core genes common to all strains of a species and accessory genes that vary across individual strains. These accessory genes are often crucial for the bacteria's pathogenicity and can include factors such as antibiotic resistance determinants, virulence factors, and genes involved in host interaction. Uropathogenic E. coli (UPEC) serves as an ideal target for DNA microarray probe design, offering highly specific and sensitive diagnostics for UTIs [20]. As a key model organism for UTI prevention and anti-microbial resistance (AMR) research, UPEC is characterized by the presence of prevalent mrk genes, extended spectrum β-lactamase (ESBL) production, and various resistance determinants, making it a critical focus in the study of resistance mechanisms and therapeutic strategies.

Multiplex, polymerase chain reaction (PCR) technique offers greater accuracy, efficiency, and cost-effectiveness than monoplex PCR for detecting these markers. In contrast, Acinetobacter baumannii (A. baumannii), a member of the S. aureus, P. aeruginosa, K. pneumoniae, Enterococcus faecium (E. faecium), A. baumannii, and Enterococcus species (E. spp.) (ESKAPE) group of pathogens, exhibits remarkable genomic plasticity and an extensive array of virulence factors. This opportunistic uropathogen possesses the ability to acquire and exchange mobile genetic elements (MGEs) via horizontal gene transfer (HGT), facilitating AMR and adaptation to hostile environments. While A. baumannii poses a significant threat to public health, its vast genetic arsenal also presents opportunities for novel therapeutic interventions aimed at mitigating its impact [18].

The arsenal of virulence factors in uropathogens includes adhesins, toxins, iron acquisition systems, and biofilm-forming capabilities, all of which contribute to their survival, colonization, and persistence within the urinary tract [20]. The diversity of the uropathogen pan-genome enables these bacteria to adapt to different environments and host conditions, making them challenging targets for both treatment and prevention strategies. By understanding the pan-genome and the genetic variability within uropathogens, researchers can gain insight into the mechanisms of infection, resistance, and pathogenesis, potentially aiding in the development of more effective diagnostics, therapeutics, and strategies to combat UTIs and antimicrobial resistance [21].

2.3. Other UTIs development factors

Women exhibit a higher susceptibility to UTIs compared to men, primarily due to anatomical differences [22]. In addition to physiological factors, various other risk elements contribute to the increased incidence of UTIs in women. These aspects include age-specific, susceptibility, pregnancy-related, behavioral, genetic, and urinary catheterization factors [23]. The clinical advent of UTIs varies from mild, self-restricting illness to acute sepsis having fatal value of 20%–40%. Both sexes are susceptible to it with female-to-male ratio of 2:1 in individuals with 70 years or above of age, and 50:1 in younger populations [22]. Infants and young children may experience UTIs due to congenital anomalies or structural abnormalities, while older adults, specifically those residing in long-term care facilities, are at increased risk due to factors such as urinary retention, catheter use, and comorbidities. Additionally, women may experience at least one UTIs in their lifecycle due to the anatomical factors such as a shorter urethra and proximity to the anus, which facilitate the ascent of uropathogens into the bladder. ESKAPE are some of the most studied uropathogens responsible for UTIs [20]. Most UTIs are associated with formation of biofilms by pathogenic bacteria that colonize both the tract of urine tissues and medical devices, including catheters.

3. Diagnosis and conventional treatment of UTIs

UTIs and genital tract infection are common infections requiring precise and rapid diagnostics due to overlapping symptoms. The accurate and timely diagnosis of UTI is critical for initiating suitable therapeutic intervention, thereby curtailing the overuse of antibiotics and addressing the increasing concern of anti-bacterial resistance [23,24]. Additionally, it will also aid in identifying underlying etiologies of recurrent UTIs which can enable embattled protective strategies and improve patient outcomes [25]. Advanced molecular techniques like PCR, microarray, and next-generation sequencing when combined with individual microbial profiling can enhance detection accuracy. Immunological biomarkers such as C-reactive protein, cytokines, and TLRs may further aid diagnosis of UTIs. The integration of these approaches can improve targeted treatment and antimicrobial stewardship emphasizing the need for continued research and innovation [26]. Various methods and techniques used for diagnosis of UTIs which include nanotechnology-based UTI self-testing kits, lateral flow assays, urine culture, computed tomography (CT) scan, ultrasound etc. The “gold standard” procedure for diagnosing of pathogens in urine involve cultural enrichment to isolate and grow the bacteria, thereby increasing their cell numbers to noticeable concentrations. This is obeyed by biochemical and serological testing, along with the assessment of antibiotic sensitivity profiles [27].

Some of the contemporary methods currently employed for treating UTIs are illustrated in Fig. 3 and detailed in the following section.

Fig. 3.

Current and innovative techniques used in the urinary tract infections (UTIs) treatment.

3.1. Antibiotics

The uncomplicated UTIs are typically treated with antibiotics such as fluoroquinolones, trimethoprim, β-lactams, nitrofurantoin, TMP-SMX, and fosfomycin tromethamine [28]. These agents show strong efficacy against uropathogens and favorable pharmacokinetics. However, antibiotic choice depends on patient history, infection severity, and causative pathogens. Compared to other antibiotics, nitrofurantoin is effective but associated with risks of peripheral neuropathy and hepatotoxicity [29,30]. It can occur with both acute and chronic use, presenting in various forms, from mild liver enzyme elevations to severe hepatitis or fulminant liver failure [30,31]. TMP-SMX has been associated with hepatotoxicity, hepatitis, myelosuppression, and multi-organ dysfunction [[32], [33], [34], [35]].

3.2. Vaccine

Vaccine approaches for UTIs focus on boosting humoral and innate immunity. Oral formulations like Uro-Vaxom (OM-89), containing lysates of 18 E. coli strains, are more studied than vaginal forms. In comparison, adhesin-based vaccines target host-pathogen interactions for effective prevention. Additionally, alkaline protease vaccination in mouse models showed epithelial toxicity but offered protection against upper UTIs [25,36,37].

3.3. Nano material

Nanomaterials have gained attention for UTI treatment and diagnostics. Compared to conventional methods, nanotechnology-enabled POC devices, such as nano-biosensors integrated with smartphones, offer rapid, user-friendly testing without specialized equipment. Additionally, surface-engineered nanocarriers enhance targeted drug delivery, overcoming multidrug resistance, inhibiting biofilm formation, and minimizing cytotoxicity [38,39].

3.4. Microbiota-transplantation

Fecal microbiota transplantation (FMT) offers a promising approach for recurrent UTIs caused by Clostridium difficile. Unlike conventional therapies, FMT restores gut microbiota by transferring fecal material from a healthy donor, enhancing microbial diversity and reducing uropathogen abundance. Recent studies highlight its potential in UTI management through modulation of the gut microbiota–immune system axis [40,41].

3.5. Phage-therapy

Phage therapy utilizes bacteriophages to selectively target and lyse bacterial pathogens, offering a precise and efficient approach for treating UTIs. Unlike broad-spectrum antibiotics, phages preserve beneficial microbiota, minimizing dysbiosis. This method has shown safety and effectiveness in both human and animal models, particularly against antimicrobial-resistant (AMR) bacteria, making it a promising alternative to conventional treatment [42,43].

3.6. Anti-adhesive therapeutics

Anti-adhesive therapeutics prevent UTIs by blocking uropathogenic bacteria from adhering to the urinary tract epithelium. Unlike antibiotics, they specifically disrupt bacterial adhesin–host receptor interactions, reducing infection risk associated with prolonged treatment, hospitalization, and catheter use [44]. These agents function as agonists, antagonists, or partial agonists, modulating adhesion-related signaling pathways. Compared to conventional antibiotics, they offer a targeted, resistance-limiting approach to interfere with early infection mechanisms and disease progression [45]. Recent identification of surface targets has enabled the development of specific modulators, presenting promising alternatives for managing adhesion-mediated infections [46].

3.7. Probiotics

Probiotics, particularly Lactobacillus species, have shown potential in both treating and preventing UTIs by maintaining a healthy urogenital microbiota [47]. Compared to conventional therapies, probiotics offer a natural approach to restoring microbial balance, especially in women with recurrent UTIs [48]. Studies suggest that reduced Lactobacillus levels correlate with higher infection risk, and supplementation may effectively lower UTI recurrence through microbiota modulation [49].

A major challenge in current modern therapeutic strategies is their limited success in preventing recurrent UTIs, particularly in individuals with anatomical or functional abnormalities. Compared to conventional treatments, these approaches are less effective for high-risk groups such as pregnant women, the elderly, and immunocompromised patients, leading to increased complications and relapse rates. This underscores the need for complementary and alternative medicine to improve therapeutic outcomes, address antimicrobial resistance, and reduce recurrence [50].

4. Herbal drug-based treatment of UTIs

Herbal drugs offer alternative non-antibiotic therapies and contribute to the advancement of precise investigative approaches. Medicinal plants have historically played a key role in the treatment and prevention of UTIs, with over 10,000 terrestrial plants discovered for their medicinal properties [51]. The bioactive compounds that have evolved to protect plants from pathogens can also help in prevention or treatment of infections in animals without contributing to the rise of AMR. Furthermore, herbal therapies instigate preventive benefits in managing recurrent UTI infections by targeting multiple pathways involved in infection progression. The anti-inflammatory, antimicrobial, and diuretic properties of Phytochemicals of herbal medicines follow different mechanisms as shown in Fig. 4.

Fig. 4.

Schematic diagram illustrates the diverse mechanisms of phytochemicals in the treatment of urinary tract infections (UTIs), primarily through the inhibition of key enzymes and cytokine-related pathways, including inducible nitric oxide synthase (iNOS), nuclear factor kappa-B (NF-κB), interleukin (IL), tumor necrosis factor-α (TNF-α), cyclooxygenase (COX), nerve growth factor (NGF), reactive oxygen species (ROS), nuclear factor erythroid 2-related factor 2 (Nrf2), and small interfering RNA (siRNA). These interactions contribute to the phytochemical anti-inflammatory, antimicrobial, and diuretic effects. Akt: protein kinase B.

4.1. Vaccinium macrocarpon

Vaccinium macrocarpon Ait., usually known as cranberry, is a fruit from the Ericaceae family that originated in North America and is predominantly cultivated in regions of central and northern Europe, North America, Canada, and Chile [44]. It possesses secondary metabolites having notable bioactive properties which makes this plant a valuable ingredient in the formulation of functional foods [52]. Cranberry is superlative well-known herbal remedies for the treatment of UTIs due to presence of polyphenols such as proanthocyanidins (PACs), which inhibit the adherence of uropathogenic bacteria to uroepithelial cells by preventing the formation of bacterial biofilms [53]. Howell et al. [54] demonstrated the in vitro anti-adhesion properties of PACs extracted from cranberry fruit, effectively inhibiting P-fimbrial adhesion of uropathogenic bacteria. Similarly, in an in vivo mouse model, PACs administered through drinking water demonstrated bacterial anti-adherence effects in urine samples, highlighting their potential role in UTI prevention. Foo et al. [55], further characterized the chemical structure of PACs, identifying epicatechin-based oligomers with containing at least one A-type interflavan linkage and degree of polymerization (DP) of 4 and 5. The anti-adhesion efficacy of cranberry-derived PACs is primarily attributed to the presence of these A-type linkages, in contrast to B-type interflavan bonds (4β-8 vs. 4β-6), where DP may also influence bioactivity [56].

In a comparative ex vivo study, Howell et al. [57] investigated the anti-adhesion potential of PACs in a double-blind, placebo-controlled, randomized trial involving urine samples from 32 participants across France, Japan, Spain, and Hungary. The study revealed that a 72 mg dose of PACs significantly reduced bacterial adhesion compared to the placebo (P < 0.001), demonstrating a dose-dependent inhibitory effect lasting up to 24 h. These findings underscore the critical role of PAC structural characteristics in modulating bacterial adhesion and their potential application in UTI management.

Feliciano et al. [58] observed that PACs containing more than one A-type interflavan bond were more common than oligomers containing all B-type interflavan bonds. Also, between trimers and undecamers, PACs containing at minimum one A-type bond comprised for almost 91% of the oligomers which is more responsible for anti-adhesion activity. Scharf et al. [44,59] discovered a novel mechanism by which the cranberry extract enhances the innate immune defense against UPEC. As per their findings, the cranberry extract promotes the secretion of Tamm-Horsfall protein (THP) in the kidneys which later binds with fimbrial domains on UPEC, thereby inhibiting bacterial adhesion to the uroepithelium.

Latest studies have investigated the role of cranberry in the development of diagnostic systems for UTIs. Urena-Saborio et al. [60] demonstrated that PAC-functionalized biosensors may be utilized for the identification and diagnosis of extraintestinal pathogenic E. coli (ExPEC)-associated UTIs. The PAC-polyaniline (PANI) nanocomposites based biosensor showed high sensitivity, with a detection limit of 1 CFU/mL of ExPEC and a linear reaction over a concentration range from 1 to 70,000 CFU/mL. The proposed mechanism of PAC action against uropathogenic bacteria is illustrated in Fig. 5.

Fig. 5.

Schematic presentation of proanthocyanidins (PAC) against urinary tract infections (UTIs) bacteria. The PAC promotes the secretion of Tamm-Horsfall protein (THP) in the kidneys, which later binds with fimbrial domains on uropathogenic Escherichia coli (E. coli) (UPEC), thereby inhibiting bacterial adhesion to the uroepithelium. COX2: cyclooxygenase 2; IL: interleukin; TNF-α: tumor necrosis factor-α.

4.2. Taraxacum officinale(T. officinale)

T. officinale, widely known as dandelion, is a diuretic herb that increased urine production leading to exclusion of bacteria from the urinary tract. While research on T. officinale for the treatment of UTIs is inadequate, existing evidence suggests that it may help in alleviating UTI symptoms. It has been traditionally used in herbal medicine for its diuretic efficacy, and enhancement of urinary tract health [61]. The bioactive components present in T. officinale may contribute to potentially providing relief from UTI-related symptoms [62,63]. González-Castejón et al. [64] found that the active phytoconstituents of T. officinale present in both roots and leaves include sesquiterpene lactones such as triterpenoids and taraxinic acid, like taraxasterol and cycloartenol which are responsible for diuretic, anti-inflammatory, and antimicrobial activities. The roots of T. officinale hold sesquiterpenes, inulin, and phenolic acids such as taraxinic acid β-glucopyranoside, eudesmanolides, taraxacolide-O-β-glucopyranoside, tetrahydroridentin B, and its 11,13-dihydro derivative, ainslioside, along with several triterpenes, their acetates, and 16-hydroxy derivatives, which also contribute to therapeutic properties. The diuretic activity of T. officinale already investigated by Clare et al. [65] involved 17-healthy human participants confirmed a significant increase in urination frequency (P < 0.05) within the 5 h period following the initial dose. The results suggested that the ethanolic extract of T. officinale may possess diuretic potential in humans.

Mo et al. [66] explored the effects of six herbal extracts T. officinale (root), Levisticum officinale (root), Urtica dioica (leaves), Juniperus communis (pseudo-fruits), Equisetum arvense, and Ilex paraguariensis (leaves) in an ex vivo biomedical setting. A total 10 volunteers per group (five males and five females) received a 7-day oral treatment with encapsulated dried extracts, following dosage guidelines established by the European Medicines Agency (EMA). Among these extracts, L. officinale demonstrated no significant effect on THP levels, while J. communis induced slight changes. In contrast, I. paraguariensis, U. dioica, and T. officinale exhibited minor reductions in THP concentrations, though these changes were not statistically significant.

4.3. Arctostaphylos uva-ursi

Arctostaphylos uva-ursi L., well-known as Bearberry, is a medicinal plant traditionally utilized for various therapeutic applications, particularly in the management of UTIs. Its primary bioactive constituent, arbutin, a glycoside compound, plays a crucial role in exerting its pharmacological effects on the urinary system. During UTIs, arbutin undergoes metabolic hydrolysis by β-glucosidase, leading to the release of hydroquinone, a potent urinary antiseptic that contributes to its antimicrobial activity [67]. Additionally, A. uva-ursi exhibits diuretic effects facilitating the elimination of bacteria and toxins from the urinary tract [68]. The anti-inflammatory activity of arbutin was detected by Lee and Kim [69] utilized a LPS-stimulated murine BV2 microglial cell model. It was perceived that arbutin significantly decreased the secretion of pro-inflammatory cytokines TNF-α and IL-1β as well as other related genes such as monocyte chemotactic protein-1 (MCP-1) and IL-6. Apart from arbutin additional valuable phenolic compounds such as corilagin, methylarbutin, hyperoside etc. present in A. uva-ursi expose antioxidant properties, which play essential role in safeguarding cells from oxidative damage induced by free radicals. This protective action may enhance overall urinary tract health and bolster the body's intrinsic shield mechanisms against UTIs [70].

Further, Schink et al. [71] found that ethanolic extracts of A. uva-ursi leaves exhibited the extreme anti-inflammatory potential, with accomplish inhibition of pro-inflammatory cytokine production. Gágyor et al. [72] conducted a, randomized controlled double-blind trial across forty-two families’ practices in Germany to assess the efficacy of A. uva-ursi in reduction antibiotic use in women with unchallenging UTIs. In this trial 398 adult women were randomly allotted to take either A. uva-ursi (105 mg, three times daily for five days) or a single dose of fosfomycin (3 g), along with respective placebos. It was observed that there was a reduction of 63.6% in antibiotic use by the A. uva-ursi group related to the fosfomycin group. However, the rate of UTI recurrence in the A. uva-ursi group was significantly higher (136.5% increase), which does not link the non-inferiority margin.

4.4. Hydrastis canadensis

H. canadensis L., commonly referred to as goldenseal, is a perennial herb indigenous to North America, which has been traditionally employed by Native American tribes for its medicinal properties [73]. The plant possesses several bioactive alkaloids such as berberine, hydrastine, and canadine, which are associated with its immunomodulatory and gastrointestinal health benefits [74]. Helicobacter pylori infection has been associated with various extra gastric diseases, including urological conditions. Studies suggest that H. pylori may contribute to prostate and bladder disorders in males, which could predispose individuals to UTIs. The chronic inflammatory response triggered by H. pylori infection may also play a role in long-term complications, including an increased risk of malignancies such as bladder and prostate cancer.

Mahady et al. [75] estimated the antibacterial properties of methanolic extracts derived from the rhizomes of Hydrastis canadensis, Sanguinaria canadensis and roots. In this in-vitro investigation, both plant extracts demonstrated significant inhibition of H. pylori, with inhibition zones ranging from 12.5 to 50.0 μg/mL. However, methanolic extracts of H. canadensis rhizomes exhibited pronounced antibacterial activity, characterized by a Minimum inhibitory concentration (MIC)₅₀ value of 12.5 μg/mL. The active constituents responsible for this activity were recognized as beta-hydrastine and berberine with MIC₅₀ values of 12.5 and 100.0 μg/mL, respectively. These findings emphasize the ability of these plant extracts as promising natural antibacterial agents against H. pylori.

Ettefagh et al. [76] investigated the anti-microbial and efflux pump inhibitory action of ethanolic extracts from the aerial and roots parts of H. canadensis (goldenseal). The results indicated a synergistic antibacterial effect between the aerial extract and berberine, as indicated by a fractional inhibitory concentration (FIC) of 0.375, while the root extract exhibited a lower level of synergy FIC 0.750. These outcomes highlighted the potential role of the aerial parts of H. canadensis in enhancing the antibacterial efficacy of berberine. However, investigations have explored its potential in the treatment of UTIs as it demonstrates broad-spectrum antimicrobial activity by inhibiting the growth of bacteria including E. coli and others fungi, and protozoa [77]. Furthermore, the alkaloid constituents of H. canadensis may mitigate urinary tract inflammation by facilitating the expulsion of bacteria and toxins from the urinary system [78].

4.5. Emblica officinalis

Emblica officinalis Gaertn., (amla) is a medicinal plant rich in phenolic compounds, including gallic acid and ellagic acid, which exhibit significant antimicrobial activity. These bioactive constituents effectively inhibit the growth of numerous bacterial pathogens, including E. coli, a major causative agent of UTIs. Additionally, E. officinalis has demonstrated anti-inflammatory properties by lowering the expression of pro-inflammatory cytokines such as TNF-α and IL-6, which play an essential role in the inflammatory response. Furthermore, phytochemicals such as quercetin and emblicanin A and B contribute to its antioxidant potential by mitigating oxidative stress and modulating inflammatory pathways. As a rich source of vitamin C, E. officinalis exhibits potent antioxidant activity, further enhancing its therapeutic efficacy [79]. These multifaceted properties underscore their potential as a natural remedy for both the prevention and management of UTIs.

Dang et al. [80] evaluated the anti-inflammatory properties of Plumbago zeylanica (Pz), Phyllanthus emblica (Pe), and Cyperus rotundus (Cr) using two acute inflammation models: (a) acetic acid-induced peritonitis in mice and (b) carrageenan-induced rat paw edema. In the paw edema model, all three plant extracts demonstrated a reduction in edema, with the combination of P. emblica and P. zeylanica exhibiting a percentage inhibition of 20.64%, which closely approximated that of aspirin (23.74%). Similarly, in the acetic acid-induced peritonitis model, all three extracts significantly reduced protein content in peritoneal exudates compared to the control group (P < 0.05). These findings highlight the potent anti-inflammatory potential of the P. emblica and P. zeylanica mixture, offering a promising therapeutic approach for inflammation management.

In a related study, Golechha et al. [81] researched the anti-inflammatory effects of hydroalcoholic extract of E. officinalis (HAEEO) using the cotton pellet granuloma model in rats. HAEEO exhibited dose-dependent inhibition of granuloma formation, with the highest suppression (52.36%) observed at 700 mg/kg (P < 0.001). While the precise mechanism underlying HAEEO's anti-inflammatory activity remains unclear, it is hypothesized that its efficacy is linked to the inhibition of inflammatory mediators such as serotonin, histamine, and prostaglandins. These comparative findings underscore the significant anti-inflammatory potential of various plant-based extracts, with P. emblica and P. zeylanica demonstrating efficacy comparable to aspirin, while HAEEO exhibited a more pronounced inhibitory effect in chronic inflammation models. Further mechanistic studies are warranted to elucidate the specific pathways involved in their anti-inflammatory actions.

4.6. Coriandrum sativum

Coriandrum sativum L., demonstrates notable anti-inflammatory and antimicrobial action, positioning it as a potential natural remedy for UTIs. The essential oils and extracts of coriander have been exhibited to inhibit the growth of UTI-related pathogens, including E. coli and S. aureus, while also mitigating inflammation [82]. The presence of an ample number of antioxidants, particularly flavonoids and polyphenols in C. sativum helps in neutralizing free radicals, thereby reducing oxidative stress and contributing to its anti-inflammatory properties. These bioactive compounds collectively enhance C. sativum efficacy in managing inflammation linked to bacterial infections [83].

Nair et al. [84] explored the anti-inflammatory effects of C. sativum hydroalcoholic extract (CSHE) by using assessed anti-granuloma activity and carrageenan-induced paw edema model through subcutaneous cotton pellet implantation and enhancement of peritoneal macrophages with entire Freund's adjuvant. CSHE significantly reduced paw edema (P < 0.05) and decreased dry granuloma weight in all treated animals at a dose of 32 mg/kg. Serum levels of IL-6 and IL-1β were also found to be lower in the CSHE-treated group in compare to controls (P < 0.05). Although serum TNF-α levels increased in the CSHE group, TNF-R1 expression on peritoneal macrophages was decreased. The results suggest that CSHE exhibits both anti-granuloma and anti-inflammatory activities.

Thangavelu et al. [85] observed that C. sativum and P. crispum leaves exhibit medicinal potency against a range of clinical conditions such as cancer diabetes, and inflammation. The group conducted in-vitro experiments using adenocarcinoma human alveolar basal epithelial (A549) cells and estimated the impacts of plant extracts on wound healing and inflammation. A total of 1761 compounds were recognized in the leaf extracts of P. crispum and C. sativum which were subsequently assessed in-silico for their binding affinity to receptors such as cluster of differentiation (CD) 36 and antitrypsin, in comparison to untreated cells and were obtained to be potent source of anti-inflammatory property.

4.7. Allium sativum

Allium sativum L., (garlic) is widely identified for its strong anti-inflammatory and antimicrobial activity, making it a valuable natural treatment for various infections, including UTIs. The primary bioactive compound responsible for these therapeutic effects is allicin, which is naturally produced upon crushing or chopping garlic. Allicin plays a pivotal role in inhibiting UTI-causing bacteria, such as S. aureus and E. coli by disrupting essential bacterial enzymes and metabolic pathways, ultimately resulting in cell death [86]. The high antioxidant content present in A. sativum neutralizes free radicals and thereby reduces oxidative stress and inflammation. Additionally, it enhances the immune system of the body resulting in effective combating of infections [87].

An in-vitro anti-bacterial activity of Chinese leek oil, A. sativum oil, and four naturally occurring diallyl sulfides present in these oils against three Aspergillus species, methicillin-resistant S. aureus (MRSA), S. aureus, and three Candida species by Tsao and Yin [88] demonstrated that disulfide bonds are critical to the antimicrobial activity of these compounds. It was observed that A. sativum oil, with a excess concentration of diallyl sulfides, exhibited stronger antimicrobial activity compared to Chinese leek oil. Furthermore, Tsao et al. [89] investigated the in vivo effects of A. sativum, diallyl sulfide, and diallyl disulfide on MRSA infection in Bagg albino (BALB/c) mice. The results demonstrated a significant diminution in MRSA viability in the plasma, liver, kidney, and spleen (P < 0.05), indicating a marked decrease in infection levels. Additionally, the compounds exhibited enhanced antioxidant activity by significantly reducing malondialdehyde (MDA) levels and lipid peroxidation in both plasma and organs (P < 0.05). The study suggests that A. sativum, diallyl disulfide and diallyl sulfide possess shielding properties against MRSA infection depicting their potential as novel therapeutic agents. Moreover, these compounds were found to reduce the synthesis of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1 thereby alleviating inflammation and pain associated with UTIs.

Phan et al. [90] explored the in vitro antibacterial effect of herbal antibiotics AgNPs from A. sativum and Phyllanthus urinaria on E. coli. The smaller sized A. sativum AgNPs exhibited higher inhibitory activity (MIC value 2 μg/mL) against E. coli in comparison to the P. urinaria AgNPs (MIC value 4 μg/mL). Recently, Zafar et al. [91] concluded the chemical composition of A. sativum extracts and assess their antioxidant activity using qualitative tests and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Additionally, computational methods were employed to examine the effect of A. sativum and its constituents on Phosphatase TENsin homolog deleted on chromosome 10 (PTEN). The 3D structures of the molecules were predicted and validated through the SWISS model and I-TASSER while docking study was performed through natural compounds from the drug-likeness, Asinex database, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of designated compounds were evaluated using operational tools. The study observed that A. sativum contains various phytoconstituents in both seeds and leaves, with saponins and alkaloids mainly found in the leaves. The methanol extract of the leaves demonstrated potent action of antioxidant and significantly inhibiting cytotoxicity. These findings were further supported by computer-aided drug design (CADD) approaches.

4.8. Terminalia chebula

Recently, Liu et al. [92] investigated the impacts and specific mechanisms of Terminalia chebula extract on hyperuricemic nephropathy (HN) via a combination of in vitro, in vivo experiments and network pharmacology. The T. chebula extract was evaluated as a rat model of HN by assessing renal function indices and conducting histopathological examinations. However, T. chebula Retz. offers a natural and effective means to combat UTIs due to strong antimicrobial & anti-inflammatory properties. Its rich content of tannins, flavonoids, and chebulagic acid enhances its ability to inhibit bacterial growth and reduce inflammation, making it a valuable addition to both preventive and therapeutic strategies for UTIs [93]. The phytoconstituents in T. chebula were identified using ultra-performance liquid chromatography (UPLC)-Q-Exactive Orbitrap/mass spectrometry (MS) and network pharmacology predicted the potential therapeutic targets for HN. The treatment of HN rats with T. chebula extract particularly reduced serum uric acid (SUA), serum creatinine (SCr), and blood urea nitrogen (BUN) levels while enriching renal pathological injury and fibrosis. The network pharmacology results suggested that the nuclear factor kappa-B (NF-κB) way might be a key pathway directly linked with the therapeutic effects of T. chebula extract on HN. Also, it was observed that the secretion of pro-inflammatory cytokines TNF-α, IL-6, and phosphorylation of P65 were notably inhibited [92].

Omran et al. [94] explored the anti-microbial activities of the Ayurvedic formulation Triphala, which consists of T. bellirica, P. emblica and T. chebulica against various pathogens, including S. aureus, E. coli, and P. aeruginosa. The study highlighted Triphala's potential in treating infections, particularly those resistant to conventional antibiotics, by modulating the immune response and reducing pro-inflammatory cytokines such as IL-13 and IL-4. Different extraction techniques were utilized to prepare various formulations, including creams and nanoemulsion hydrogels. The formulations incorporated a hydrophilic Triphala extract (TAE, 5 mg/mL) and lipophilic oil of carvacrol (5 mg/mL) and their antimicrobial activity was evaluated.The results demonstrated that the nanoemulsion gel system exhibited significantly higher antimicrobial activity compared to conventional cream formulations, indicating its potential as an effective delivery system for TAE-carvacrol. These outcomes suggest that optimizing this nano formulation could be beneficial for industrial applications, particularly for topical use, and may enhance the efficacy of conventional antibiotics when combined with TAE.

A comprehensive study on T. chebula and T. arjuna was performed by Khan et al. [95] evaluate their phytochemical constituents and biological activities including in-vitro anticholinesterase inhibition, antioxidant, and antimicrobial properties. The group analyzed the antioxidant activity using metal chelation, lipid peroxidation inhibition, and reducing power complementary assay technique while acetylcholinesterase inhibition was measured spectrophotometrically following Ellman's method. The antimicrobial activity was estimated using both disc and well diffusion techniques. T. arjuna demonstrated lipid peroxidation inhibitory concentration (IC₅₀: 57.7 ± 3.7 μg/mL), greater metal chelation capacity (IC₅₀: 115 ± 5.01 μg/mL), and superior decreasing power (A_0.5: 0.63 ± 0.4 mg/mL) compared to T. chebula. Both T. arjuna and T. chebula displayed potent acetylcholinesterase inhibitory action with IC₅₀: 29.6 ± 3.9 and 29.7 ± 0.5 μg/mL, respectively. T. chebula exhibited inhibition rates of 72.44% and 60.0% against Bacillus sp. and Staphylococcus sp., respectively, and MIC values of 5.0 and 2.5 mg/mL. These findings suggest that both Terminalia species serve as excellent antimicrobial agents due to existence of polyphenolic compounds which are known for their strong antioxidant and antibacterial properties.

4.9. Terminalia bellirica

Terminalia bellirica Gaertn., commonly referred to as Baheda, Bahera, Beleric, or Bastard Myrobalan, is one of the oldest medicinal plants utilized throughout Sri Lanka, India, Nepal, Bangladesh, Pakistan, and Southeast Asia. T. bellirica exhibits a broad spectrum of biological actions such as anti-inflammatory, immunomodulatory, hepatoprotective, antioxidant, antimicrobial, antidiabetic, antihyperlipidemic, and anticancer properties. These valuable properties are attributed to its rich composition of bioactive phytochemicals, including ellagic acid, glucosides, gallic acid, tannins, corilagin, galloyl glucose, chebulagic acid, ethyl gallate, and arjunolic acid [96].

Dharmaratne et al. [97] investigated the antibacterial potency of 12 different solvent extract of T. bellirica fruits against Multi drug resistance (MDR) bacteria. The results indicated substantial antibacterial effects against 16 strains of MDR including Acinetobacter spp., MRSA, K. pneumoniae and P. aeruginosa. The sequential aqueous extracts inhibited ESBL producing E. coli with a MIC value of 4 mg/mL while they were found to be ineffective against MDR K. pneumoniae. Also, the antibacterial and antioxidant activities were found to be highest for methanolic extract with an effective concentration (EC₅₀) value of 6.99 ppm in DPPH radical scavenging assays and a total phenolic content of 188.71 mg/g. These findings suggest that T. bellirica fruits have a potential to be used as broad-spectrum antibacterial agents against MDR bacteria, while also providing health benefits due to their higher antioxidant activity and lower toxicity to mammalian cells.

The anti-inflammatory, hepatoprotective and antioxidant activities of T. bellirica against liver injury due to long-term use and overdose of diclofenac (DCF) in both vitro and in vivo rat models was analyzed by Gupta et al. [98]. The researchers conducted in-vitro antioxidant assays using ferric reducing antioxidant power (FRAP), and 2,2-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS) methods and evaluated anti-inflammatory activity using albumin denaturation method. For the in vivo component, T. bellirica extracts and ellagic acid (EA) were administered to rats over a 21-day period to assess hepatoprotective effects against DCF toxicity. The findings were compared to those obtained with the standard hepatoprotective agent, silymarin. It was observed that DCF treatment led to elevated serum hepatic markers and decreased total serum protein. However, supplementation with T. bellirica extracts, EA, and silymarin significantly improved these adverse effects.

4.10. Ficus racemosa

Ficus racemosa Linn., commonly known as udumbara, possesses notable anti-inflammatory and antimicrobial properties, rendering it an effective natural remedy for UTIs. Its rich composition of tannins, flavonoids, and essential oils enhances its ability to inhibit bacterial growth and ease inflammation. F. racemosa has demonstrated inhibitory effects against various bacterial strains, including E. coli, a prevalent causative agent of UTIs [99]. Ahmed et al. [100] studied the effect of aqueous extract of F. racemosa Linn. (Moraceae) bark for anticholinesterase, anti-inflammatory and antioxidant activities in rats.

Mohan et al. [101] investigated the anti-inflammatory activity of ethanolic extract of F. racemosa (EEFR) in albino rats, exploring natural alternatives to conventional medicines such as aspirin and diclofenac for anti-inflammatory property. The anti-inflammatory impacts of EEFR were assessed using different models such as carrageenan-induced paw edema, formalin-induced peritonitis and cotton pellet-induced granuloma. In the paw edema model, EEFR demonstrated significant in-vitro anti-inflammatory activity exhibiting 61.37% inhibition at a dosage of 400 mg/kg in comparison to 62.95% inhibition for diclofenac. EEFR significantly reduced exudate volume in the formalin-induced peritonitis model and inhibited granuloma formation in the cotton pellet model, showing 28.36% inhibition at 400 mg/kg versus 28.00% for diclofenac. The findings suggest that F. racemosa has the potential to be utilized as a safer alternative to standard anti-inflammatory medications.

Recent study conducted by Mandal et al. [102] investigated the antibacterial potential effect of F. racemosa Linn. leaf extracts against several bacterial strains, including B. subtilis, E. coli, P. aeruginosa, S. aureus, and B. pumilis. The petroleum ether extract exhibited the most significant antibacterial activity compared to chloramphenicol. Preliminary screenings revealed that the petroleum ether extract demonstrated significant inhibitory effects across various concentrations from 150 to 350 mg/mL effectively inhibiting all tested bacterial strains. These results emphasize the potential of F. racemosa leaves as a valuable source of natural antibacterial agents.

4.11. Melaleuca alternifolia

Melaleuca alternifolia (Maiden & Betche) Cheel. (Tea Tree) oil exhibits antimicrobial properties, primarily attributed to its active phyto-component, terpinen-4-ol. It has indicated potent antibacterial action against common uropathogenic bacteria, E. coli. terpinen-4-ol present in M. alternifolia exerts its antimicrobial effect by disrupting bacterial cell membranes, leading to apoptosis. Additionally, M. alternifolia impedes the formation of pro-inflammatory cytokines, such as TNF-α and IL-6 thereby reducing the inflammation associated with bacterial infections [103].

Gallart-Mateu et al. [104] developed a technique for the management of terpenes quality in commercial tea tree oil samples, utilizing static headspace gas chromatography linked with mass spectrometry (HS-GC-MS). The results demonstrated that essential oil samples derived from the M. alternifolia exhibited varying terpene profiles, depending on the geographical location of plant cultivation. Zhang et al. [105] performed the in-vitro study to estimate the antimicrobial and antioxidant activities of the essential oil from M. alternifolia. The antioxidant potential was assessed using the Thio-barbituric acid reactive substances (TBARS) assay, DPPH method and hydroxyl radical scavenging activity method. The essential oil exhibited an Half maximal EC₅₀ value of 48.35 μg/mL for DPPH reduction, an IC₅₀ of 135.9 μg/mL for lipid peroxidation inhibition, and an EC₅₀ of 43.71 μg/mL for hydroxyl radical scavenging. Antimicrobial activity was tested through Minimum bactericidal concentration (MBC) and MIC assays, revealing that the essential oil strongly stopped the growth of various microorganisms, including P. digitatum, S. aureus, E. coli, P. aeruginosa, and P. italicum. The robust antioxidant and antibacterial activities suggest that the essential oil and extracts from M. alternifolia possess strong protective activities.

Vörös-Horváth et al. [106] developed a pickering emulsions (PEs) with precise properties for the targeted delivery of a combination antifungal therapy comprising tioconazole and M. alternifolia essential oil by using nanotechnological approach. The antifungal efficacy of the PEs was tested against Trichophyton rubrum and C. albicans, two primary pathogens responsible for fungal infections. The in-vitro microbiological results demonstrated that PEs exhibit remarkable synergistic effect with drug which makes them highly suitable for topical treatment of onychomycosis. Furthermore, Iseppi et al. [107] studied the anti-biofilm activity of two essential oils (EOs), E. globulus Labill (Eucalyptus oil (EEO)) and M. alternifolia Cheel. (tea tree oil (TTO)). The biofilms were produced by strains from three major categories of vancomycin-resistant enterococci (VRE), antibiotic-resistant bacteria (ARB), MRSA, and ESBL. The study was performed utilizing EOs alone, in connotation through each other and in blend with antibiotics against both single and multi-species biofilm. The results showed promising efficacy against biofilms in the early stages of formation. Also, the mature biofilms produced by ESBL E. coli were found to be most sensitive to the essential oils as exhibited by the quantification of viable cells in multi-species biofilm assays.

Vila Nova et al. [108] incorporated M. alternifolia essential oil (MaEO) into an alginate-chitosan hydrogel for the treatment of wounds infected by S. aureus. The researchers developed a hydrogel containing 1% MaEO, hydrogel M. alternifolia (HMa 1%), which exhibited interconnected porous structures with irregular surfaces with oil crystals dispersed throughout the hydrogel matrix. The hydrogel exhibited significant antimicrobial activity, inhibiting the advancement of S. aureus in both ex-vivo with in-vitro models. During ex-vivo, performed by using porcine skin and murine model for skin lesion, HMa 1%, substantially reduced the wound size, bacterial load, and inflammation scores while promoting modulating inflammatory mediators and tissue re-epithelialization. The findings suggest that MaEO-incorporated hydrogel holds strong potential for therapeutic application in the management of infected wounds.

4.12. Cinnamomum verum

Cinnamomum verum J. Presl., oil has been traditionally recognized for its effective anti-inflammatory and antimicrobial properties. The primary constituent of C. verum is cinnamaldehyde which is found to demonstrate substantial antibacterial properties against a range of bacterial species, including uropathogenic strains [109]. The anti-inflammatory property of C. verum bark extract was elucidated by Schink et al. [110] particularly in relation to signaling ways of inflammation through TLR4 and TLR2. The researchers employed gas chromatography (GC)-MS and high-performance liquid chromatography (HPLC) techniques on C. verum ethanolic extract for bioassay-guided fractionation and identification of phytocompounds, respectively. It was observed that p-cymene and trans-cinnamaldehyde present in C. verum extract inhibited the secretion of LPS-induced IL-8 in THP-1 monocytes. The results indicate that both trans-cinnamaldehyde and p-cymene play a significant role in the strong anti-inflammatory effects of C. verum extract. The study also recommended that phytocompounds without anti-inflammatory properties may still work synergistically to enhance the overall therapeutical effects of C. verum bark extract.

Lee et al. [111] evaluated the inhibition zones of C. verum oil key marker compounds such as trans-cinnamaldehyde, salicylaldehyde, and hydro cinnamaldehyde, against Agrobacterium tumefaciens, which were found to be 1.28, 1.73, and 1.24 cm, respectively, at a concentration of 0.625 mg per paper disc. Gene expression analysis revealed significant modulation when A. tumefaciens were treated with salicylaldehyde and trans-cinnamaldehyde with 117 and 27 up-regulated genes and 43 and 29 down-regulated genes, respectively. The study found that the antibacterial activity of the phytocompounds is due to reactive oxygen species (ROS) production through the Fenton reaction affected by the downregulation of ATP synthesis-associated genes, disruption of iron ion homeostasis, and an impaired ROS defense. These elevated ROS levels caused inhibition of bacterial membrane, ultimately leading to cell death.

The antioxidant and anti-inflammatory activities of the C. verum extract was studied by Kim et al. [112] in phorbol 12-myristate 13-acetate (PMA) stimulated THP-1 cells using reverse transcription-PCR (RT-PCR) technique, immunofluorescence staining, 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) staining, immunoblotting techniques. The bioactive key components coumarin and cinnamic acid significantly reduced the representation of inflammatory mediators, such as IL-8, Cyclooxygenase-2 (COX-2), IL-1β, and C-C motif chemokine ligand 5 (CCL5). Moreover, C. verum extract effectively inhibited inflammation and oxidative stress during the differentiation of monocytes into macrophages, and downregulated inflammatory signaling via the ROS/Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases-2 (NOX2) and c-Jun N-terminal kinase (JNK)/NF-κB/Protein kinase C-δ (PKCδ)/activator protein-1 (AP-1) pathways. Al-Mijalli et al. [113] assessed the antimicrobial and antifungal efficacy of C. verum EO against a spectrum of Gram-negative and Gram-positive yeasts, bacteria and molds. C. verum EO with inhibition zones ranging from 13.9 ± 1.47 mm to 32.36 ± 2.42 mm for bacterial strains and from 22.13 ± 2.25 mm to 15.26 ± 0.73 mm for fungal species demonstrated broad-spectrum antimicrobial activity. Also, low MIC, MBC, and Minimum fungicidal concentration (MFC) values were obtained, range starting 0.031%–1.0% (v/v) intended for bacteria and 0.125%–1.0% (v/v) for fungi. The MBC or MIC and MIC or MFC ratios indicated that C. verum EO possesses strong bactericidal and fungicidal properties highlighting its potential as an effective antimicrobial agent at low concentrations.

4.13. Origanum vulgare

Origanum vulgare L., oil is composed of carvacrol and thymol exhibiting potent antimicrobial properties counter to a wide range of bacterial species, including uropathogens. O. vulgare has also demonstrated strong antifungal and antibacterial efficacy making it effective in treating various infections, such as candidiasis (yeast infections) [114]. EOs from O. vulgare subsp. hirtum (OVH) and O. vulgare subsp. vulgare (OVV) were assesed for their, antioxidant, antifungal, and antibacterial properties using various assays, including FRAP, ABTS, DPPH, phosphomolybdenum, linoleic/β-carotene acid, CUPric Reducing Antioxidant Capacity (CUPRAC) and metal chelating, methods by Sarikurkcu et al. [115]. The results confirmed that the EOs of both subspecies demonstrated moderate antifungal activities and antibacterial with MIC values ranging from 426.7 to 85.3 μg/mL. O. vulgare subsp. vulgare displayed higher action against Sarcina lutea, with MIC of 85.3 μg/mL, while OVH showed powerful activity against C. albicans, also with an MIC of 85.3 μg/mL. Additionally, the EOs exhibited inhibitory activity against butyrylcholinesterase, tyrosinase, acetylcholinesterase, α-glucosidase and α-amylase enzymes associated with oxidative stress.

Oniga et al. [116] utilized the agar-well diffusion technique for the evaluation of antimicrobial activity particularly against A. niger and S. enteritidis. Furthermore, the hepatoprotective effects of the O. vulgare extract were examined in a model of carbon tetrachloride (CCl₄)-induced hepatotoxicity in rats with liver injury biomarkers such as MDA, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). The results demostrated that the extract exhibited strong hepatoprotective activity with high antioxidant action which was associated to its rich phenolic content, particularly rosmarinic and chlorogenic acids. Vinciguerra et al. [117] conducted the antifungal properties of EOs derived from Thymus vulgaris and O. vulgare L. against 27 clinical isolates of Malassezia furfur. The study utilized GC-MS to identify carvacrol as the primary component of EOs. The study employed modified broth microdilution protocols specifically tailored for Malassezia species to evaluate the MICs. The results indicated that both carvacrol and EOs exhibited minimal MIC values, ranging from 450 to 900 μg/mL against M. furfur with insignificant changes in antifungal action between sensitive and resistant fluconazole isolates.

A transdermal microemulsion was prepared by Laothaweerungsawat et al. [118] using O. vulgare essential oil to enhance the delivery of carvacrol which is known compound for anti-inflammatory with analgesic properties. Pseudo-ternary phase diagrams were produced to optimize the components of the microemulsion-1 (ME-1), which is comprised of 45% deionized water, 5% O. vulgare essential oil, 25% butylene glycol and 25% Tween 60. ME-1 demonstrated significantly reduced irritation compared to both the blank formulation and the O. vulgare oil solution. In terms of carvacrol delivery, ME-1 achieved a notable skin retention rate and enhanced transdermal absorption. Also, microemulsion significantly subdued IL-6 levels suggesting an improved anti-inflammatory effects.

Recently, Saci et al. [119] researched the antibacterial property of O. vulgare hydroalcohalic extract (HE), alone and together mixed with antibiotics, counter to E. coli strains related with avian colibacillosis. The chemical composition of the extract was identified with sixteen phenolic compounds by using HPLC. Antibacterial efficacy evaluated through agar diffusion methods depicted moderate effectiveness with MBC ranging from 31.2 to 62.4 and MIC from 3.9 to 7.8 mg/mL. The combination of the extract through antibiotics such as tetracycline and ampicillin enhanced antibacterial effect, demonstrating a synergistic outcome and underscoring the significance of combination therapies counter to resistant strains. The mode of action of the HE include integrity inhibiting adenosine triphosphate (ATPase/H⁺) proton pumps and disrupting bacterial cell membrane, which are important for bacterial existence. The Structure, and their pharmacological shown activity given in Table 1 [59,73,80,95,98,101,105,110,113,[119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144]].

Table 1.

List of phytochemicals, structure, and pharmacological activity of herbal drugs for the treatment of urinary tract infections (UTIs).

Herbal Drug	Phytochemical	Structure
Vaccinium macrocarpon	Proanthocyanidins
Hydrastis canadensis	Berberine
Emblica officinalis	Ascorbic acid (vitamin C)
Terminalia chebula	Chebulic acid
Terminalia bellirica	Ellagic acid
Ficus racemose	Sterols
Melaleuca alternifolia	Terpinen-4-ol
Arctostaphylos uva-ursi	Arbutin
Cinnamomum verum	Cinnamaldehyde
Origanum vulgare	Carvacrol
Taraxacum officinale	Ferulic acid
Coriandrum sativum	Linalool
Allium sativum	Allicin
Equisetum Arvense	Silicic acid
Zea mays	Quercetin
Althaea officinalis	Mucilage
Juniperus communis	Terpenoids
Petroselinum crispum	Apiole
Urtica dioica	Tannin
Echinacea spp.	Alkamides
Agathosma Betulina	Diosphenol
Elymus Repens	Triticin
Galium aparine	Iridoid glycosides (asperuloside)
Eupatorium purpureum	Eupatorin
Camellia sinensis	Catechins (EGCG)
Solidago virgaurea	Saponins
Mentha piperita	Menthyl acetate
Eucalyptus globulus	1,8-Cineole (Eucalyptol)
Thymus vulgaris	Thymol
Lavandula angustifolia	Linalyl acetate

E. coli: Escherichia coli; EGCG: epigallocatechin gallate.

5. Limitations or challenges

Herbal treatments for UTIs are slowly becoming popular as natural alternatives to conventional antibiotics. However, several challenges must be addressed to ensure their broader acceptance, including issues of efficacy, standardization, safety concerns, delayed therapeutic onset, incomplete bacterial eradication, misinformation, and potential interaction with underlying health conditions. Despite their natural origin, herbal remedies may cause adverse effects such as gastrointestinal upset, allergic reactions, or liver toxicity, often linked to improper dosage misinformation [145]. This limitation can be mitigated through modern analytical standardization techniques and expert guidance. Herbal treatment may require longer durations to achieve therapeutic effects compared to antibiotics, potentially allowing disease progression or complications, such as pyelonephritis or sepsis [146].

Incomplete eradication of pathogens is another concern, as it can lead to recurrent infection and potentially contribute to antibiotic resistance. However, evidence suggests that combining herbal remedies with antibiotics enhances treatment outcomes. Furthermore, individuals with pre-existing conditions such as kidney or liver disease, allergies, or autoimmune disorder must approach herbal treatments with caution, as these can exacerbate existing health issues [147]. The lack of stringent regulatory oversight also raises concerns about consistency, potency, purity, and clinical trial of herbal formulations [148].

6. Conclusion and future perspective

This review primarily focuses on herbal treatments for UTIs highlighting the advantages of herbal remedies due to their lower incidence of side effects compared to conventional treatments. Conventional therapies, particularly antibiotics, are associated with their significant adverse effects and risks of organ damage. In contrast, herbal medications are generally perceived as safer alternatives with minimal risks of major organ damage. The presence of sufficient number of antioxidants, particularly flavonoids and polyphenols in herbal drugs neutralizes free radicals, decreases the creation of pro-inflammatory cytokines and inhibit bacterial biofilms formation, thereby reducing oxidative stress and contributing to its anti-inflammatory properties. The mechanism such as shown by cranberry where it effectively flushes out inhibits from the urinary tract by increasing the expression of THP in the kidneys or by O. vulgare where it inhibits ATPase/H⁺ proton pumps and disrupts bacterial cell membrane integrity presents a promising avenue for UTI treatment with reduced safety concerns. Further research is required on the molecular mechanisms of numerous phytochemicals found in potential herbal drugs examining their effects on different uropathogens and the process of uropathogenesis. Moreover, the integration of nanotechnology could enhance the delivery and stability of these agents. However, proper scientific validation through well-conducted clinical trials will provide a valuable tool in emphasizing the use of these traditional remedies for the prevention of these common yet highly discomforting ailments.

CRediT authorship contribution statement

Md Saddam: Writing – original draft, Validation, Formal analysis. Sujeet K. Mishra: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Neelam Singh: Writing – review & editing. Shyam Baboo Prasad: Writing – review & editing. Smriti Tandon: Writing – review & editing. Hemant Rawat: Writing – review & editing. Ganesh Dane: Writing – review & editing. Vijay Kumar: Writing – review & editing, Supervision. Ajay Kumar Meena: Funding acquisition. Ravindra Singh: Resources, Project administration. Arjun Singh: Resources, Project administration. Ch V. Narasimhaji: Resources, Project administration. Narayanam Srikanth: Resources, Project administration. Rabinarayan Acharya: Supervision, Resources, Project administration.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.