An In-Silico Identification of Potential Flavonoids against Kidney Fibrosis Targeting TGFßR-1.

Fibrosis is a hallmark of progressive kidney diseases. The overexpression of profibrotic cytokine, namely transforming growth factor ß (TGF-ß) due to excessive inflammation and tissue damage, induces kidney fibrosis. The inhibition of TGF-ß signaling is markedly limited in experimental disease models. Targeting TGF-ß signaling, therefore, offers a prospective strategy for the management of kidney fibrosis. Presently, the marketed drugs have numerous side effects, but plant-derived compounds are relatively safer and more cost-effective. In this study, TGFßR-1 was targeted to identify the lead compounds among flavonoids using various computational approaches, such as ADME/T (absorption, distribution, metabolism, and excretion/toxicity) analysis, molecular docking, and molecular dynamics simulation. ADME/T screening identified a total of 31 flavonoids with drug-like properties of 31 compounds, a total of 5 compounds showed a higher binding affinity to TGFßR-1, with Epicatechin, Fisetin, and Luteolin ranking at the top three (-13.58, -13.17, and -10.50 kcal/mol, respectively), which are comparable to the control drug linagliptin (-9.074 kcal/mol). The compounds also exhibited outstanding protein-ligand interactions. The molecular dynamic simulations revealed a stable interaction of these compounds with the binding site of TGFßR-1. These findings indicate that flavonoids, particularly Epicatechin, Fisetin, and Luteolin, may compete with the ligand-binding site of TGFßR-1, suggesting that these compounds can be further evaluated for the development of potential therapeutics against kidney fibrosis. Further, in-vitro and in-vivo studies are recommended to support the current findings.

Therapeutic Aspects and Molecular Targets of Autophagy to Control Pancreatic Cancer Management.

Pancreatic cancer (PC) begins within the organ of the pancreas, which produces digestive enzymes, and is one of the formidable cancers for which appropriate treatment strategies are urgently needed. Autophagy occurs in the many chambers of PC tissue, including cancer cells, cancer-related fibroblasts, and immune cells, and can be fine-tuned by various promotive and suppressive signals. Consequently, the impacts of autophagy on pancreatic carcinogenesis and progression depend greatly on its stage and conditions. Autophagy inhibits the progress of preneoplastic damage during the initial phase. However, autophagy encourages tumor formation during the development phase. Several studies have reported that both a tumor-promoting and a tumor-suppressing function of autophagy in cancer that is likely cell-type dependent. However, autophagy is dispensable for pancreatic ductal adenocarcinoma (PDAC) growth, and clinical trials with autophagy inhibitors, either alone or in combination with other therapies, have had limited success. Autophagy's dual mode of action makes it therapeutically challenging despite autophagy inhibitors providing increased longevity in medical studies, highlighting the need for a more rigorous review of current findings and more precise targeting strategies. Indeed, the role of autophagy in PC is complicated, and numerous factors must be considered when transitioning from bench to bedside. In this review, we summarize the evidence for the tumorigenic and protective role of autophagy in PC tumorigenesis and describe recent advances in the understanding of how autophagy may be regulated and controlled in PDAC.

Autophagy Modulation in Aggresome Formation: Emerging Implications and Treatments of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most prevailing neurodegenerative diseases in the world, which is characterized by memory dysfunction and the formation of tau and amyloid ß (Aß) aggregates in multiple brain regions, including the hippocampus and cortex. The formation of senile plaques involving tau hyperphosphorylation, fibrillar Aß, and neurofibrillary tangles (NFTs) is used as a pathological marker of AD and eventually produces aggregation or misfolded protein. Importantly, it has been found that the failure to degrade these aggregate-prone proteins leads to pathological consequences, such as synaptic impairment, cytotoxicity, neuronal atrophy, and memory deficits associated with AD. Recently, increasing evidence has suggested that the autophagy pathway plays a role as a central cellular protection system to prevent the toxicity induced by aggregation or misfolded proteins. Moreover, it has also been revealed that AD-related protein aggresomes could be selectively degraded by autophagosome and lysosomal fusion through the autophagy pathway, which is known as aggrephagy. Therefore, the regulation of autophagy serve as a useful approach to modulate the formation of aggresomes associated with AD. This review focuses on the recent improvements in the application of natural compounds and small molecules as a potential therapeutic approach for AD prevention and treatment via aggrephagy.

Recent Advances in Ovarian Cancer: Therapeutic Strategies, Potential Biomarkers, and Technological Improvements.

Aggressive and recurrent gynecological cancers are associated with worse prognosis and a lack of effective therapeutic response. Ovarian cancer (OC) patients are often diagnosed in advanced stages, when drug resistance, angiogenesis, relapse, and metastasis impact survival outcomes. Currently, surgical debulking, radiotherapy, and/or chemotherapy remain the mainstream treatment modalities; however, patients suffer unwanted side effects and drug resistance in the absence of targeted therapies. Hence, it is urgent to decipher the complex disease biology and identify potential biomarkers, which could greatly contribute to making an early diagnosis or predicting the response to specific therapies. This review aims to critically discuss the current therapeutic strategies for OC, novel drug-delivery systems, and potential biomarkers in the context of genetics and molecular research. It emphasizes how the understanding of disease biology is related to the advancement of technology, enabling the exploration of novel biomarkers that may be able to provide more accurate diagnosis and prognosis, which would effectively translate into targeted therapies, ultimately improving patients' overall survival and quality of life.

Analysis of SYK Gene as a Prognostic Biomarker and Suggested Potential Bioactive Phytochemicals as an Alternative Therapeutic Option for Colorectal Cancer: An In-Silico Pharmaco-Informatics Investigation.

BACKGROUND: SYK gene regulates the expression of SYK kinase (Spleen tyrosine kinase), an important non-receptor protein-tyrosine kinase for immunological receptor-mediated signaling, which is also considered a tumor growth metastasis initiator. An onco-informatics analysis was adopted to evaluate the expression and prognostic value of the SYK gene in colorectal cancer (CRC), the third most fatal cancer type; of late, it may be a biomarker as another targeted site for CRC. In addition, identify the potential phytochemicals that may inhibit the overexpression of the SYK kinase protein and minimize the human CRC. MATERIALS & METHODS: The differential expression of the SYK gene was analyzed using several transcriptomic databases, including Oncomine, UALCAN, GENT2, and GEPIA2. The server cBioPortal was used to analyze the mutations and copy number alterations, whereas GENT2, Gene Expression Profiling Interactive Analysis (GEPIA), Onco-Lnc, and PrognoScan were used to examine the survival rate. The protein-protein interaction network of SYK kinase and its co-expressed genes was conducted via Gene-MANIA. Considering the SYK kinase may be the targeted site, the selected phytochemicals were assessed by molecular docking using PyRx 0.8 packages. Molecular interactions were also observed by following the Ligplot+ version 2.2. YASARA molecular dynamics simulator was applied for the post-validation of the selected phytochemicals. RESULTS: Our result reveals an increased level of mRNA expression of the SYK gene in colorectal adenocarcinoma (COAD) samples compared to those in normal tissues. A significant methylation level and various genetic alterations recurrence of the SYK gene were analyzed where the fluctuation of the SYK alteration frequency was detected across different CRC studies. As a result, a lower level of SYK expression was related to higher chances of survival. This was evidenced by multiple bioinformatics platforms and web resources, which demonstrated that the SYK gene can be a potential biomarker for CRC. In this study, aromatic phytochemicals, such as kaempferol and glabridin that target the macromolecule (SYK kinase), showed higher stability than the controls, and we have estimated that these bioactive potential phytochemicals might be a useful option for CRC patients after the clinical trial. CONCLUSIONS: Our onco-informatics investigation suggests that the SYK gene can be a potential prognostic biomarker of CRC. On the contrary, SYK kinase would be a major target, and all selected compounds were validated against the protein using in-silico drug design approaches. Here, more in vitro and in vivo analysis is required for targeting SYK protein in CRC.

Potential of Bioactive Food Components against Gastric Cancer: Insights into Molecular Mechanism and Therapeutic Targets.

Gastric cancer, also known as stomach cancer, is a cancer that develops from the lining of the stomach. Accumulated evidence and epidemiological studies have indicated that bioactive food components from natural products play an important role in gastric cancer prevention and treatment, although its mechanism of action has not yet been elucidated. Particularly, experimental studies have shown that natural bioactive food products display a protective effect against gastric cancer via numerous molecular mechanisms, such as suppression of cell metastasis, anti-angiogenesis, inhibition of cell proliferation, induction of apoptosis, and modulation of autophagy. Chemotherapy remains the standard treatment for advanced gastric cancer along with surgery, radiation therapy, hormone therapy, as well as immunotherapy, and its adverse side effects including neutropenia, stomatitis, mucositis, diarrhea, nausea, and emesis are well documented. However, administration of naturally occurring bioactive phytochemical food components could increase the efficacy of gastric chemotherapy and other chemotherapeutic resistance. Additionally, several studies have suggested that bioactive food components with structural stability, potential bioavailability, and powerful bioactivity are important to develop novel treatment strategies for gastric cancer management, which may minimize the adverse effects. Therefore, the purpose of this review is to summarize the potential therapeutic effects of natural bioactive food products on the prevention and treatment of gastric cancer with intensive molecular mechanisms of action, bioavailability, and safety efficacy.

Candidate antiviral drugs for COVID-19 and their environmental implications: a comprehensive analysis.

Emerging from Wuhan, China, SARS-CoV-2 is the new global threat that killed millions of people, and many are still suffering. This pandemic has not only affected people but also caused economic crisis throughout the world. Researchers have shown good progress in revealing the molecular insights of SARS-CoV-2 pathogenesis and developing vaccines, but effective treatment against SARS-CoV-2-infected patients are yet to be found. Several vaccines are available and used in many countries, while many others are still in clinical or preclinical studies. However, this involves a long-term process, considering the safety procedures and requirements and their long-term protection capacity and in different age groups are still questionable. Therefore, at present, the drug repurposing of the existing therapeutics previously designed against other viral diseases seems to be the only practical approach to mitigate the current situation. The safety of most of these therapeutic agents has already been tested. Recent clinical reports revealed promising therapeutic efficiency of several drugs such as remdesivir, tenofovir disoproxil fumarate, azithromycin, lopinavir/ritonavir, chloroquine, baricitinib, and cepharanthine. Besides, plasma therapies were used to treat patients and prevent fatal outcomes. Thus, in this article, we have summarized the epidemiological and clinical data from several clinical trials conducted since the beginning of the pandemic, emphasizing the efficiency of the known agents against SARS-CoV-2 and their harmful side effects on the human body as well as their environmental implications. This review shows a clear overview of the current pharmaceutical perspective on COVID-19 treatment.

Modulatory Effects of Autophagy on APP Processing as a Potential Treatment Target for Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the formation of intracellular aggregate composed of heavily phosphorylated tau protein and extracellular deposit of amyloid-ß (Aß) plaques derived from proteolysis cleavage of amyloid precursor protein (APP). Autophagy refers to the lysosomal-mediated degradation of cytoplasmic constituents, which plays a critical role in maintaining cellular homeostasis. Importantly, recent studies reported that dysregulation of autophagy is associated in the pathogenesis of AD, and therefore, autophagy modulation has gained attention as a promising approach to treat AD pathogenesis. In AD, both the maturation of autolysosomes and its retrograde transports have been obstructed, which causes the accumulation of autophagic vacuoles and eventually leads to degenerating and dystrophic neurites function. However, the mechanism of autophagy modulation in APP processing and its pathogenesis have not yet been fully elucidated in AD. In the early stage of AD, APP processing and Aß accumulation-mediated autophagy facilitate the removal of toxic protein aggregates via mTOR-dependent and -independent pathways. In addition, a number of autophagy-related genes (Atg) and APP are thought to influence the development of AD, providing a bidirectional link between autophagy and AD pathology. In this review, we summarized the current observations related to autophagy regulation and APP processing in AD, focusing on their modulation associated with the AD progression. Moreover, we emphasizes the application of small molecules and natural compounds to modulate autophagy for the removal and clearance of APP and Aß deposits in the pathological condition of AD.

Molecular Insights into the Multifunctional Role of Natural Compounds: Autophagy Modulation and Cancer Prevention.

Autophagy is a vacuolar, lysosomal degradation pathway for injured and damaged protein molecules and organelles in eukaryotic cells, which is controlled by nutrients and stress responses. Dysregulation of cellular autophagy may lead to various diseases such as neurodegenerative disease, obesity, cardiovascular disease, diabetes, and malignancies. Recently, natural compounds have come to attention for being able to modulate the autophagy pathway in cancer prevention, although the prospective role of autophagy in cancer treatment is very complex and not yet clearly elucidated. Numerous synthetic chemicals have been identified that modulate autophagy and are favorable candidates for cancer treatment, but they have adverse side effects. Therefore, different phytochemicals, which include natural compounds and their derivatives, have attracted significant attention for use as autophagy modulators in cancer treatment with minimal side effects. In the current review, we discuss the promising role of natural compounds in modulating the autophagy pathway to control and prevent cancer, and provide possible therapeutic options.