Mishra, Amit Kumar

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.

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.

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.

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.

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.

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.

Delivering macromolecules across the skin poses challenges due to the barrier properties of stratum corneum. Different strategies have been reported to cross this barrier, such as chemical penetration enhancers and physical methods like microneedles, sonophoresis, electroporation, laser ablation, etc. Herein, we explored a cationic lipo-polymeric nanocarrier to deliver a model protein across the skin. A cationic amphiphilic lipo-polymer was used to prepare blank nanoplexes, which were subsequently complexed with anionic fluorescein-tagged bovine serum albumin (FITC-BSA). Blank nanoplexes and FITC-BSA complexed nanoplexes showed sizes of 93.72 ± 5.8 (PDI-0.250) and 145.9 ± 3.2 nm (PDI-0.258), respectively, and zeta potentials of 25.6 ± 7.0 mV and 9.17 ± 1.20 mV. In vitro cell culture, and toxicity studies showed optimal use of these nanocarriers, with hemocompatibility data indicating non-toxicity. Ex vivo skin permeation analysis showed a skin permeation rate of 33% after 24 h. The optimized formulation was loaded in a carbopol-based gel that exhibits non-Newtonian flow characteristics with shear-thinning behavior and variable thixotropy. The nanoplexes delivered via gel demonstrated skin permeation of 57% after 24 h in mice skin ex vivo. In vivo skin toxicity testing confirmed the low toxicity profile of these nanocarriers. These results are promising for the transdermal/dermal delivery of macromolecules, such as protein therapeutics, using nanoplexes.

Acetaminophen is a known antipyretic and non-opioid analgesic for mild pain and fever. Numerous studies uncover their hidden chemotherapeutics applications, including chronic cancer pain management. Acetaminophen also represents an anti-proliferative effect in some cancer cells. Few studies also suggest that the use of Acetaminophen can trigger apoptosis and impede cellular growth. However, Acetaminophen's molecular potential and precise mechanism against improper cellular proliferation and use as an effective anti-proliferative agent still need to be better understood. Here, our current findings show that Acetaminophen induces proteasomal dysfunctions, resulting in aberrant protein accumulation and mitochondrial abnormalities, and consequently induces cell apoptosis. We observed that the Acetaminophen treatment leads to improper aggregation of ubiquitylated expanded polyglutamine proteins, which may be due to the dysfunctions of proteasome activities. Our in-silico analysis suggests the interaction of Acetaminophen and proteasome. Furthermore, we demonstrated the accumulation of proteasome substrates and the depletion of proteasome activities after treating Acetaminophen in cells. Acetaminophen induces proteasome dysfunctions and mitochondrial abnormalities, leading to pro-apoptotic morphological changes and apoptosis successively. These results suggest that Acetaminophen can induce cell death and may retain a promising anti-proliferative effect. These observations can open new possible molecular strategies in the near future for developing and designing specific and effective proteasome inhibitors, which can be helpful in conjugation with other anti-tumor drugs for their better efficiency.

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.

Drug-resistant tuberculosis (TB) outbreak has emerged as a global public health crisis. Therefore, new and innovative therapeutic options like host-directed therapies (HDTs) through novel modulators are urgently required to overcome the challenges associated with TB. In the present study, we have investigated the anti-mycobacterial effect of 4-(Benzyloxy)phenol. Cell-viability assay asserted that 50 μM of 4-(Benzyloxy)phenol was not cytotoxic to phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 (dTHP-1) cells. It was observed that 4-(Benzyloxy)phenol activates p53 expression by hindering its association with KDM1A. Increased ROS, intracellular Ca2+ and phagosome-lysosome fusion, were also observed upon 4-(Benzyloxy)phenol treatment. 4-(Benzyloxy)phenol mediated killing of intracellular mycobacteria was abrogated in the presence of specific inhibitors of ROS, Ca2+ and phagosome-lysosome fusion like NAC, BAPTA-AM, and W7, respectively. We further demonstrate that 4-(Benzyloxy)phenol mediated enhanced ROS production is mediated by acetylation of p53. Blocking of p53 acetylation by Pifithrin-α (PFT- α) enhanced intracellular mycobacterial growth by blocking the mycobactericidal effect of 4-(Benzyloxy)phenol. Altogether, the results showed that 4-(Benzyloxy)phenol executed its anti-mycobacterial effect by modulating p53-mediated ROS production to regulate phagosome-lysosome fusion through Ca2+ production.