Hypoxia-inducible factors(HIFs)are the key transcription factors that sense and regulate cellular oxygen concentration in vivo. HIF-1 is composed of 2 subunits,α and β,in which,the molecular regulatory mechanism of HIF-1α involves the main processes of its degradation and activation. The degradation of HIF-1α is regulated by oxygen-dependent pathways,including "von hippel-lindau protein(pVHL)-dependent pathway" and "pVHL-independent pathway". The activation of HIF-1α is regulated by oxygen-independent pathways,including mammalian target of rapamycin(mTOR)/eukaryotic initiation factor 4 E-binding protein 1(4 EBP1)/HIF-1α pathway,phosphatidylinositol 3-kinase(PI3 K)/proteirrserinc-threonine kinases(Akt)/HIF-1α pathway and silent information regulator1(Sirt1)/HIF-1α pathway. In recent years,based on the molecular regulatory mechanism of HIFs,Roxadustat,a new drug for the treatment of renal anemia has been developed. Besides, some macromolecular substances with similar pharmacological effect to HIFs have been found in the extracts from Chinese herbal medicine(CHM),such as emodin,notoginseng triterpenes,honokiol and clematichinenoside. These natural macromolecular substances play the regulatory roles in inflammatory response,epigenetic modification and auto-phagy. It is worth noting that,for common hypoxic-related diseases including diabetic kidney disease,HIFs-mediated "pyroptosis" may be a new target of CHMs for clearing dampness and heat and its representative classical prescriptions(Ermiao Pills)in treating inflammatory injury in cells and tissues.
14-Deoxy-11,12-didehydroandrographolide (14-DDA), a major diterpenoid isolated from Andrographis paniculata (Burm.f.) Nees, is known to be cytotoxic and elicits a non-apoptotic cell death in T-47D breast carcinoma cells. In this study, the mechanistic toxicology properties of 14-DDA in T-47D cells were further investigated. 14-DDA is found to induce the formation of endoplasmic reticulum (ER) vacuoles and autophagosomes, with concurrent upregulation of LC3-II in the breast carcinoma cells. It stimulated an increase in cytosolic calcium concentration and caused a collapse in mitochondrial membrane potential in these cells. In addition, both DDIT3 and GADD45A, molecules implicated in ER stress pathway, were significantly upregulated. DDIT3 knockdown suppressed the formation of both ER vacuoles and autophagosomes, indicating that 14-DDA-induced ER stress and autophagy is dependent on this transcription factor. Collectively, it is possible that GADD45A/p38 MAPK/DDIT3 pathway is involved in the 14-DDA-induced ER-stress-mediated autophagy in T-47D cells.
Disturbances of extracellular matrix homeostasis are associated with a number of pathological conditions. The ability of extracellular matrix to provide contextual information and hence control the individual or collective cellular behavior is increasingly being recognized. Hence, newer therapeutic approaches targeting extracellular matrix remodeling are widely investigated. We reviewed the current literature showing the effects of resveratrol on various aspects of extracellular matrix remodeling. This review presents a summary of the effects of resveratrol on extracellular matrix deposition and breakdown. Mechanisms of action of resveratrol in extracellular matrix deposition involving growth factors and their signaling pathways are discussed. Involvement of phosphoinositol-3-kinase/Akt and mitogen-activated protein kinase pathways and role of transcription factors and sirtuins on the effects of resveratrol on extracellular matrix homeostasis are summarized. It is evident from the literature presented in this review that resveratrol has significant effects on both the synthesis and breakdown of extracellular matrix. The major molecular targets of the action of resveratrol are growth factors and their signaling pathways, phosphoinositol-3-kinase/Akt and mitogen-activated protein kinase pathways, transcription factors, and SIRT-1. The effects of resveratrol on extracellular matrix and the molecular targets appear to be related to experimental models, experimental environment as well as the doses.
Gestational diabetes mellitus (GDM) carries many risks, where high blood pressure, preeclampsia and future type II diabetes are widely acknowledged, but less focus has been placed on its effect on cognitive function. Although the multifactorial pathogenesis of maternal cognitive impairment is not completely understood, it shares several features with type 2 diabetes mellitus (T2DM). In this review, we discuss some key pathophysiologies of GDM that may lead to cognitive impairment, specifically hyperglycemia, insulin resistance, oxidative stress, and neuroinflammation. We explain how these incidents: (i) impair the insulin-signaling pathway and/or (ii) lead to cognitive impairment through hyperphosphorylation of τ protein, overexpression of amyloid-β and/or activation of microglia. The aforementioned pathologies impair the insulin-signaling pathway primarily through serine phosphorylation of insulin receptor substances (IRS). This then leads to the inactivation of the phosphatidylinositol 3-kinase/Protein kinase B (PI3K/AKT) signaling cascade, which is responsible for maintaining brain homeostasis and normal cognitive functioning. PI3K/AKT is crucial in maintaining normal cognitive function through the inactivation of glycogen synthase kinase 3β (GSκ3β), which hyperphosphorylates τ protein and releases pro-inflammatory cytokines that are neurotoxic. Several biomarkers were also highlighted as potential biomarkers of GDM-related cognitive impairment such as AGEs, serine-phosphorylated IRS-1 and inflammatory markers such as tumor necrosis factor α (TNF-α), high-sensitivity C-reactive protein (hs-CRP), leptin, interleukin 1β (IL-1β), and IL-6. Although GDM is a transient disease, its complications may be long-term, and hence increased mechanistic knowledge of the molecular changes contributing to cognitive impairment may provide important clues for interventional strategies.
Hyperglycaemia causes pancreatic β-cells to release insulin that then attaches to a specific expression of receptor isoform and reverses high glucose concentrations. It is well known that insulin is capable of initiating insulin-receptor substrate (IRS)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling pathways in target cells; such as liver, adipose tissues, and muscles. However, recent discoveries indicate that many other pathways, such as the Hedgehog (Hh) and growth factor-stimulating Wingless-related integration (Wnt) signaling pathways; are activated in hyperglycaemia as well. Although these two pathways are traditionally thought to have a decisive role in cellular growth and differentiation only, recent reports show that they are involved in regulating cellular homeostasis and energy balance. While insulin-activated IRS/PI3K/PKB pathway cascades are primarily known to reduce glucose production, it was recently discovered to increase the Hh signaling pathway's stability, thereby activating the PI3K/PKB/mammalian target of rapamycin complex 2 (mTORC2) signaling pathway. The Hh signaling pathway not only plays a role in lipid metabolism, insulin sensitivity, inflammatory response, diabetes-related complications, but crosstalks with the Wnt signaling pathway resulting in improved insulin sensitivity and decrease inflammatory response in diabetes.
Lithium, the lightest natural-occurring alkali metal with an atomic number of three, stabilizes the mood to prevent episodes of acute manic and depression. Multiple lines of evidence point to lithium as an anti-suicidal, anti-viral, anti-cancer, immunomodulatory, neuroprotective and osteoprotective agent. This review article provides a comprehensive review of studies investigating the bone-enhancing effects of lithium and its possible underlying molecular mechanisms. Most of the animal experimental studies reported the beneficial effects of lithium in defective bones but not in healthy bones. In humans, the effects of lithium on bones remain heterogeneous. Mechanistically, lithium promotes osteoblastic activities by activating canonical Wingless (Wnt)/beta (β)-catenin, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and bone morphogenetic protein-2 (BMP-2) transduction pathways but suppresses osteoclastic activities by inhibiting the receptor activator of nuclear factor-kappa B (RANK)/receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) system, nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and calcium signaling cascades. In conclusion, lithium confers protection to the skeleton but its clinical utility awaits further validation from human clinical trials.
Epithelial-mesenchymal transition (EMT) is currently recognized as the main cellular event that contributes to airway remodeling. Eosinophils can induce EMT in airway epithelial cells via increased transforming growth factor (TGF)-β production. We assessed the effect of synthetic 2,4,6-trihydroxy-3-geranyl acetophenone (tHGA) upon eosinophil-induced EMT in a cellular model. The human eosinophil cell line EoL-1 was used to induce EMT in BEAS-2B human bronchial epithelial cells. The induction of EMT was dose-dependently suppressed following tHGA treatment in which the epithelial morphology and E-cadherin expression were not altered. Protein and mRNA expression of vimentin, collagen I and fibronectin in eosinophil-induced epithelial cells were also significantly suppressed by tHGA treatment. Following pathway analysis, we showed that tHGA suppressed eosinophil-induced activator protein-1-mediated TGF-β production by targeting c-Jun N-terminal kinase and phosphoinositide 3-kinase signaling pathways. These findings corroborated previous findings on the ability of tHGA to inhibit experimental murine airway remodeling.
The nutraceutical benefits of β-sitosterol (SIT) are well documented. The present study investigated the in vitro effects of SIT on adipogenesis, glucose transport, and lipid mobilization in rat adipocytes. Primary cultures of rat preadipocytes and differentiated adipocytes were used in this study. Glucose uptake was measured by the uptake of radio-labeled glucose. Adipogenesis and lipolysis were measured by oil-red-O and glycerol quantification methods, respectively. The expression of protein kinase B (Akt), glucose transporter 4 (GLUT4), hormone sensitive lipase (HSL), and phosphatidylinositol-3-kinase (PI3 K) genes in SIT-treated adipocytes were assessed by real-time reverse transcription polymerase chain reaction (RT-PCR). The data showed that SIT induced glucose uptake in adipocytes. It also stimulated adipogenesis in differentiating preadipocytes. Interestingly, although SIT displayed general insulin-mimetic activity by stimulating glucose uptake and adipogenesis, it also induced lipolysis in adipocytes. Furthermore, the SIT-induced lipolysis was not attenuated by insulin and co-incubation of SIT with epinephrine improved epinephrine-induced lipolysis. GLUT4 gene expression was highly down-regulated in SIT-treated adipocytes, compared to insulin-treated adipocytes, which was up-regulated. Insulin- and SIT-treated adipocytes showed similar levels of Akt, HSL, and PI3 K gene down-regulation. These observations suggest that the elevation of glucose uptake in SIT-treated adipocytes was unrelated to de novo synthesis of GLUT4 and the SIT-induced lipolysis is associated with the down-regulation of Akt and PI3K genes. The unique effects of SIT on the regulation of glucose uptake, adipogenesis, and lipolysis in adipocytes show that it has potential to be utilized in diabetes and weight management.
Cancer, a complex yet common disease, is caused by uncontrolled cell division and abnormal cell growth due to a variety of gene mutations. Seeking effective treatments for cancer is a major research focus, as the incidence of cancer is on the rise and drug resistance to existing anti-cancer drugs is major concern. Natural products have the potential to yield unique molecules and combinations of substances that may be effective against cancer with relatively low toxicity/better side effect profile compared to standard anticancer therapy. Drug discovery work with natural products has demonstrated that natural compounds display a wide range of biological activities correlating to anticancer effects. In this review, we discuss formononetin (C16H12O4), which originates mainly from red clovers and the Chinese herb Astragalus membranaceus. The compound comes from a class of 7-hydroisoflavones with a substitution of methoxy group at position 4. Formononetin elicits antitumorigenic properties in vitro and in vivo by modulating numerous signaling pathways to induce cell apoptosis (by intrinsic pathway involving Bax, Bcl-2, and caspase-3 proteins) and cell cycle arrest (by regulating mediators like cyclin A, cyclin B1, and cyclin D1), suppress cell proliferation [by signal transducer and activator of transcription (STAT) activation, phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT), and mitogen-activated protein kinase (MAPK) signaling pathway], and inhibit cell invasion [by regulating growth factors vascular endothelial growth factor (VEGF) and Fibroblast growth factor 2 (FGF2), and matrix metalloproteinase (MMP)-2 and MMP-9 proteins]. Co-treatment with other chemotherapy drugs such as bortezomib, LY2940002, U0126, sunitinib, epirubicin, doxorubicin, temozolomide, and metformin enhances the anticancer potential of both formononetin and the respective drugs through synergistic effect. Compiling the evidence thus far highlights the potential of formononetin to be a promising candidate for chemoprevention and chemotherapy.