Inflammation is a comprehensive array of physiological response to a foreign organism, including human pathogens, dust particles, and viruses. Inflammations are mainly divided into acute and chronic inflammation depending on various inflammatory processes and cellular mechanisms. Recent investigations have clarified that inflammation is a major factor for the progression of various chronic diseases/disorders, including diabetes, cancer, cardiovascular diseases, eye disorders, arthritis, obesity, autoimmune diseases, and inflammatory bowel disease. Free radical productions from different biological and environmental sources are due to an imbalance of natural antioxidants which further leads to various inflammatory associated diseases. In this review article, we have outlined the inflammatory process and its cellular mechanisms involved in the progression of various chronic modern human diseases. In addition, we have discussed the role of free radicals-induced tissue damage, antioxidant defence, and molecular mechanisms in chronic inflammatory diseases/disorders. The systematic knowledge regarding the role of inflammation and its associated adverse effects can provide a clear understanding in the development of innovative therapeutic targets from natural sources that are intended for suppression of various chronic inflammations associated diseases.
Matched MeSH terms: Signal Transduction/drug effects
In the present investigation, we prepared four different solvent fractions (chloroform, hexane, butanol, and ethyl acetate) of Moringa oleifera extract to evaluate its anti-inflammatory potential and cellular mechanism of action in lipopolysaccharide (LPS)-induced RAW264.7 cells. Cell cytotoxicity assay suggested that the solvent fractions were not cytotoxic to macrophages at concentrations up to 200 µg/mL. The ethyl acetate fraction suppressed LPS-induced production of nitric oxide and proinflammatory cytokines in macrophages in a concentration-dependent manner and was more effective than the other fractions. Immunoblot observations revealed that the ethyl acetate fraction effectively inhibited the expression of inflammatory mediators including cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor (NF)-κB p65 through suppression of the NF-κB signaling pathway. Furthermore, it upregulated the expression of the inhibitor of κB (IκBα) and blocked the nuclear translocation of NF-κB. These findings indicated that the ethyl acetate fraction of M. oleifera exhibited potent anti-inflammatory activity in LPS-stimulated macrophages via suppression of the NF-κB signaling pathway.
Matched MeSH terms: Signal Transduction/drug effects*
The causal and functional connection between inflammation and cancer has become a subject of much research interest. Modulation of cell signaling pathways, such as those involving mitogen activated protein kinases (MAPKs), nuclear factor kappa β (NF-κB), phosphatidylinositol 3-kinase and protein kinase B (PI3K/Akt), and Wnt, and their outcomes play a fundamental role in inflammation and cancer. Activation of these cell signaling pathways can lead to various aspects of cancer-related inflammation. Hence, compounds able to modulate inflammation-related molecular targets are sought after in anticancer drug development programs. In recent years, plant extracts and their metabolites have been documented with potential in the prevention and treatment of cancer and inflammatory ailments. Plants possessing anticancer and anti-inflammatory properties due to their bioactive constituents have been reported to modulate the molecular and cellular pathways which are related to inflammation and cancer. In this review we focus on the flavonoids (astragalin, kaempferol, quercetin, rutin), lignans (phyllanthin, hypophyllanthin, and niranthin), tannins (corilagin, geraniin, ellagic acid, gallic acid), and triterpenes (lupeol, oleanolic acid, ursolic acid) of Phyllanthus amarus, which exert various anticancer and anti-inflammatory activities via perturbation of the NF-κB, MAPKs, PI3K/Akt, and Wnt signaling networks. Understanding the underlying mechanisms involved may help future research to develop drug candidates for prevention and new treatment for cancer and inflammatory diseases.
Matched MeSH terms: Signal Transduction/drug effects*
Apoptosis and autophagic cell deaths are programmed cell deaths and they play essential roles in cell survival, growth and development and tumorigenesis. The huge increase of publications in both apoptosis and autophagic signaling pathways has contributed to the wealth of knowledge in facilitating the understanding of cancer pathogenesis. Deciphering the molecular pathways and molecules involved in these pathways has helped scientists devise and develop targeted strategies against cancer. Various drugs targeting the apoptotic TRAIL, Bcl-2 and proteasome pathways are already in Phase II/III clinical trials. The first mTOR inhibitor, temsirolimus has already been approved by the FDA, USA for the treatment of advanced renal cell carcinoma and more mTOR inhibitors are expected to be in the market in a few years time. Strategizing against aberrant autophagy activities in various cancers by using either pro-autophagics or autophagy inhibitors are currently been investigated. This review aims to discuss the most recent antitumor strategies targeting the apoptosis and autophagy signaling pathways and the latest outcome of clinical trials of the above drugs.
Matched MeSH terms: Signal Transduction/drug effects*
Neuroinflammation, an inflammatory response within the nervous system, has been shown to be implicated in the progression of various neurodegenerative diseases. Recent in vivo studies showed that lipopolysaccharide (LPS) preconditioning provides neuroprotection by activating Toll-like receptor 4 (TLR4), one of the members for pattern recognition receptor (PRR) family that play critical role in host response to tissue injury, infection, and inflammation. Pre-exposure to low dose of LPS could confer a protective state against cellular apoptosis following subsequent stimulation with LPS at higher concentration, suggesting a role for TLR4 pre-activation in the signaling pathway of LPS-induced neuroprotection. However, the precise molecular mechanism associated with this protective effect is not well understood. In this article, we provide an overall review of the current state of our knowledge about LPS preconditioning in attenuating apoptosis mechanism and conferring neuroprotection via TLR4 signaling pathway.
Matched MeSH terms: Signal Transduction/drug effects*
Despite the progressive advances, current standards of treatments for peripheral nerve injury do not guarantee complete recovery. Thus, alternative therapeutic interventions should be considered. Complementary and alternative medicines (CAMs) are widely explored for their therapeutic value, but their potential use in peripheral nerve regeneration is underappreciated. The present systematic review, designed according to guidelines of Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols, aims to present and discuss the current literature on the neuroregenerative potential of CAMs, focusing on plants or herbs, mushrooms, decoctions, and their respective natural products. The available literature on CAMs associated with peripheral nerve regeneration published up to 2020 were retrieved from PubMed, Scopus, and Web of Science. According to current literature, the neuroregenerative potential of Achyranthes bidentata, Astragalus membranaceus, Curcuma longa, Panax ginseng, and Hericium erinaceus are the most widely studied. Various CAMs enhanced proliferation and migration of Schwann cells in vitro, primarily through activation of MAPK pathway and FGF-2 signaling, respectively. Animal studies demonstrated the ability of CAMs to promote peripheral nerve regeneration and functional recovery, which are partially associated with modulations of neurotrophic factors, pro-inflammatory cytokines, and anti-apoptotic signaling. This systematic review provides evidence for the potential use of CAMs in the management of peripheral nerve injury.
Matched MeSH terms: Signal Transduction/drug effects
Cardamonin is a natural chalcone that has been shown to exhibit high anticancer activity. In an attempt to discover analogues of cardamonin with enhanced anticancer activity, 19 analogues were synthesized and tested against A549 and HK1 cell lines. Results of the MTS cell viability assay showed that several derivatives possessed cytotoxic activities that were several-fold more potent than cardamonin. SAR analysis showed the importance of the ketone and alkene groups for bioactivity, while substituting cardamonin's phenolic groups with more polar moieties resulted in activity enhancement. As part of the SAR study and further exploration of chemical space, the effect of metal coordination on cytotoxicity was also investigated, but it was only possible to successfully obtain the Cu (II) complex of cardamonin (19). Compound 19 was the most active analogue possessing IC50 values of 13.2μM and 0.7μM against A549 and HK1 cells, corresponding to a 5- and 32-fold increase in activity, respectively. It was also able to significantly inhibit the migration of A549 and HK1 cells. Further mode of action studies have shown that the most active analogue, 19, induced DNA damage resulting in G2/M-phase cell- cycle arrest in both cell lines. These events further led to the induction of apoptosis by the compound via caspase-3/7 and caspase-9 activation, PARP cleavage and downregulation of Mcl-1 expression. Moreover, 19 inhibited the expression levels of p-mTOR and p-4EBP1, which indicated that it exerted its anticancer activity, at least in part, via inhibition of the mTOR signalling pathway.
Matched MeSH terms: Signal Transduction/drug effects*
Pre-eclampsia remains a major cause of maternal and fetal morbidity and mortality. Despite intensive research over the last 50 years, significant therapeutic advances have yet to be realised. We recently reported on the role of activin A in the pathophysiology of pre-eclampsia, whereby a pre-eclampsia-like disease state was induced in pregnant mice through activin A infusion. Using the same animal model, the effects of inhibiting activin A signalling on this pre-eclampsia-like disease state have now been assessed with low molecular weight compounds structurally related to activin-receptor-like kinase (ALK) inhibitors.
Matched MeSH terms: Signal Transduction/drug effects
Grifolin is a volatile compound contained in essential oils of several medicinal plants. Several studies show that this substance has been the subject of numerous pharmacological investigations, which have yielded interesting results. Grifolin demonstrated beneficial effects for health via its multiple pharmacological activities. It has anti-microbial properties against bacteria, fungi, and parasites. In addition, grifolin exhibited remarkable anti-cancer effects on different human cancer cells. The anticancer action of this molecule is related to its ability to act at cellular and molecular levels on different checkpoints controlling the signaling pathways of human cancer cell lines. Grifolin can induce apoptosis, cell cycle arrest, autophagy, and senescence in these cells. Despite its major pharmacological properties, grifolin has only been investigated in vitro and in vivo. Therefore, further investigations concerning pharmacodynamic and pharmacokinetic tests are required for any possible pharmaceutical application of this substance. Moreover, toxicological tests and other investigations involving humans as a study model are required to validate the safety and clinical applications of grifolin.
Matched MeSH terms: Signal Transduction/drug effects*
High-fat diet (HFD) has been associated with certain negative bone-related outcomes, such as bone metabolism disruption and bone loss. Sciadonic acid (SC), one of the main nutritional and functional components of Torreya grandis seed oil, is a unique Δ5-unsaturated-polymethylene-interrupted fatty acid (Δ5-UPIFA) that has been claimed to counteract such disorders owing to some of its physiological effects. However, the role of SC in ameliorating bone metabolism disorders due to HFD remains unclear. In the present investigation, we observed that SC modulates the OPG/RANKL/RANK signaling pathway by modifying the lipid metabolic state and decreasing inflammation in mice. In turn, it could balance bone resorption and formation as well as calcium and phosphorus levels, enhance bone strength and bone mineral density (BMD), and improve its microstructure. In addition, SC could inhibit fat vacuoles in bone, reverse the phenomenon of reduced numbers and poor continuity of bone trabeculae, and promote orderly arrangement of collagen fibers and cartilage repair. This study provides some theoretical basis for SC as a dietary intervention agent to enhance bone nutrition.
Matched MeSH terms: Signal Transduction/drug effects
Colorectal cancer (CRC) is the third most common type of cancer in the world, causing thousands of deaths annually. Although chemotherapy is known to be an effective treatment to combat colon cancer, it produces severe side effects. Natural products, on the other hand, appear to generate fewer side effects than do chemotherapeutic drugs. Flavonoids are polyphenolic compounds found in various fruits and vegetables known to possess antioxidant activities, and the literature shows that several of these flavonoids have anti-CRC propertiesFlavonoids are classified into five main subclasses: flavonols, flavanones, flavones, flavan-3-ols, and flavanonols. Of these subclasses, the flavanonols have a minimum effect against CRC, whereas the flavones play an important role. The main targets for the inhibitory effect of flavonoids on CRC signaling pathways are caspase; nuclear factor kappa B; mitogen-activated protein kinase/p38; matrix metalloproteinase (MMP)-2, MMP-7, and MMP-9; p53; β-catenin; cyclin-dependent kinase (CDK)2 and CDK4; and cyclins A, B, D, and E. In this review article, we summarize the in vitro and in vivo studies that have been performed since 2000 on the anti-CRC properties of flavonoids. We also describe the signaling pathways affected by flavonoids that have been found to be involved in CRC. Some flavonoids have the potential to be an effective alternative to chemotherapeutic drugs in the treatment of colon cancer; well-controlled clinical studies should, however, be conducted to support this proposal.
Matched MeSH terms: Signal Transduction/drug effects
Cervical cancer ranked fourth most common malignancy among women worldwide despite the establishment of vaccination programmes. This systematic review evaluates the anti-cancer properties of turmeric and ginger bioactive compounds, specifically curcumin, 6/10-gingerol, and 6/10-shogaol, and their combination in cervical cancer through in-vitro and in-vivo models. A comprehensive electronic search was performed using Science Direct, PubMed, and Scopus from inception until the second week of June 2024 for studies published in English. Only studies investigating the effects of curcumin, gingerol, shogaol, and/or their combination in human cervical cancer cell lines and/or rodent animal models implanted with cervical cancer xenografts were included. Altogether, 27 studies were included in this review. The evidence gathered indicated that curcumin, 6/10-gingerol and 6-shogaol exert their anticancer action through modulation of cell signalling pathways, including AMPK, WNT, PI3K/AKT, and NF-κB pathway, and mediators including Bax/Bcl2, TNF-α, EGFR, COX-2, caspases-3, -9, p53, and pRb. However, the synergistic effect of these bioactive compounds is not known due to lack of evidence. In conclusion, curcumin, 6/10-gingerols, and 6-shogaols hold promise as therapeutic agents for cervical cancer. Yet, further research is essential to understand their combined efficacy, emphasising the need for additional studies exploring the synergistic anticancer effects of these bioactive compounds. Additional factors to explore include long-term effects and susceptibility of chemoresistant cervical cancer cells towards curcumin, shogaols, and gingerols.
Matched MeSH terms: Signal Transduction/drug effects
Epithelial-mesenchymal transition (EMT) is a significant dynamic process that causes changes in the phenotype of epithelial cells, changing them from their original phenotype to the mesenchymal cell phenotype. This event can be observed during wound healing process, fibrosis and cancer. EMT-related diseases are usually caused by inflammation that eventually leads to tissue remodeling in the damaged tissue. Prolonged inflammation causes long-term EMT activation that can lead to tissue fibrosis or cancer. Due to activation of EMT by its signaling pathway, therapeutic approaches that modulate that pathway should be explored. Olea europaea (OE) is well-known for its anti-inflammatory effects and abundant beneficial active compounds. These properties are presumed to modulate EMT events. This article reviews recent evidence of the effects of OE and its active compounds on EMT events and EMT-related diseases. Following evidence from the literature, it was shown that OE could modulate TGFβ/SMAD, AKT, ERK, and Wnt/β-catenin pathways in EMT due to a potent active compound that is present therein.
Matched MeSH terms: Signal Transduction/drug effects
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the synovium and progressive joint destruction which significantly affects both quality of life and socioeconomic status. Admittedly, various treatments are available, but they are usually accompanied by various side effects, from mild to severe, and potentially with adverse events. Tumour necrosis factor-alpha (TNF-α) plays a crucial role in the pathophysiology of RA. It promotes inflammatory, apoptosis and necroptosis via TNF receptor-1 (TNFR1) but elicit anti-inflammatory effects via TNFR2. Herein, targeting TNFR2 has gained attention in RA studies. Understanding the role of nanomedicine in modulating TNFR2 signalling may be the instrument in development of RA therapies. Nanotechnology has made a significant progress in treating various conditions of diseases since its inception. Due to this, nanomedicine has emerged as a promising therapeutics approach for RA. Recent studies have demonstrated the potential of nanomedicine in RA theranostics, combining therapy and diagnostics for improved treatment outcomes. Owing to the challenges and advancements in the field of nanotechnology, nanoparticles are seen as an applicable candidate in the treatment of RA. In this review, we provide an overview of the role of nanomedicine in targeting TNFR2 for the treatment of RA and highlight the limitations of current therapies as well as the potential of nanocarriers with controlled drug release and active targeting abilities.
Matched MeSH terms: Signal Transduction/drug effects
Persistent methamphetamine use causes many toxic effects in various organs, including the brain, heart, liver, kidney and eyes. The extent of its toxicity depends on numerous pharmacological factors, including route of administration, dose, genetic polymorphism related to drug metabolism and polysubstance abuse. Several molecular pathways have been proposed to activate oxidative stress, inflammation and apoptosis: B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax)/Bcl2/caspase-3, nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1), protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p70S6K, trace amine-associated receptor 1 (TAAR1)/cAMP/lysyl oxidase, Sigmar1/ cAMP response element-binding protein (CREB)/mitochondrial fission-1 protein (Fis1), NADPH-Oxidase-2 (NOX-2), renal autophagy pathway, vascular endothelial growth factor (VEGF)/phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS), Nupr1/Chop/P53/PUMA/Beclin1 and Toll-like receptor (TLR)4/MyD88/TRAF6 pathways. The activation promotes pathological changes, including the disruption of the blood-brain barrier, myocardial infarction, cardiomyopathy, acute liver failure, acute kidney injury, chronic kidney disease, keratitis, retinopathy and vision loss. This review revisits the pharmacological profiles of methamphetamine and its effects on the brain, heart, liver, eyes, kidneys and endothelium. Understanding the mechanisms of methamphetamine toxicity is essential in developing treatment strategies to reverse or attenuate the progress of methamphetamine-associated organ damage.
Matched MeSH terms: Signal Transduction/drug effects
Bisphenol A (BPA), an endocrine disruptor, is linked to cancer progression in estrogen-responsive tissues, but its role in promoting colorectal cancer (CRC) progression in the context of obesity remains underexplored. This study examines BPA's influence on CRC in obese Sprague-Dawley rats using network toxicology and experimental models. Computational analysis using the Database for Annotation, Visualization, and Integrated Discovery identified pathways such as "CRC" and "chemical carcinogenesis-receptor activation", implicating the PI3K-AKT pathway in IL-1 beta upregulation and BPA's role in CRC during obesity. Thirty male rats were grouped (n = 6) as follows: N (normal diet), NC (normal diet + CRC), HC (high-fat diet + CRC), NCB (normal diet + CRC + BPA), and HCB (high-fat diet + CRC + BPA). CRC was induced with 1,2-dimethylhydrazine (40 mg/kg), and BPA (25 mg/kg) was administered for 19 weeks. Although BPA exposure did not affect body weight or biochemical parameters, the HCB group exhibited significant histopathological changes in the colon, including lymphoid hyperplasia, liver damage, and increased IL-1β levels. Furthermore, diet influenced adipocyte size, exacerbating BPA's effects on CRC progression. Findings suggest BPA may worsen CRC progression in obese rats through identified pathways, promoting multi-organ pathology and underscoring the need for stricter regulations, especially for vulnerable populations. ENVIRONMENTAL IMPLICATION: Bisphenol A (BPA), a widespread environmental contaminant, is increasingly linked to serious health issues, including cancer, in susceptible populations. Our study highlights BPA's role in promoting obesity-driven colorectal cancer (CRC) progression, demonstrating its carcinogenic potential in high-risk contexts. These findings emphasize the urgent need for regulatory scrutiny of BPA exposure, particularly in obese individuals, and support the development of safer alternatives. Addressing BPA's impact can contribute to preventive health strategies and inform policies aimed at reducing environmental and public health risks associated with endocrine-disrupting chemicals.
Matched MeSH terms: Signal Transduction/drug effects
Colorectal cancer (CRC) is a growing concern all over the world. There has been a concerted effort to identify natural bioactive compounds that can be used to prevent or overcome this condition. Tocotrienols (T3s) are a naturally occurring form of vitamin E known for various therapeutic effects, such as anticancer, antioxidant, neuroprotective, and anti-inflammatory activities. The literature evidence suggests that two T3 analogues, ie, gamma (γ)- and delta (δ)-T3, can modulate cancers via several cancer-related signaling pathways. The aim of this review was to compile and analyze the existing literature on the diverse anticancer mechanisms of γT3 and δT3 exhibited in CRC cells, to showcase the anticancer potential of T3s. Medline was searched for research articles on anticancer effects of γT3 and δT3 in CRC published in the past 2 decades. A total of 38 articles (26 cell-based, 9 animal studies, 2 randomized clinical trials, and 1 scoping review) that report anticancer effects of γT3 and δT3 in CRC were identified. The findings reported in those articles indicate that γT3 and δT3 inhibit the proliferation of CRC cells, induce cell cycle arrest and apoptosis, suppress metastasis, and produce synergistic anticancer effects when combined with well-established anticancer agents. There is preliminary evidence that shows that T3s affect telomerase functions and support anticancer immune responses. γT3 and δT3 have the potential for development as anticancer agents.
Matched MeSH terms: Signal Transduction/drug effects
A decline in mitochondrial functions associated with ageing is the key factor of free radical generation which contributes to age-related pathologies. Protecting healthy functional mitochondrial networks with antioxidants is critical in promoting healthy ageing. This study aimed to investigate the protective effect of ergothioneine (EGT)-rich Lentinula edodes extract (LE-ETH) against tert-butyl hydroperoxide (t-BHP) assaulted senescent HT22 cells. Mitochondrial function was evaluated by measuring mitochondrial membrane potential (MMP), ATP levels and mitochondrial toxicity. The protective mechanisms were elucidated via the exploration of antioxidant and mitochondrial biogenesis signalling pathways. Our results revealed that a low dose of t-BHP increases mitochondrial toxicity. The pretreatment with 100 µg/mL of LE-ETH and the equimolar concentration of EGT for 8 h significantly improve the mitochondrial function and reduced inflammation. Through gene expression studies, we demonstrated that pretreatment of LE-ETH significantly improves the antioxidant and mitochondrial biogenesis pathway via Nrf2 signaling axis. However, the downstream genes of the mitochondrial biogenesis pathway were unaffected by equimolar EGT concentration. Gas chromatography-mass spectrum (GC-MS) analysis was carried out to identify the bioactive compounds that are present in LE-ETH extract which contributed to its efficacy in improving the mitochondrial functions. A total of 23 compounds consisting of phenols, fatty acids, and sterols were identified in the ethanolic extract. Pentanoic acid was the major compound identified in LE-ETH. These findings demonstrated that EGT-rich L.edodes mushroom is a potential neuroprotective agent which could serve as a potential therapeutic strategy for the preservation of mitochondrial functions in healthy ageing explorations.
Matched MeSH terms: Signal Transduction/drug effects
A failure of a cell to self destruct has long been associated with cancer progression and development. The fact that tumour cells may not instigate cell arrest or activate cell death mechanisms upon cancer drug delivery is a major concern. Autophagy is a mechanism whereby cell material can be engulfed and digested while apoptosis is a self-killing mechanism, both capable of hindering multiplication after cell injury. In particular situations, autophagy and apoptosis seem to co-exist simultaneously or interdependently with the aid of mutual proteins. This review covers roles of microRNAs and chemopreventive agents and makes an attempt at outlining possible partnerships in maximizing cancer cell death with minimal normal cell damage.
Matched MeSH terms: Signal Transduction/drug effects
Melanoma is a lethal form of skin cancer with rising global incidence. However, limited treatment options are available for advanced melanoma and this is further compounded by the development of resistance toward existing drugs. Panduratin A (PA), a cyclohexanyl chalcone found in Boesenbergia rotunda, was investigated for its cytotoxic potentials against human malignant melanoma A375 cells. Our initial findings revealed that mitochondrion is the primary acting site of PA on A375 cancer cells and the cytotoxic mechanisms of PA were further investigated using a temporal quantitative proteomics approach by iTRAQ 2D-LC-MS/MS. Comprehensive proteomics analysis identified 296 proteins that were significantly deregulated in PA-treated A375 cells and revealed the involvement of mitochondrial oxidative phosphorylation, secretory and ER stress pathway, and apoptosis. We further confirmed that the PA-induced apoptosis was mediated by prolonged ER stress at least in part via the PERK/eIF2α/ATF4/CHOP pathway. Pretreatment with cycloheximide, an ER stress inhibitor rescued PA-induced cell death, which was accompanied by the suppression of ER-stress-related HSPA5 and CHOP proteins. The present study provides comprehensive mechanistic insights into the cytotoxic mechanisms of PA.
Matched MeSH terms: Signal Transduction/drug effects