Pesticides and the Gut Microbiota: Implications for Parkinson's Disease.

Parkinson's disease (PD) affects more people worldwide than just aging alone can explain. This is likely due to environmental influences, genetic makeup, and changes in daily habits. The disease develops in a complex way, with movement problems caused by Lewy bodies and the loss of dopamine-producing neurons. Some research suggests Lewy bodies might start in the gut, hinting at a connection between these structures and gut health in PD patients. These patients often have different gut bacteria and metabolites. Pesticides are known to increase the risk of PD, with evidence showing they harm more than just dopamine neurons. Long-term exposure to pesticides in food might affect the gut barrier, gut bacteria, and the blood-brain barrier, but the exact link is still unknown. This review looks at how pesticides and gut bacteria separately influence PD development and progression, highlighting the harmful effects of pesticides and changes in gut bacteria. We have examined the interaction between pesticides and gut bacteria in PD patients, summarizing how pesticides cause imbalances in gut bacteria, the resulting changes, and their overall effects on the PD prognosis.

Recent Contributions of Mass Spectrometry-Based "Omics" in the Studies of Breast Cancer.

Breast cancer (BC) is one of the most heterogeneous groups of cancer. As every biotype of BC is unique and presents a particular "omic" signature, they are increasingly characterized nowadays with novel mass spectrometry (MS) strategies. BC therapeutic approaches are primarily based on the two features of human epidermal growth factor receptor 2 (HER2) and estrogen receptor (ER) positivity. Various strategic MS implementations are reported in studies of BC also involving data independent acquisitions (DIAs) of MS which report novel differential proteomic, lipidomic, proteogenomic, phosphoproteomic, and metabolomic characterizations associated with the disease and its therapeutics. Recently many "omic" studies have aimed to identify distinct subsidiary biotypes for diagnosis, prognosis, and targets of treatment. Along with these, drug-induced-resistance phenotypes are characterized by "omic" changes. These identifying aspects of the disease may influence treatment outcomes in the near future. Drug quantifications and characterizations are also done regularly and have implications in therapeutic monitoring and in drug efficacy assessments. We report these studies, mentioning their implications toward the understanding of BC. We briefly provide the MS instrumentation principles that are adopted in such studies as an overview with a brief outlook on DIA-MS strategies. In all of these, we have chosen a model cancer for its revelations through MS-based "omics".

The Emerging Role of Natural Products in Cancer Treatment.

The exploration of natural products as potential agents for cancer treatment has garnered significant attention in recent years. In this comprehensive review, we delve into the diverse array of natural compounds, including alkaloids, carbohydrates, flavonoids, lignans, polyketides, saponins, tannins, and terpenoids, highlighting their emerging roles in cancer therapy. These compounds, derived from various botanical sources, exhibit a wide range of mechanisms of action, targeting critical pathways involved in cancer progression such as cell proliferation, apoptosis, angiogenesis, and metastasis. Through a meticulous examination of preclinical and clinical studies, we provide insights into the therapeutic potential of these natural products across different cancer types. Furthermore, we discuss the advantages and challenges associated with their use in cancer treatment, emphasizing the need for further research to optimize their efficacy, pharmacokinetics, and delivery methods. Overall, this review underscores the importance of natural products in advancing cancer therapeutics and paves the way for future investigations into their clinical applications.

A Review on the Recent Applications of Deep Learning in Predictive Drug Toxicological Studies.

Drug toxicity prediction is an important step in ensuring patient safety during drug design studies. While traditional preclinical studies have historically relied on animal models to evaluate toxicity, recent advances in deep-learning approaches have shown great promise in advancing drug safety science and reducing animal use in preclinical studies. However, deep-learning-based approaches also face challenges in handling large biological data sets, model interpretability, and regulatory acceptance. In this review, we provide an overview of recent developments in deep-learning-based approaches for predicting drug toxicity, highlighting their potential advantages over traditional methods and the need to address their limitations. Deep-learning models have demonstrated excellent performance in predicting toxicity outcomes from various data sources such as chemical structures, genomic data, and high-throughput screening assays. The potential of deep learning for automated feature engineering is also discussed. This review emphasizes the need to address ethical concerns related to the use of deep learning in drug toxicity studies, including the reduction of animal use and ensuring regulatory acceptance. Furthermore, emerging applications of deep learning in drug toxicity prediction, such as predicting drug-drug interactions and toxicity in rare subpopulations, are highlighted. The integration of deep-learning-based approaches with traditional methods is discussed as a way to develop more reliable and efficient predictive models for drug safety assessment, paving the way for safer and more effective drug discovery and development. Overall, this review highlights the critical role of deep learning in predictive toxicology and drug safety evaluation, emphasizing the need for continued research and development in this rapidly evolving field. By addressing the limitations of traditional methods, leveraging the potential of deep learning for automated feature engineering, and addressing ethical concerns, deep-learning-based approaches have the potential to revolutionize drug toxicity prediction and improve patient safety in drug discovery and development.

Melatonin counteracts necroptosis and pulmonary edema in cadmium-induced chronic lung injury through the inhibition of angiotensin II.

The renin-angiotensin system (RAS) is an important regulator in pulmonary physiology. In our study, we identified the efficacy of melatonin to control the RAS in cadmium (Cd) induced chronic lung injury in a mouse model. Swiss albino mice exposed to CdCl2 intraperitoneally (I.P.) (1 mg/kg b.w.; 12 weeks) showed increased release of lactate dehydrogenase in bronchoalveolar lavage fluid, generating reactive oxygen species, impaired antioxidant enzymes function, and disrupted alveolar structure along with increased expression of Angiotensin-II (Ang-II) in lung tissue. Cd-induced angiotensin-converting enzyme-2-Ang-II axis imbalance triggered the onset of Ang-II induced tumour necrosis factor alpha  (TNF-α) mediated necroptosis by upregulating the signalling molecules RIP-1, RIP-3, and p-mixed lineage kinase domain-like. In an in vitro study, colocalization of Ang-II-RIP-3 molecule in Cd intoxicated L-132 cells (human alveolar epithelial cell line), as well as pretreatment of Cd exposed cells with the inhibitor's captopril (10 µM), necrostatin-1 (50 µM), and etanercept (5 µg/ml) indicated TNF-α induced necroptotic cell death via activation of the key molecule, Ang-II. Moreover, Ang-II disrupted the alveolar-capillary barrier by decreasing tight junctional proteins (zonula occludens-1 and occludin) and endothelial VE-cadherin expression. The use of human umbilical vein endothelial cells as a model of junctional protein-expressing cells showed that captopril pretreatment (25 µM) restored VE-cadherin expression in Cd-treated human umbilical vein endothelial cells. In CdCl2 intoxicated mice, melatonin pretreatment (10 mg/kg b.w.; 12 weeks, I.P.) inhibited inflammatory mediators (TNF-α, interleukin [IL]-1ß, and IL-6) release and effectively suppressed (Cd-induced) Ang-II mediated necroptotic cell death and alveolar-capillary breaching due to Cd toxicity.

Potential Drug Strategies to Target Coronaviruses.

INTRODUCTION: As the world has witnessed three severe coronavirus outbreaks in the past two decades, including the recent pandemic COVID19, caused by SARS-CoV2, it has become of utmost importance to develop drugs and vaccines against coronaviruses. The previous two outbreaks, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) emerged in China and Saudi Arabia in 2003 and 2012, respectively. COVID19 is considered the worst of all and has taken more than 4 million lives so far and crippled the socioeconomic life of human beings in the entire world. Extensive research is being carried out to find out a solution that will not only help us to fight the current situation but also prepare us to prevent further intervention by similar viruses in the future. Here, we aim to highlight potential drug target sites in coronavirus infection or life cycle in general. METHODS: We have gone through the research papers published on coronavirus, with special emphasis on SARS-CoV, MERS-CoV, and SARS-CoV2, in peer-reviewed journals and tried to identify the possible sites in the coronavirus life cycle which can be used as potential drug targets. RESULTS: Studies showed that there are several unique enzymes and mechanisms involved in the coronavirus life cycle which can be manipulated to develop drugs against it. However, it has been always a challenge to develop drugs or vaccines against viruses as they utilize the host cell machinery and more difficult against RNA viruses because of their high mutation rate. CONCLUSIONS: Effective control of the current (2020) pandemic necessarily depends on the development of either a vaccine or an effective therapeutic agent. In the past, many attempts were taken to develop vaccines after the outbreak of SARS-CoV and MERS-CoV, though no successful vaccine reached to the market as the situation came under control. In the current scenario, many laboratories have developed effective vaccines against SARS-CoV2, which have reduced both the severity of the infection and the rate of mortality considerably. However, world needs to be prepared for similar viral outbreaks in future and research must be continued to develop more effective vaccines and therapeutics against coronaviruses.

PKCζ mediated anti-proliferative effect of C2 ceramide on neutralization of the tumor microenvironment and melanoma regression.

Immunotherapy, which has advantages over chemotherapy due to lesser toxicity and higher specificity, is on the rise to treat cancer. Recently, pro-apoptotic glycolipid, ceramide has emerged as a key regulator in cancer immunotherapy. The present study elucidated the potential anti-melanoma efficacy of cell-permeable, exogenous C2 ceramide on cell death and amelioration of tumor microenvironment (TME). We, for the first time, demonstrated that C2 ceramide triggered apoptosis of melanoma cells by augmenting PKCζ along with pro-inflammatory cytokines and signaling factors. C2 ceramide showed a PKCζ-mediated tumor-suppressive role in melanoma without exhibiting hepatotoxicity and nephrotoxicity. Moreover, PKCζ was revealed as one of the key regulators of Akt and ceramide during C2 ceramide-mediated apoptosis. C2 ceramide was effective in repolarization of M2 macrophage phenotype and reduction of angiogenic factors such as VEGF, VEGFR1, VEGFR2, HIF1α. Interestingly, PKCζ knockdown attenuated C2 ceramide-mediated inhibition of melanoma progression. Restoration of the Th1 type TME by C2 ceramide enhanced cytotoxic T cell-mediated killing of melanoma cells. Altogether, the study unraveled that C2 ceramide-induced PKCζ was associated with favorable immune cell functioning in TME leading to melanoma regression. Thus, our findings explored a novel mechanistic insight into C2 ceramide as a promising immunotherapeutic agent in melanoma treatment.

Matrix metalloproteinase: An upcoming therapeutic approach for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a debilitating condition where excess collagen deposition occurs in the extracellular matrix. At first sight, it is expected that the level of different kinds of matrix metalloproteinases might be downregulated in IPF as it is a matrix degrading collagenase. However, the role of some matrix metalloproteinases (MMPs) is profibrotic where others have anti-fibrotic functions. These profibrotic MMPs effectively promote fibrosis development by stimulating the process of epithelial to mesenchymal transition. These profibrotic groups also induce macrophage polarization and fibrocyte migration. All of these events ultimately disrupt the balance between profibrotic and antifibrotic mediators, resulting aberrant repair process. Therefore, inhibition of these matrix metalloproteinases functions in IPF is a potential therapeutic approach. In addition to the use of synthetic inhibitor, various natural compounds, gene silencing act as potential natural MMP inhibitor to recover IPF.

ROS-associated immune response and metabolism: a mechanistic approach with implication of various diseases.

The immune system plays a pivotal role in maintaining the defense mechanism against external agents and also internal danger signals. Metabolic programming of immune cells is required for functioning of different subsets of immune cells under different physiological conditions. The field of immunometabolism has gained ground because of its immense importance in coordination and balance of immune responses. Metabolism is very much related with production of energy and certain by-products. Reactive oxygen species (ROS) are generated as one of the by-products of various metabolic pathways. The amount, localization of ROS and redox status determine transcription of genes, and also influences the metabolism of immune cells. This review discusses ROS, metabolism of immune cells at different cellular conditions and sheds some light on how ROS might regulate immunometabolism.

Targeting the crosstalks of Wnt pathway with Hedgehog and Notch for cancer therapy.

Wnt pathway is an evolutionarily conserved signaling pathway determining patterning of animal embryos, cell fate, cell polarity, and a substantial role in the origin and maintenance of stem cells. It has been found to crosstalk with two other major developmental pathways, Hedgehog and Notch, in many embryological development cascades and in maintaining stemness of stem cells Research has shown that all the three pathways are potent in inducing tumorigenesis, driving tumor progression and aiding epithelial to mesenchymal transition in malignant cells, apart from maintaining cancer stem cells population inside the tumor tissue. Cancer stem cells are thought to aid in the process of tumor relapse, as they survive therapy by displaying drug resistance and then repopulating tumor tissues. Hence the role of these crosstalks in cancer is under intensive research. Inhibition of all the three pathways individually have resulted in tumor regression, but not optimally, as treatment failure and cancer relapse have been found to occur. Hence, instead of targeting a single pathway, targeting the crosstalk network could be a better alternative to conventional cancer treatment. Also, elimination of both tumor cells as well as cancer stem cells implies a reduced chance of relapse. Drugs developed to target these crosstalking networks, when used in combinatorial therapy, can potentially increase the efficacy of the therapy to a very large extent.

Nutraceuticals: An emerging therapeutic approach against the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is regarded as a progressive and devastating neurodegenerative disorder. In aged individuals, it is the most prevalent cause of dementia and is characterized by gradual loss of cognitive functions. In the last decade, numerous research works were undertaken to investigate the pathogenesis of AD. Although the etiology of AD is still not clear, several histopathological studies confirm prominent changes in the AD affected brains. The major changes include the formation of senile plaques and neurofibrillary tangles primarily owing to the deposition of amyloid ß plaques (Aß) and hyper-phosphorylation of tau protein. Disruption of the redox homeostasis in the brain is a major triggering factor for the development of such pathophysiological conditions. Chemical formulations usually act by inhibiting activities of the enzymes responsible for the development of AD. But with time, these pharmacotherapies develop many side effects including toxicity in different organs. Recent researches are henceforth focused on the identification of novel therapeutic molecules from the nature's basket. This review aims to emphasize the therapeutic effects and regulation of molecular targets of different natural products such as curcumin, resveratrol, genistein and others. These prophylactic multipotent natural compounds have the potency to interfere with the formation as well as deposition of the Aß peptides. These natural compounds have also been found in modulating different intracellular signalling molecules and enzymes including ß-secretase and γ-secretase. This review article is expected to be helpful in understanding the recent progress in natural product research as a therapeutic approach in amelioration and/or delaying the detrimental effects of AD.

Targeted delivery of quercetin loaded mesoporous silica nanoparticles to the breast cancer cells.

BACKGROUND: Mesoporous silica nanoparticles (MSNs) have been promising vehicles for drug delivery. Quercetin (Q), a natural flavonoid, has been reported to have many useful effects. However, poor water solubility as well as less bioavailability has confined its use as a suitable anti-cancer drug. Therefore, profound approach is required to overcome these drawbacks. METHODS: We have synthesized folic acid (FA) armed mesoporous silica nanoparticles (MSN-FA-Q) loaded with quercetin and then characterized it by DLS, SEM, TEM and FTIR. MTT, confocal microscopy, flow cytometry, scratch assay and immunoblotting were employed to assess the cell viability, cellular uptake, cell cycle arrest, apoptosis, wound healing and the expression levels of different signalling molecules in breast adenocarcinoma cells. Nanoparticle distribution was investigated by using ex vivo optical imaging and CAM assay was employed to assess tumor regression. RESULTS: MSN-FA-Q facilitates higher cellular uptake and allows more drug bioavailability to the breast cancer cells with over-expressed folate receptors. Our experimental results suggest that the newly synthesized MSN-FA-Q nanostructure caused cell cycle arrest and apoptosis in breast cancer cells through the regulation of Akt & Bax signalling pathways. Besides, we also observed that MSN-FA-Q has a concurrent anti-migratory role as well. CONCLUSION: This uniquely engineered quercetin loaded mesoporous silica nanoparticle ensures a targeted delivery with enhanced bioavailability. GENERAL SIGNIFICANCE: Effective targeted therapeutic strategy against breast cancer cells.

Curcumin ameliorates testicular damage in diabetic rats by suppressing cellular stress-mediated mitochondria and endoplasmic reticulum-dependent apoptotic death.

In the present study, we sought to explore whether curcumin plays any beneficial role against STZ induced testicular abnormalities in diabetic rats, and if so, what possible mechanism it utilizes to provide protection. Exposure to STZ (50mg/kg body weight, i.p., once) reduced testis-to-body weight ratio, enhanced blood glucose level and intracellular ROS, altered testicular markers, diminished serum testosterone and impaired cellular redox balance. Administration of curcumin at a dose of 100mg/kg body weight for 8 weeks effectively normalized all the alterations. Curcumin also showed inhibitory effect on the elevation of pro-inflammatory cytokines and translocation of NFκB into the nucleus and promoted the activation of the transcription factor Nrf-2 to provide protection against oxidants. To protect cells from STZ-induced stress-mediated damage, curcumin acted on the key mediators of the apoptotic cell death such as JNK and p38. In addition, this active molecule upregulated Bcl-2 expression, blocked the expression of pro-apoptotic proteins (Bax, Bad and Bid), decreased intracellular Ca(2+) level, inhibited active caspase cascade and attenuated PARP cleavage. These results suggest that curcumin provides protection against cellular stress-mediated mitochondrial and endoplasmic reticulum-dependent apoptotic death of the testicular cells under diabetic condition and suggests the possibility of using this molecule as a potential therapeutic in the treatment of stress-mediated diabetic testicular dysfunction.

Morin protects gastric mucosa from nonsteroidal anti-inflammatory drug, indomethacin induced inflammatory damage and apoptosis by modulating NF-κB pathway.

BACKGROUND: Deregulation in prostaglandin (PG) biosynthesis, severe oxidative stress, inflammation and apoptosis contribute to the pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. Unfortunately, most of the prescribed anti-ulcer drugs generate various side effects. In this scenario, we could consider morin as a safe herbal potential agent against IND-gastropathy and rationalize its action systematically. METHODS: Rats were pretreated with morin for 30 min followed by IND (48 mgkg(-1)) administration for 4 h. The anti-ulcerogenic nature of morin was assessed by morphological and histological analysis. Its effects on the inflammatory (MPO, cytokines, adhesion molecules), ulcer-healing (COXs, PGE(2)), and signaling parameters (NF-κB and apoptotic signaling) were assessed by biochemical, RP-HPLC, immunoblots, IHC, RT-PCR, and ELISA at the time points of their maximal changes due to IND administration. RESULTS: IND induced NF-κB and apoptotic signaling in rat's gastric mucosa. These increased proinflammatory responses, but reduced the antioxidant enzymes and other protective factors. Morin reversed all the adverse effects to prevent IND-induced gastric ulceration in a PGE2 independent manner. Also, it did not affect the absorption and/or primary pharmacological activity of IND. CONCLUSIONS: The gastroprotective action of morin is primarily attributed to its potent antioxidant nature that also helps in controlling several IND-induced inflammatory responses. GENERAL SIGNIFICANCE: For the first time, the study reveals a mechanistic basis of morin mediated protective action against IND-induced gastropathy. As morin is a naturally abundant safe antioxidant, future detailed pharmacokinetic and pharmacodynamic studies are expected to establish it as a gastroprotective agent.

Morin and Its Role in Chronic Diseases.

Chronic diseases can be referred to the long-term medical conditions which are mostly progressive in nature, i.e., it deteriorates over time. Diabetes, arthritis, heart disease, stroke, cancer, and chronic respiratory problems (e.g., COPD) are not a few examples of chronic diseases and chronic diseases are the leading causes of death and disability all over the world. Chronic diseases and conditions are among the most common, costly, and preventable of all health problems. Affordable cost, presence mostly in the consumables, and minimal side effects make the naturally occurring compounds interesting and attractive for pharmacological study in recent years. Plants produce diverse types of low molecular weight products mainly for the defense purpose. Among them, the group of secondary metabolites related to a polyphenolic group has been named flavonoids and are of great interest due to their incredible pharmacological properties. In these regard, due to its potent anti-inflammatory, anti-apoptotic and many important pharmacological properties (relevant to chronic diseases, e.g., urate transporter inhibitor related to gout, modulator of immunosystem related to chronic hypersensitivity, etc.), morin [morin hydrate:2-(2,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopy ran-4-one; 3,5,7,20,40 pentahydroxyflavone], widely found among the Moraceae family, considered as one of the most important key bioflavonols. However, little is known about the molecular mechanisms of its action on such conditions. In this chapter, we have summarized most of the findings, if not all, available till date.

Curcumin enhances recovery of pancreatic islets from cellular stress induced inflammation and apoptosis in diabetic rats.

The phytochemical, curcumin, has been reported to play many beneficial roles. However, under diabetic conditions, the detail mechanism of its beneficial action in the glucose homeostasis regulatory organ, pancreas, is poorly understood. The present study has been designed and carried out to explore the role of curcumin in the pancreatic tissue of STZ induced and cellular stress mediated diabetes in eight weeks old male Wistar rats. Diabetes was induced with a single intraperitoneal dose of STZ (65 mg/kg body weight). Post to diabetes induction, animals were treated with curcumin at a dose of 100 mg/kg body weight for eight weeks. Underlying molecular and cellular mechanism was determined using various biochemical assays, DNA fragmentation, FACS, histology, immunoblotting and ELISA. Treatment with curcumin reduced blood glucose level, increased plasma insulin and mitigated oxidative stress related markers. In vivo and in vitro experimental results revealed increased levels of proinflammatory cytokines (TNF-α, IL1-ß and IFN-γ), reduced level of cellular defense proteins (Nrf-2 and HO-1) and glucose transporter (GLUT-2) along with enhanced levels of signaling molecules of ER stress dependent and independent apoptosis (cleaved Caspase-12/9/8/3) in STZ administered group. Treatment with curcumin ameliorated all the adverse changes and helps the organ back to its normal physiology. Results suggest that curcumin protects pancreatic beta-cells by attenuating inflammatory responses, and inhibiting ER/mitochondrial dependent and independent pathways of apoptosis and crosstalk between them. This uniqueness and absence of any detectable adverse effect proposes the possibility of using this molecule as an effective protector in the cellular stress mediated diabetes mellitus.