The PI3K/Akt pathway: a target for curcumin’s therapeutic effects

Abstract

Purpose

The purpose of this review study is to investigate the effect of curcumin on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in various diseases. Curcumin, the main compound found in turmeric, has attracted a lot of attention for its diverse pharmacological properties. These properties have increased the therapeutic potential of curcumin in chronic diseases such as cardiovascular disease, Type 2 diabetes, obesity, non-alcoholic fatty liver disease, kidney disease, and neurodegenerative diseases. One of the main mechanisms of the effect of curcumin on health is its ability to modulate the PI3K/Akt signaling pathway. This pathway plays an important role in regulating vital cellular processes such as growth, cell survival, metabolism, and apoptosis. Disruption of the PI3K/Akt signaling pathway is associated with the incidence of several diseases.

Methods

Electronic databases including PubMed, Google Scholar, and Scopus were searched with the keywords “phosphoinositide 3-kinase” AND “protein kinase B “AND “curcumin” in the title/abstract. Also, following keywords “non-alcoholic fatty liver disease” AND “diabetes” AND “obesity” AND “kidney disease” and “neurodegenerative diseases” was searched in the whole text.

Results

Research indicates that curcumin offers potential benefits for several health conditions. Studies have shown it can help regulate blood sugar, reduce inflammation, and protect the heart, kidneys, and brain.

Conclusion

This protective effect is partially achieved by regulating the PI3K-Akt survival pathway, which helps improve metabolic disorders and oxidative stress. By examining how curcumin affects this vital cell pathway, researchers can discover new treatment strategies for a range of diseases.

Introduction

Over the past few years, there has been an increase in enthusiasm for curcumin, the main bioactive compound of turmeric, due to its diverse pharmacological properties [1]. These properties include anti-inflammatory, and antioxidant which contribute to its therapeutic potential for various chronic diseases [2]. These diseases are often characterized by metabolic dysfunction and inflammation, such as cardiovascular diseases (CVD) [3], type 2 diabetes [4], obesity [5], non-alcoholic fatty liver disease (NAFLD) [6], kidney diseases and neurodegenerative disease [7]. A key mechanism behind the health benefits of curcumin is its ability to modulate the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. This pathway is crucial in regulating essential cellular processes like growth, survival, metabolism, and apoptosis. Dysregulation of the PI3K/Akt signaling pathway has been linked to the emergence of several diseases [8, 9]. Research has shown that curcumin improves insulin resistant (IR) [10], hyperglycemia, and dyslipidemia by modulating the PI3K/Akt signaling pathway. This modulation helps to enhance insulin signaling and glucose uptake, promoting glycemic control and reducing the risk of developing type 2 diabetes. Additionally, anti-inflammatory effects of curcumin may further contribute to its benefits in CVD and kidney disease [8]. Curcumin has also been found to safeguard against myocardial ischemia-reperfusion injury by reducing infarct size and apoptosis. This cardioprotective effect is partly mediated by the regulation of the PI3K-Akt survival pathway and the Sirt1-Foxo1 pathway, which helps to improve metabolic abnormalities and oxidative stress in the heart. Curcumin enhances liver and kidney function in aging and chronic renal failure [11], and is crucial for neuronal survival and growth, making it a potential therapeutic agent for neurodegenerative disorders [12]. The objective of the review is to take a glimpse of the impact of curcumin on the PI3K/AKT signaling pathway in various disease contexts. By investigating how curcumin affects this crucial cellular pathway, researchers aim to uncover novel treatment strategies for a range of health conditions.

Methods and search strategy

Databases online such as PubMed, Google Scholar, and Scopus were queried using the keywords “phosphoinositide 3-kinase” AND “protein kinase B” AND “curcumin” in the title or abstract. The terms “non-alcoholic fatty liver disease,” “diabetes,” “obesity,” “kidney disease,” and “neurodegenerative diseases” were searched across the whole text. The papers that have mentioned keywords were collected until 2024. The inclusion criteria included in vitro, in vivo, or clinical studies assessing the consequences of curcumin on PI3K/AKT in the indicated disorders. The exclusion criteria included those without full text in English and those without accessible full text. Two independent investigators examined the primary search results.

PI3K/Akt signaling pathway

Akt kinases belong to the AGC family of protein kinases, encompassing protein kinase A/protein kinase G/kinase C kinase. These kinases are linked with both adenine monophosphate (AMP)/guanosine monophosphate (GMP) and protein kinase C kinase, which is comprised of 518 members in humans [13]. The involvement of Akt in an abundance of biological processes and pathologies, especially metabolic diseases, is well documented. The overarching signaling pathway involving Akt is known as the PI3Ks, a family of lipid kinases characterized by their ability to phosphorylate the 3’-OH group of the inositol ring in inositol phospholipids. This process generates the second messenger, phosphatidylinositol 3,4,5-triphosphate (PI-3,4,5-P), which interacts with Akt, causing its translocation to the inner membrane. Here, Akt is phosphorylated and activated by phosphoinositide-dependent kinases (PDK)1 and PDK2. Due to its pivotal role in the PI3K signaling pathway, Akt is recognized as one of the most highly activated downstream effectors [14, 15].

The PI3K/Akt signaling pathway serves as a critical regulator of various cellular processes, including the control of cell size and growth, proliferation, survival, glucose metabolism, genome stability, and neovascularization [16, 17]. Alterations in genes that are significant in these signaling pathways can result in the development of various ailments, including obesity, diabetes, coronary vesicular disease, and acute or chronic kidney disease [18–21]. Targeting this signaling pathway at a molecular level provides novel therapeutic applications for these diseases and can prevent them. However, the use of PI3K/Akt inhibitors can cause adverse effects due to their toxicity to healthy cells [22]. This has led to a growing interest in targeting downstream effectors of the PI3K/Akt pathway, such as the mammalian target of rapamycin (mTOR), as a potential therapeutic approach for various diseases [23]. Consequently, targeting the PI3K/Akt/mTOR pathway has emerged as a promising treatment strategy for a range of health conditions. This approach offers a novel and potentially more effective way to address various ailments while minimizing the negative effects associated with traditional PI3K/Akt inhibition (Fig. 1) [24, 25].

Fig. 1.

The overview of signaling of curcumin. TLR: Toll like receptor, IKK: IκB kinase, NF-KB: Nuclear factor kappa B, TNF-α: Tumor necrosis factor Alpha, COX-2: Cyclooxygenase-2, AMPK: AMP-activated protein kinase, Nrf2: Nuclear factor erythroid 2, PI3K: Phosphoinositide 3-kinases, AKT: Protein kinase B, mTOR: Mammalian target of rapamycin, BCL2: B-cell lymphoma-2, JAK: Janus kinase, STAT: Signal transducer and activator of transcription, ROS: Reactive oxygen species

Curcumin

More than 50% of the medicines discovered to date consist of natural substances or their analogs [26, 27]. As a case in point, a substantial proportion, around 65%, of patients in Europe and the United States reportedly utilize herbal remedies for liver-related health issues due to their wide availability, complex chemical composition, pharmacokinetic properties, low toxicity, and fewer side effects when compared to synthetic drugs [28–30].

Curcumin is an activated polyphenol that was first discovered in 1815 by Vogel and Pelletier as a yellow pigment [31]. Curcumin is the main component of turmeric, which belongs to the ginger family Zingiberaceae and is derived from the rhizomes of Curcuma longa L [32]. Turmeric is commonly used as a spice, imparting specific flavors and colors to curries [33]. Two distinct phases of curcumin metabolism have been documented. The initial phase, referred to as Phase-I metabolism, is characterized by the reduction of double bonds within curcumin. This process results in the formation of di, tetra, hexa, and octa hydro curcumin. In contrast, Phase-II metabolism entails the conjugation of glucuronide or sulfate to curcumin and its hydrogenated metabolites [34]. Specifically, the reductases are responsible for the reduction of the double bond of curcumin into di, tetra, hexa, and ultimately octa hydro curcumin [35] (Fig. 2).

Fig. 2.

The schematic overview of curcumin metabolism

Its therapeutic efficacy, cost-effectiveness, and acceptable safety specifications have made it widely used. Curcumin has been found to possess several biological activities, including anti-inflammatory [36], immunomodulatory, anti-microbial [37], cardioprotective [38], anticancer [39], antioxidant [40], and wound-healing abilities [41].Both preclinical studies involving animals and phase I clinical trials have demonstrated that curcumin exhibits low toxicity, even when administered at high doses, although some gastrointestinal disturbances have been reported [42]. Studies have indicated the strong intrinsic activity of curcumin as a remedy for various diseases. However, it has been found that the absorption, distribution, metabolism, excretion, and bioavailability of curcumin are poor. Curcumin is a hydrophobic molecule having a log_P of 3.2 and is practically insoluble in water [43]. Its stability in alkaline pH is minimal, and it has a reported half-life of just 10 min in phosphate buffer at physiological pH = 7.4 [44]. These limitations significantly restrict the curative value of curcumin, and it continues to be a primary concern in its clinical application. Despite administering gram doses of conventional curcumin, detecting very low plasma curcumin levels is common [35]. In the following, we will comprehensively review the protective role of curcumin against a wide range of diseases through the regulation of the PI3K/Akt signaling pathway.

Diabetes

Diabetes is a metabolic disease characterized by hyperglycemia caused by a disturbance in glucose homeostasis. This disorder is usually caused by insulin deficiency, insulin resistance, or both [45]. The universal prevalence of diabetes is estimated at 10.5% in 2021 (536.6 million) among people aged 20 to 79 years, which will reach 12.2% in 2045 (783.2 million) [46]. Multiple signaling pathways, including the PI3K/Akt pathway, play an important role in the pathogenesis of diabetes [47–49]. Research has shown that this defective signaling pathway is related to the development of type 2 diabetes and its complications. IR is associated with worsening the PI3K/Akt signaling pathway, creating a vicious cycle leading to disease progression [50]. Moreover, Akt is effective in regulating genes related to glycogen synthesis, gluconeogenic, adipogenic, and transporting the insulin-sensitive glucose transporter (GLUT4). Research also indicated that the upregulation of PI3/Akt affects the improvement of IR and β-cells function [51, 52].

Kim and colleagues. investigated the effect of curcumin on insulin sensitivity and blood glucose regulation in diabetic rats. The results showed that dietary administration of curcumin improved the PI3K/Akt signaling pathway in the liver of obese rats and was suggested as an adjuvant treatment for type 2 diabetes [53]. Notably, in another study, only a combination of insulin with curcumin had antidiabetic effects through activation of the PI3K/Akt pathway, increased insulin sensitivity, and glucose uptake in muscle cells [54]. In this regard, Mahmoudi and colleagues reported that curcumin exerts its anti-diabetic effects mainly through modulating the PI3K/Akt signaling pathway in the liver. Also, it showed that curcumin prevents hyperglycemia by suppressing the EGF/EGFR signaling pathway and related downstream pathways such as Akt and extracellular signal-regulated kinases (ERK) [55]. Another study found that curcumin prevents apoptosis through activation of Akt, suppression of FoxO1 nuclear translocation, and mitochondrial survival pathway in the MIN6 pancreatic beta-cell line [56]. Regarding the effect of curcumin in facilitating the absorption of glucose into cells, the study of Ardekani and colleagues has revealed that curcumin increased the expression of GLUT4 and its transfer to the cell membrane by affecting the Akt and AMPK signaling pathways [57].

In several researches, the effect of curcumin on the heart function of diabetic models was evaluated. For example, Yu and colleagues showed that diabetic rats are associated with reduced phosphorylation of Akt and GSK-3β, which was restored by curcumin. This group revealed that curcumin has great therapeutic potential in the treatment of diabetic cardiomyopathy, regarding the reduction of fibrosis, oxidative stress, inflammation, and cell death of heart tissue, possibly through improving Akt/GSK-3β signaling pathway [58]. In addition, in a similar study on diabetic cardiomyopathy in rats, curcumin reduced myocardial dysfunction, oxidative stress, and apoptosis in the heart of diabetic rats by activating the PI3K-Akt pathway [8]. In the study of Chen and colleagues the potential effects of curcumin and its possible mechanism were investigated on cardiac hypertrophy in diabetes. They found that curcumin supplementation can ameliorate the hypertrophy of cardiomyocytes caused by high glucose in vitro through activation of the PPARγ/Akt/NO signaling pathway. Furthermore, they documented curcumin has beneficial effects on diabetic nephropathy [59]. Similarly, Tu and colleagues have found that curcumin has beneficial effects in improving the complications of diabetic nephropathy, nonetheless, its mechanism is still unknown. In this study, curcumin decreased the levels of p-Akt and P13K in diabetic rats and the MPC5 cell line. Also, it has been stated that curcumin acts via PI3k/Akt/mTOR through changes in the induction of autophagy and reduction of podocyte epithelial-mesenchymal transition (EMT) to protect kidney cells. Moreover, they also noticed the effects of curcumin in improving diabetic retinopathy (Table 1) [60]. This result showed that curcumin can be effective in improving diabetes and its complications by influencing the PI3K/Akt pathway.

Table 1.

The overview of the main findings of the effect of curcumin on different diseases. Akt: protein kinase B, Nrf-2: nuclear factor erythroid factor 2, HO-1: Heme Oxygenase-1, ROS: reactive oxygen stress, SOD: Superoxide dismutase, mTOR: mammalian target of rapamycin, GSH: glutathione, MAPK: Mitogen-activated protein kinase, ERK: extracellular signal-regulated kinases, PI3K: Phosphoinositide 3-kinase, INR: insulin receptor, IRS-1: insulin receptor substrate 1, H2O2: hydrogen peroxide

Disease	Model	Curcumin treatment	Delivery routes	Main findings	Ref
Cardiovascular disease	In-vitro	100 µM	-	Enhancing phosphorylation, Akt increased Nrf2, overexpression HO-1, Increased Bcl-2, inhibition of Bax and caspase‐3, Reduced ROS and SOD.	[69]
Ischemia-reperfusion	In-vivo (Rats) In-vitro (H9C2 cell)	In-vivo: (25,50,100 mg/kg) In-vitro: (1.5, 3.125,6.25,12.5,25,50, 100, and 200 µg/mL)	Intraperitoneal	Activation of PI3K/Akt/mTOR signaling pathway, suppressed BAX, increased BCL-2, SOD, GSH-Px.	[70]
Obesity	In-vivo (C57BL/C HFD mice)	0.2% (w/w)	Oral	Improving insulin sensitivity and whole-body energy metabolism via the FNDC5/p38 MAPK/ERK pathways.	[66]
Obesity	In-vivo (A/J HFD mice)	0.4% (wt%)	Oral	Suppresses activation of the PI3K/Akt/mTOR/NF-κB/Wnt caused promoted tumorigenesis and suppressing cytokine-mediated.	[72]
Obesity	in vivo (C57BL/6 mice)	0.2% (w/w)	Oral	Curcumin improves the phosphorylation level of Akt, and improves insulin sensitivity.	[68]
Alzheimer’s disease	APPs/PS1 transgenic mice	100–200 mg/kg)	Gavage and feed adjunct	The decrease of INR and IRS-1 signaling pathway increased the expression of PI3K/Akt causing improvement. Pathway and induce autophagy, causing Increased levels of LC3-II and Beclin 1, promoting the proliferation of neural cells, and playing a neuroprotective role.	[89]
Alzheimer’s disease	APP/PS1 double transgenic mice	160–1000 ppm	Oral	Downregulation PI3K/Akt/mTOR signaling pathway. Increased the expression of LC3 and the ratio of LC3-II/LC3- I and beclin-1 in the CA1 regions.	[88]
Alzheimer’s disease	In vivo: (C57BL/C mice) In vitro: (hCMEC/D3 cell)	In vitro: 20 µg In vivo: 5 µg	Intraperitoneal	Activation of the PI3k/Akt signaling pathway suppresses tau hyperphosphorylation	[90]
Alzheimer’s disease	In vivo (Wistar rats)	Free curcumin (50 mg/kg/day) and Nano Capsular (2.5 mg/kg/day)	Intraperitoneal	Activation of the PI3k/Akt signaling pathway suppresses tau hyperphosphorylation	[91]
Parkinson’s disease	In vivo (Lewis rats) In vitro(HEK 293 and SKNSH)	In vivo: 0.5 µl/min In vitro: 0.1 µg/µl	Intraperitoneal	Activation of the Akt / Nfr2 signaling pathway reduced ROS levels and increased expression of the antioxidant genes.	Cui et al., 2015 [95]
Parkinson’s disease	In vivo (Sprague Dawley rats)	5, 10, 20 mg/ kg	Intraperitoneal	Increased PI3K protein expression, regeneration or proliferation of neurons in the damaged hippocampus	[96]
Huntington’s disease	In vivo (Wistar strain rat)	40 mg/kg	Oral	Increased expression Activation of Akt / Nfr2 signaling, increased activity of mitochondrial complexes and cytochrome levels, reduced lipid peroxidase	[98]
Spinal cord injury	In vivo (Wistar rat)	0.01 ml	Intraperitoneal	The behavioral tests revealed a significant improvement.	[103]
Spinal cord injury	In vivo (Wistar rat)	100 mg/kg	Intraperitoneal	Neuroprotection of damaged neurons is achieved by increasing the production of NGF, which then activates TrkA and the PI3K/Akt cell survival signaling pathway.	[104]

Obesity and non-alcoholic fatty liver disease

As a global health crisis, obesity is associated with many chronic diseases, including cardiovascular disease, type 2 diabetes, and some cancers. The root of obesity can be found in metabolic disorders, especially insulin resistance and chronic inflammation [61]. One of the common complications of obesity is NAFLD. In this disease, the abnormal accumulation of fat in the liver leads to inflammation and cell damage. Insulin resistance and increased production of reactive oxygen stress (ROS) also play an important role in the pathogenesis of NAFLD [62–64].

Curcumin, due to its strong anti-inflammatory and antioxidant properties, has been considered a potential agent in the treatment of obesity and NAFLD. Several studies have shown that curcumin helps to improve insulin sensitivity and reduce fat accumulation in the liver by activating the PI3K/Akt pathway [65]. In this connection, Yu and colleagues indicated that Dihydrocurcumin plays regulatory roles in key genes of hepatic lipid metabolism such as PPARα, and SREBP-1c. Additionally, it regulates the oxidative stress regulator nuclear factor erythroid factor 2 (Nrf2) and the insulin signaling pathway related to PI3K/Akt. This study reported that Dihydrocurcumin enhanced hepatic glucose uptake by upregulating PAkt and PI3K proteins [66]. Leptin stimulates the activation of hepatic satellite cells by increasing intracellular glucose levels. Navkar and colleagues reported that curcumin eliminates this effect of leptin by inhibiting the transfer of GLUT4 to the membrane and inducing the conversion of glucose to glucose-6-phosphate. This reduces intracellular glucose and inhibits the activation of hepatic satellite cells. This action takes place through disruption of the IRS/PI3K/Akt signaling pathway, which leads to the inhibition of GLUT4 transfer to the membrane [67]. In another paper, Li and colleagues indicate that strong correlation between curcumin consumption and metabolic parameters. Curcumin as an anti-hyperglycemic factor improves insulin sensitivity by affecting the phosphorylation level of Akt and suppressing serine phosphorylation of IRS1 [68]. Available evidence shows that curcumin has great potential for the treatment and prevention of obesity and NAFLD. By modulating glucose and lipid metabolism, reducing inflammation, and enhancing insulin sensitivity via the PI3K/Akt pathway, curcumin could potentially improve metabolic health.

Cardiovascular disease

In recent years, cardiovascular disease (CVD) has remained the predominant cause of death around the world. According to WHO statistics, approximately 17.9 million fatalities worldwide in 2019 were due to CVDs, representing up to 32% of all deaths. Among CVD diseases, ischemic heart disease (IHD) and congestive heart failure are the main reasons for incidence and mortality.

Li and colleagues in an in vitro study, showed that curcumin via enhancing phosphorylation of PI3K/Akt has a cardiac protection effect. They induced apoptosis with staurosporine and reported that Bisdemethoxycurcumin by modulation of the PI3K/Akt pathway could cause overexpression of Nrf-2, induction of Bcl-2, and inhibition of Bax and caspase-3. Also, they documented that curcumin increased the ratio of apoptotic myocardium [69]. Similarly, WU and colleagues indicate that curcumin can protect the myocardium through modulation of the P13K/Akt/mTOR signaling pathway. They found that curcumin increases mTOR-mediated PI3K and p-Akt protein production. These studies both in-vivo and in-vitro experiments documented that curcumin by inducing the expression of p-Akt, increased the expression of proapoptotic genes such as Bcl2, and antioxidants genes such as superoxide dismutase (SOD), and glutathione (GSH) [70]. Furthermore, Yu and colleagues observed that curcumin via upregulated of Akt and mTOR and induced autophagy could benefit for cardiomyocytes to survive against doxorubicin (DOX)-induced toxicity. Specifically, curcumin increases the phosphorylation of Akt, a key mediator in the mTOR signaling pathway within the heart. This suggests that curcumin-mediated reduction in DOX-induced pyroptosis and autophagy may be linked to the activation of the Akt/mTOR signaling pathway. Additionally, curcumin decreased Beclin-1, an essential component of the class III of PI3K protein, which is involved in both autophagic and apoptotic processes. Curcumin also resulted in a decreased LC3II-to-LC3I ratio, which indicates reduced autophagosome formation [71].

Ischemic heart disease (IHD) is the primary reason for CVD morbidity and mortality. In this regard Wu and colleagues showed that curcumin increases NO production, upregulates Bcl-2, and downregulates Bax expression through upregulating levels of mTOR, P13K, and p-Akt. Consequently, curcumin inhibits inflammation and oxidative stress and modulates the PI3K/Akt/mTOR signaling pathway to protect against IHD [72]. In another study, Jeong and colleagues showed that curcumin significantly reduced infarct size. They suggested that the protective effect of curcumin on ischemia-reperfusion injury in rat hearts is mediated by enhanced activation of the PI3K-Akt signaling pathway. This study revealed that preconditioning with curcumin before left anterior descending (LAD) coronary artery occlusion protected against focal myocardial ischemia-reperfusion injury, partially by activating the PI3K-Akt and ERK1/2 signaling pathways. The prevention of cellular damage is achieved through the activation of reperfusion injury salvage kinase (RISK) pathways, which involve PI3K-Akt and ERK1/2. These pathways converge on the mitochondrial permeability transition pore (mPTP) through GSK-3β inhibition, thus preventing its opening [73]. Further supporting these findings GUO et al. demonstrated that curcumin can protect hy926 cells, from the harmful impacts of oxidative stress in the context of esophageal atresia by blocking apoptosis and triggering autophagy through the Akt/mTOR pathway. These results indicated that the downregulation of AKT/mTOR caused induced LC3-II expression and autophagy (Table 1) [74].

Kidney diseases

Renal fibrosis, a key characteristic of end-stage renal disease involves the process of EMT. Transforming growth factor-β1 (TGF-β1) is known to be a remarkable mediator in the development of renal fibrosis, acting as a primary inducer of EMT through the Akt/mTOR pathway. In this context, Zhu and colleagues found that targeting mTOR activity can reduce tubulointerstitial fibrosis in models of diabetes and polycystic kidney disease. This group reported that curcumin by an inhibitory role in the Akt/mTOR pathway inhibits TGF-β1 induced EMT. Overall, curcumin has shown an anti-fibrotic effect and prevents changes in the phenotype and function of the tubular epithelium [75]. Also, Tu and colleagues showed curcumin significantly improved podocyte loss, fusion, and the formation of autophagic vacuoles in rats with nephritis. The results indicated that curcumin decreased apoptosis-related proteins and reduced the activity of the PI3K/Akt/mTOR signaling pathway while increasing autophagy-associated proteins and antioxidant response in the animal model [76]. Obstructive uropathy is a cause of renal interstitial fibrosis, characterized by alterations such as EMT. Wang and colleagues documented that curcumin treatment affects the proliferation of human kidney tubular epithelial cells, inhibiting the expression of myofibroblast markers and suppressing the loss of epithelial markers. The results showed that curcumin antagonizes TGF-β1-induced EMT by reducing PI3K and Akt protein phosphorylation, demonstrating its anti-fibrosis effect. Also through toll like receptor (TLR)4/NF-kB and PI3K/Akt pathways, curcumin can prevent EMT, ECM deposition, and inflammation, improving renal function [77]. Also, Lu and colleagues demonstrated that in rats with unilateral ureteral obstruction, curcumin administration leads to inhibition of the PI3K/Akt signaling pathway, increased autophagosome formation, upregulation of LC3B and Beclin-1, and downregulation of mTOR [11]. In another study, Reséndiz and colleagues indicated that curcumin could be beneficial for treating heart disease in rats with chronic kidney disease. This may be due to its ability to reduce oxidative stress-related processes, such as cardiac remodeling, mitochondrial dysfunction, and cell death. Nonetheless, this study did not detect activation of the PI3K/Akt/GSK3β cascade or the MEK1/2-ERK1/2 cascade in cardiac ERK tissue and calcineurin [78].

Acute kidney injury (AKI) is among the most solemn and common with increased morbidity and mortality which is characterized by a decline in renal function [79]. Scientific studies have demonstrated that tubular necrosis/apoptosis is one of the main mechanisms underlying ischemia-induced AKI. In ischemia-reperfusion-induced AKI, the infiltration of inflammatory and immune cells, along with modified chemokine and cytokine production, may promote necrosis and death in renal tubular epithelial cells. Curcumin has been shown to have anti-inflammatory, anti-fibrotic, and antioxidant properties, making it a valuable tool in treating kidney damage caused by apoptosis. Accordingly, Hongtao and colleagues demonstrated that curcumin inhibits apoptosis and protects against ischemia-reperfusion-induced AKI in both in vivo and in vitro models. They revealed that curcumin exerts these effects through upregulated the expression of APPL1, (the adaptor protein between adipokine and its receptor), and inhibits the activation of the Akt signaling pathway [80]. Similarly, the study conducted by Fan and colleagues showed that curcumin caused overregulation of APPL1 to mitigate apoptosis through inhibition of Akt phosphorylation in renal tubular epithelial cells treated with hypoxia-reoxygenation [81]. Additionally, Wu and colleagues found that curcumin has renoprotective effects by preventing oxidative stress in AKI caused by rhabdomyolysis by regulating the AMPK and Nrf2/HO-1 signaling pathways. It also reduced renal damage and cell death linked to rhabdomyolysis by triggering the PI3K/Akt pathway [82].

Neurodegenerative disease

Neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Spinal cord injury (SCI) cause progressive damage to the nervous system and are affecting millions worldwide, particularly the elderly [83]. Some biological processes that lead to these diseases are inflammation, impaired protein processing, mitochondrial dysfunction, and oxidative stress. Dysregulation of this pathway has been shown in a variety of neurodegenerative diseases [84, 85].

AD is the most common NDD among older people, with an incidence of 5.3 million in the United States [86]. AD is characterized by gradual brain degeneration, synaptic dysfunction, cholinergic neuron damage, and pathology signs like Aβ and tau fibrillary tangles [87]. It has been shown that curcumin stops tau phosphorylation in APP/PS1 double-transgenic AD mice (an animal model for AD). This suggests that curcumin may be a promising therapeutic agent for managing AD by regulating signal transmission.

One potential mechanism of action involves the downregulation of the PI3K/Akt/mTOR signaling pathway. This pathway is implicated in AD pathogenesis and plays a role in regulating various cellular processes, including protein synthesis and degradation. In this regard, Wang and colleagues demonstrated that curcumin promotes Aβ clearance, decreases Aβ generation, and induces autophagy by downregulating PI3K/Akt/mTOR signaling [88]. Conversely, Feng and colleagues revealed that curcumin enhanced the expression of PI3K, phosphorylation of PI3K and Akt while decreasing the expression of insulin receptor and insulin receptor substrate-1 (IRS-1) in the brain of Alzheimer’s disease transgenic mice [89].

Since the low bioavailability of curcumin is a drawback, researchers are exploring ways to boost it to potentially speed up the healing process. In this context, Wong and colleagues discovered that exosomes containing curcumin can more effectively prevent neuronal death in vitro and in vivo by inhibiting Tau phosphorylation via the Akt/GSK pathway, which may reduce AD symptoms [90]. In addition, curcumin-loaded lipid core nanocapsules (Cur-LNC) can elevate the bioavailability of curcumin. Concerning this Hope and colleagues reported that Cur-LNC exerted its regulatory effect by up-regulating brain-derived neurotrophic factor (BDNF), which activated Akt and inhibited GSK-3β. This study revealed that curcumin was efficacious in neuroinflammation, tau hyperphosphorylation, as well as cell signaling disturbances that were triggered by Aβ (Table 1) [91].

Parkinson’s disease (PD) is an age-related neurodegenerative disorder, affecting 80% of cases due to dopaminergic neuron loss in the substantia nigra [92]. The impairment of mitochondrial function and the subsequent accumulation of ROS results in damage to cellular components. This damage is partially due to decreased PI3K/Akt activity, as this system system naturally shields mitochondria from oxidative stress [93]. Additionally, there is a significant protective effect for PI3K/Akt signaling against neuronal death [94]. In this context, Cui and colleagues indicated that curcumin stimulates PI3k/Akt signaling pathways that involve nerve regeneration and anti-apoptotic activities. Curcumin significantly affects the activation of the Akt/Nrf2 signaling pathway and induces antioxidant defense by upregulating gene expression in this pathway [95]. In connection with this Yang and colleagues showed that curcumin enhanced the expression of the BDNF, TrkB, and PI3K proteins in PD-affected mice (Table 1) [96].

Huntington’s disease (HD), an autosomal dominant disorder, is a prevalent condition affecting 4–6 per 100,000 people. As with PD, mitochondria contribute to the development of HD by triggering gene expression linked to oxidative stress [97]. Accordingly, Sandhir and colleagues found that curcumin, through increases in the activation of Akt/Nrf-2 signaling, led to increased SOD and GSH, in an experimental model of Huntington’s disease. These results indicate the potential of curcumin for neurotoxin exposure and preventing HD in rats [98].

Spinal cord injury (SCI) is a serious nerve injury that causes disability, loss of neural pathways, movement, and sensation injuries [99, 100]. SCI triggers an inflammatory response, cytokine production, edema, free radical formation, ischemia, apoptosis, and necrosis of neurons and glial cells [101]. Studies have shown that curcumin promotes post-SCI functional recovery, decreases neuronal apoptosis, and improves spinal cord integrity while inhibiting the inflammatory response. Curcumin also modulated autophagy by suppressing the PI3K/Akt signaling pathway, exerting its neuroprotective effect [102]. In this regard, Krupa and colleagues found that curcumin effectively inhibited inflammatory reactions through the PI3K/Akt signaling pathway in rats with an experimental model of SCI. Also, this group reported that treatment with curcumin led to controlling apoptosis and inflammation, improved behavioral tests, glial scarring, and new axon sprouting [103]. Similarly, Sang and colleagues demonstrated that curcumin protects damaged neurons by promoting the release of nerve growth factor and PI3K/Akt survival signals. Notably, the antiapoptotic impact of curcumin on PC-12 neurons was lessened when Akt activation was inhibited (Table 1) [104].

Conclusion

Curcumin, a bioactive compound derived from turmeric, has emerged as a promising therapeutic agent for various chronic disorders. Its various pharmacological properties contribute to its potential benefits in conditions such as cardiovascular disease, type 2 diabetes, obesity, non-alcoholic fatty liver disease, kidney disease, and neurodegenerative disorders (Fig. 3).

Fig. 3.

An overview of the effect of curcumin on the different organelles by Pi3K/Akt

One of the important mechanisms underlying the therapeutic effects of curcumin is its ability to modulate the PI3K/Akt signaling pathway. This pathway plays a crucial role in essential cellular processes regulating, and its dysregulation is linked to the development of several diseases. However, curcumin can interact with conventional drugs primarily through its effects on drug-metabolizing enzymes and transport proteins. The main reason why curcumin might interact with common drugs is that it stops liver enzymes from working, especially those in the cytochrome P450 family. This could alter the metabolism of drugs processed by these enzymes, leading to either reduced efficacy or increased toxicity. Additionally, curcumin’s modulation of P-glycoprotein might influence drug absorption and clearance. These interactions, especially when using formulations with enhanced bioavailability, highlight the need for caution and further clinical studies to ensure safe co-administration [105]. Overall, the ability of curcumin to modulate the PI3K/Akt signaling pathway proposes promising therapeutic potential for several chronic diseases. Future research should focus on exposing the precise mechanisms of action of curcumin, mainly its interaction with the PI3K/Akt pathway. By addressing these challenges and exploring the therapeutic potential of curcumin, researchers may explain new avenues for a wide range of disease treatments.

Abbreviations

CVD

Cardiovascular diseases

PI3K

Phosphoinositide 3-kinase

Akt

Protein kinase B

IR

Insulin resistant

AMP

Adenine monophosphate

GMP

Guanosine monophosphate

PDK

Phosphoinositide-dependent kinases

mTOR

Mammalian target of rapamycin

GLUT

Glucose transporter

ERK

Extracellular signal-regulated kinases

PPARγ

Peroxisome proliferator-activated receptor gamma

EMT

Epithelial-mesenchymal transition

NAFLD

Non-alcoholic fatty liver disease

ROS

Reactive oxygen stress

Nrf2

Nuclear factor erythroid factor 2

IHD

Ischemic heart disease

SOD

Superoxide dismutase

GSH

Glutathione

DOX

Doxorubicin

mPTP

Mitochondrial permeability transition pore

TGF-β1

Transforming growth factor-β1

TLR

Toll-like receptor

LC3

Light chain 3

AKI

Acute kidney injury

AD

Alzheimer’s disease

PD

Parkinson’s disease

HD

Huntington’s disease

SCI

Spinal cord injury

Cur-LNC

Curcumin-loaded lipid core nanocapsules

BDNF

Brain-derived neurotrophic factor

Funding

No funding.

Data availability

Data can be supplied on request to the authors.

Declarations

Ethical approval

Not applicant.

Competing interests

The authors declare no conflict of interests.