Mishra, Amit Kumar

2024, Goutami Naidu, Deepak Kumar Tripathi, Nupur Nagar, Mishra, Amit Kumar, Krishna Mohan Poluri

Ethnopharmacological relevance: Infection and inflammation are critical to global human health status and the goal of current pharmacological interventions intends formulating medications/preventives as a measure to deal with this situation. Chemokines and their cognate receptors are major regulatory molecules in many of these ailments. Natural products have been a keen source to the drug development industry, every year contributing significantly to the growing list of FDA approved drugs. A multiverse of natural resource is employed as a part of curative regimen in folk/traditional/ethnomedicine which can be employed to discover, repurpose, and design potent medications for the diseases of clinical concern. Aim of the study: This review aims to systematically document the ethnopharmacologically active agents targeting the infectious-inflammatory diseases through the chemokine-receptor nexus. Materials and methods: Articles related to chemokine/receptor modulating ethnopharmacological anti-inflammatory, anti-infectious natural sources, bioactive compounds, and formulations have been examined with special emphasis on women related diseases. The available literature has been thoroughly scrutinized for the application of traditional medicines in chemokine associated experimental methods, their regulatory outcomes, and pertinence to women's health wherever applicable. Moreover, the potential traditional regimens under clinical trials have been critically assessed. Results: A systematic and comprehensive review on the chemokine-receptor targeting ethnopharmaceutics from the available literature has been provided. The article discusses the implication of traditional medicine in the chemokine system dynamics in diverse infectious-inflammatory disorders such as cardiovascular diseases, allergic diseases, inflammatory diseases, neuroinflammation, and cancer. On this note, critical evaluation of the available data surfaced multiple diseases prevalent in women such as osteoporosis, rheumatoid arthritis, breast cancer, cervical cancer and urinary tract infection. Currently there is no available literature highlighting chemokine-receptor targeting using traditional medicinal approach from women's health perspective. Moreover, despite being potent in vitro and in vivo setups there remains a gap in clinical translation of these formulations, which needs to be strategically and scientifically addressed to pave the way for their successful industrial translation. Conclusions: The review provides an optimistic global perspective towards the applicability of ethnopharmacology in chemokine-receptor regulated infectious and inflammatory diseases with special emphasis on ailments prevalent in women, consecutively addressing their current status of clinical translation and future directions.

2024, Sumit Kinger, Yuvraj Anandrao Jagtap, Ankur Rakesh Dubey, Prashant Kumar, Akash Choudhary, Surojit Karmakar, Girdhari Lal, Vijay Kumar Prajapti, Hem Chandra Jha, Ravi Kumar Gutti, Mishra, Amit Kumar

Several studies suggest Valproate's (VPA) therapeutic use in treating seizures, epilepsy, and bipolar disorder. Valproate is a class I histone deacetylases (HDACs) inhibitor and an attractive chemotherapeutic agent for targeting cancer. Few reports suggest that Valproate can suppress cell growth and cell differentiation and is linked with anti-tumor activity. However, Valproate-associated anti-tumoral function and intracellular signaling cascade-mediated anti-cellular proliferation activities still need to be better understood. This current study suggests that Valproate can elevate proteasomal dysfunctions, resulting in misfolded protein accumulation and abnormal mitochondrial functions that successively induce apoptosis. Present findings indicate that treatment of Valproate inhibits Proteasome activities and also aggravates accumulation of expanded polyglutamine proteins and other proteasomal substrates. Overall, the aggregation of aberrant proteins and mitochondrial dysfunctions are observed, such as cytochrome c release, and disturbed mitochondrial membrane potential. Treatment of Valproate induces apoptotic morphological changes and cell death. These observations suggest that Valproate can cause mitochondrial abnormalities associated with apoptosis. These findings can provide new possible insights and suggest molecular approaches for developing better and specific Proteasome inhibitors that can be better useful with other anti-tumor drugs for treatment of cancer and other complex diseases.

2024, Dharmendra Kashyap, Manushree Tanwar, Chanchal Rani, Pranit Hemant Bagde, Siddharth Singh, Nidhi Varshney, Vaishali Saini, Mishra, Amit Kumar, Rajesh Kumar, Hem Chandra Jha

Helicobacter pylori and Epstein–Barr Virus (EBV) are Group 1 carcinogens that can enhance gastric cancer progression. Bioactive substances extracted from plants can be effective therapeutic agents in cancer treatment. For example, Withania somnifera extract-WSE reduces the Gankyrin oncoprotein, which is upregulated in the presence of H. pylori and EBV. The various biochemical and metabolic changes upon 24 hrs post-infection followed by W. somnifera extract (WSE) treatment on gastric epithelial cells (AGS) can be studied using spectroscopic techniques. In the biomedical sciences, Raman and NMR spectroscopy have been extensively employed to interpret cellular alterations contributing to the onset of infection and the severity of gastric cancer. More specifically, alterations in cellular biochemical homeostasis are linked to the moieties of cholesterol, collagen, choline, carbohydrate, lipids, tyrosine, and phenylalanine. Further, we have found significantly elevated FWHM for carbohydrates, tumor associated protein, collagen, cholesterol, and cholesterol ester in the co-infection model. We also looked into the potential correlation between these molecules using molecular network analysis and found several related factors that can be modulated through biomolecular levels. These molecules are crucial in several physiological functions, including cell division, cell proliferation, apoptosis, necrosis, cell migration, and lipid transport. Our study paves the pathway to study H. pylori and EBV co-infection in human gastric epithelial cells and the therapeutic interventions of WSE in this scenario and highlights specific biomolecular alterations, which can be focused for further mechanistic investigations.

2024, Chandra S. Bhatt, Divya S. Parimi, Salman Khan, Veda V. Dasari, Bhagyasree Paila, Sreekar Marpu, Anil K. Suresh, Mishra, Amit Kumar

Nanocatalysts are extremely crucial for the expedited synthesis of various chemicals, fuels, and pharmaceutical molecules both in academia and industry. To overcome the limitations of nanocatalysts and or microstructure supported catalysts such as agglomeration (due to inter-particle dipolar forces preventing longer shelf-lives), compromised catalytic activity (e.g., nickel-titanium dioxide bimetallic catalyst, showed high selectivity to hydrogenate 3-nitrostyrene into 3-vinylaniline (90.2 %) compared to unmodified nickel (55.3 %), due to metal-plane formation by titanium dioxide), cytotoxicity (with over 90 % cell killing in the presence of the nanocatalysts above ∼ 0.2 mg/mL), catalyst retrieval (demanding energy intensive procedures such as centrifugation (∼10,000 g and above), membrane filtrations (∼0.2 µm), magnetic separations (0.9–1.1 T) and absurd practical implementation there is a tremendous development of 3-dimensional wide-area supported catalysts. This review update the readers on the evolution of highly catalytic nanoparticles for various heterogeneous catalysis. Uniquely, wide-area supported catalysts wherein the nanoparticles are grafted to 3-dimensional nature-inspired or pristine natural materials as sustainable strategies are discussed. The role of wide-area of the support in overcoming the limitations of nanocatalysts and microstructures by enabling bidirectional reactant access, catalyst efficiency, reusability, stability and sustainability are highlighted. Next, we focus on the metal-affinity and redox-potential of the natural support that aid autogenic biosynthesis and self-assembly of nanocatalysts. Followed by discussions on supplementary properties of the support such as type, structural-hierarchy, surface-area, absorption, porosity and rigidity in tuning the stability, biodegradability, compatibility, functionality and performance of the catalyst. Accentuated, with the impact of support in dictating the choice of fixed batch vs continuous flow reactors, co-relative to modulating the catalytic efficiency and turnover frequencies. Finally, the exclusive role of wide-area of the support and its biological nature in allowing the extraction of noble precursor off the support after catalyst poisoning is emphasized. These discussions, for the first time, spotlight the versatility, resilient nature of the emerging ultra-efficient wide-area supported catalysts that are generated using sustainable procedures for diverse large-volume heterogeneous catalysis.

2024, Aakanksha Pathak, Nishchay Verma, Shweta Tripathi, Mishra, Amit Kumar, Krishna Mohan Poluri

Heparin, being a widely employed anticoagulant in numerus clinical complications, requires strict quantification and qualitative screening to ensure the safety of patients from potential threat of thrombocytopenia. However, the intricacy of heparin's chemical structures and low abundance hinders the precise monitoring of its level and quality in clinical settings. Conventional laboratory assays have limitations in sensitivity and specificity, necessitating the development of innovative approaches. In this context, nanosensors emerged as a promising solution due to enhanced sensitivity, selectivity, and ability to detect heparin even at low concentrations. This review delves into a range of sensing approaches including colorimetric, fluorometric, surface-enhanced Raman spectroscopy, and electrochemical techniques using different types of nanomaterials, thus providing insights of its principles, capabilities, and limitations. Moreover, integration of smart-phone with nanosensors for point of care diagnostics has also been explored. Additionally, recent advances in nanopore technologies, artificial intelligence (AI) and machine learning (ML) have been discussed offering specificity against contaminants present in heparin to ensure its quality. By consolidating current knowledge and highlighting the potential of nanosensors, this review aims to contribute to the advancement of efficient, reliable, and economical heparin detection methods providing improved patient care.

2023, Prashant Kumar, Sumit Kinger, Ankur Rakesh Dubey, Yuvraj Anandrao Jagtap, Akash Choudhary, Amit Prasad, Hem Chandra Jha, Rohan Dhiman, Ravi Kumar Gutti, Mishra, Amit Kumar

Accumulation of misfolded proteins compromises overall cellular health and fitness. The failure to remove misfolded proteins is a critical reason for their unwanted aggregation in dense cellular protein pools. The accumulation of various inclusions serves as a clinical feature for neurodegenerative diseases. Previous findings suggest that different cellular compartments can store these abnormal inclusions. Studies of transgenic mice and cellular models of neurodegenerative diseases indicate that depleted chaperone capacity contributes to the aggregation of damaged or aberrant proteins, which consequently disturb proteostasis and cell viability. However, improving these abnormal proteins’ selective elimination is yet to be well understood. Still, molecular strategies that can promote the effective degradation of abnormal proteins without compromising cellular viability are unclear. Here, we reported that the trehalose treatment elevates endogenous proteasome levels and enhances the activities of the proteasome. Trehalose-mediated proteasomal activation elevates the removal of both bona fide misfolded and various neurodegenerative disease-associated proteins. Our current study suggests that trehalose may retain a proteasome activation potential, which seems helpful in the solubilization of different mutant misfolded proteins, improving cell viability. These results reveal a possible molecular approach to reduce the overload of intracellular misfolded proteins, and such cytoprotective functions may play a critical role against protein conformational diseases.

2023, Anubha Chaudhary, Parul Mehra, Anand K Keshri, Suraj S Rawat, Mishra, Amit Kumar, Amit Prasad

2024, Suraj Singh Rawat, Anand Kumar Keshri, Naina Arora, Rimanpreet Kaur, Mishra, Amit Kumar, Rajiv Kumar, Amit Prasad

The excretory–secretory proteome plays a pivotal role in both intercellular communication during disease progression and immune escape mechanisms of various pathogens including cestode parasites like Taenia solium. The cysticerci of T. solium causes infection in the central nervous system known as neurocysticercosis (NCC), which affects a significant population in developing countries. Extracellular vesicles (EVs) are 30–150-nm-sized particles and constitute a significant part of the secretome. However, the role of EV in NCC pathogenesis remains undetermined. Here, for the first time, we report that EV from T. solium larvae is abundant in metabolites that can negatively regulate PI3K/AKT pathway, efficiently internalized by macrophages to induce AKT and mTOR degradation through auto-lysosomal route with a prominent increase in the ubiquitination of both proteins. This results in less ROS production and diminished bacterial killing capability among EV-treated macrophages. Due to this, both macro-autophagy and caspase-linked apoptosis are upregulated, with a reduction of the autophagy substrate sequestome 1. In summary, we report that T. solium EV from viable cysts attenuates the AKT–mTOR pathway thereby promoting apoptosis in macrophages, and this may exert immunosuppression during an early viable stage of the parasite in NCC, which is primarily asymptomatic. Further investigation on EV-mediated immune suppression revealed that the EV can protect the mice from DSS-induced colitis and improve colon architecture. These findings shed light on the previously unknown role of T. solium EV and the therapeutic role of their immune suppression potential.

2024, Aniket Tiwari, Beauty Kumari, Srividhya Nandagopal, Mishra, Amit Kumar, Kamla Kant Shukla, Ashok Kumar, Naveen Dutt, Ahirwar, Dinesh Kumar

SCLC is refractory to conventional therapies; targeted therapies and immunological checkpoint inhibitor (ICI) molecules have prolonged survival only marginally. In addition, ICIs help only a subgroup of SCLC patients. Different types of kinases play pivotal roles in therapeutics-driven cellular functions. Therefore, there is a significant need to understand the roles of kinases in regulating therapeutic responses, acknowledge the existing knowledge gaps, and discuss future directions for improved therapeutics for recalcitrant SCLC. Here, we extensively review the effect of dysregulated kinases in SCLC. We further discuss the pharmacological inhibitors of kinases used in targeted therapies for recalcitrant SCLC. We also describe the role of kinases in the ICI-mediated activation of antitumor immune responses. Finally, we summarize the clinical trials evaluating the potential of kinase inhibitors and ICIs. This review overviews dysregulated kinases in SCLC and summarizes their potential as targeted therapeutic agents. We also discuss their clinical efficacy in enhancing anticancer responses mediated by ICIs.

2024, Manjari Shukla, Ghanshyam Mali, Supriya Sharma, Sushobhan Maji, Vinay Kumar Yadav, Bhattacharyya, Sudipta, Mishra, Amit Kumar, Erande, Rohan Diliprao

New therapeutic leads are in global demand against multiple drug-resistant Staphylococcus aureus, as presently there is no drug of choice left to treat this pathogen. In the present work, we have designed, synthesized, and in vitro validated dimedone-coupled 2,3-dihydrofuran (DDHF)-based inhibitor scaffolds against Staphylococcal thioredoxin reductase (SaTR), a pivotal drug target enzyme of Gram-positive pathogens. Accordingly, a green multicomponent method that is both efficient and one pot has been optimized to synthesize DDHF derivatives. The synthesized DDHF derivatives were found to inhibit a purified SaTR enzyme. The best inhibitor derivative, DDHF20, inhibits SaTR as a competitive inhibitor for the NADPH binding site at low micromolar concentrations. DDHF20-capped silver nanoparticles are synthesized and characterized, and their bactericidal property has been checked in vitro. Furthermore, detailed in silico-based structure-guided functional studies have been carried out to uncover the plausible mode of action of DDHF20 as a potential anti-Staphylococcal therapeutic lead.