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The Thane Creek-Ulhas estuary confluence region acts as a naturally active infiltration system, crucial for altering water quality in the area and Arabian Sea. Particle-water exchange, hydrodynamics, and anthropogenic discharge influence nutrient transfer and transformation, highlighting the need for effective water quality management in this urbanized ecosystem. We analyzed monthly hydrography and nutrient data in water, and particulates from April 2021 to March 2022, including period of Cyclone Gulab at four locations along the inflow and outflow sectors. Our results revealed prevalent hypoxic conditions in the confluence waters, driven by microbial oxygen demand that surpassed the chemical load due to indiscriminate sewage inflow. Phosphorus emerged as the limiting nutrient, inhibited by adsorption/desorption equilibrium. Dissolved phosphate was transformed into particulate form under intermediate suspended load, with further transform into organic phosphorous during non-monsoon season. Excessive ammonium from sewage during the cyclone and elevated urea during non-monsoon indicated regenerated nitrogen forms, rendering the region eutrophic and hyper-eutrophic, with intermittent organic pollution. Engineering interventions may help mitigate water quality alterations that pose significant ecological risks in this mangrove-dominant confluence ecosystem., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Antimicrobial resistance (AMR) is a global health crisis that has already claimed millions of lives and is projected to affect millions more unless urgent action is taken. Effective control of AMR requires the correct choice and dosage of antibiotics, as well as robust surveillance and research. Understanding the mechanisms of antibiotic action and the emergence of resistance phenotypes along with their genotypes is essential. This knowledge, combined with insights into resistance prevalence and spread, empowers clinicians to propose alternative therapies. Nitrofurantoin, a 70-year-old antibiotic, remains effective for the treatment of uncomplicated lower UTIs. Preventing emergence and spread of nitrofurantoin resistant superbugs would preserve the efficacy of this antibiotic which is crucial for ongoing and future AMR efforts. Nitrofurantoin resistance evolves slowly, leading to low prevalence compared to other antibiotics. However, it is often linked with extensive drug resistance, complicating treatment outcomes. Even a minor percentage of nitrofurantoin-resistant bacteria can cause significant clinical challenges due to irreversible evolution. While detailed study of these mechanisms can guide the development of strategies to combat nitrofurantoin resistance, early detection of resistant infections is critical for saving lives. The current review aims to provide a comprehensive analysis of nitrofurantoin's mechanisms of action, resistance evolution, prevalence, and resistance prediction. Our goal is to offer valuable insights for researchers and clinicians to enhance nitrofurantoin use and address the challenges posed by AMR., (The Author(s). Published by S. Karger AG, Basel.)

Heterocycle derived moieties, namely, N -(4-methoxyphenyl)-1-(1 H -pyrrol-2-yl)methanimine (MPM), 1-(furan-2-yl)- N -(4-methoxyphenyl)methanimine (FMM), and N -(4-methoxyphenyl)-1-(thiophen-2-yl)methanimine (MTM), were synthesized followed by analysis of their structural aspects using FTIR and 1 H NMR spectroscopic techniques. The corrosion retarding abilities of the same were distinguished by gravimetric and certain electrochemical measures for mild steel in 0.5 M H 2 SO 4 , and MTM was obtained with maximum inhibition efficiency of 97.93% at 250 mg L -1 concentration; the thermodynamic and activation parameters were recorded in this regard. The results were further seen to be supported by various surface studies: SEM-EDS, XPS, AFM, contact angle, and UV-visible spectroscopy. Potentiodynamic polarization studies unveiled the mixed nature of heterocyclic inhibitors with overriding anodic effect. Furthermore, the adsorption of inhibitors over mild steel coupons demarcates the prevalence of physical and chemical interactions in the environment. In addition, the computational studies, global and local reactivity, molecular dynamics, and density functional theory, were employed and the experimental results obtained were found in correlation with the theoretical results.

Introduction: The processes and course of several fatal illnesses, such as cancer, inflammatory diseases, and neurological disorders are closely correlated with HDAC8. Therefore, novel HDAC8 inhibitors represent effective therapeutic possibilities that may help treat these conditions. To yet, there are not any such particular HDAC8 inhibitors available for sale. This review was conducted to examine recent HDAC8 inhibitors that have been patented over the last 10 years., Areas Covered: This review focuses on HDAC8 inhibitor-related patents and their therapeutic applications that have been published within the last 10 years and are accessible through the Patentscope and Google Patents databases., Expert Opinion: A handful of HDAC8 inhibitor-related patents have been submitted over the previous 10 years, more selective, and specific HDAC8 inhibitors that are intended to treat a variety of medical diseases. This could lead to the development of novel treatment approaches that target HDAC8. Employing theoretical frameworks and experimental procedures can reveal the creation of new HDAC8 inhibitors with enhanced pharmacokinetic characteristics. A thorough understanding of the role that HDAC8 inhibitors play in cancer, including the mechanisms behind HDAC8 in other disorders is necessary.

The current research endeavour aimed to synthesize ferulic acid grafted tamarind gum/guar gum (FA-g-TG/GG) based powders as wound dressings, which could form in situ gels upon contact with wound exudates. In this context, variable amounts of FA were initially grafted with TG via the Steglich esterification reaction protocol and the resulting conjugates were subsequently amalgamated with GG and lyophilized to produce dry powders (F-1 - -F-3) with average particle size within 5.10-5.54 μm and average angle of repose ∼30°. These powders were structurally characterized with 1 H NMR, FTIR, DSC, TGA, XRD and SEM analyses. Pristine TG, FA-g-TG and FA-g-TG/GG powders (F-2) revealed their distinct morphological structures and variable negative zeta potential values (-11.06 mV-25.50 mV). Among various formulation (F-1-F-3), F-2 demonstrated an acceptable powder-to-gel conversion time (within 20 min), suitable water vapour transmission rates (WVTR, 2564.94 ± 32.47 g/m 2 /day) and excellent water retention abilities and swelling profiles (4559.00 ± 41.57 %) in wound fluid. The powders were cytocompatible and conferred antioxidant activities. The powders also displayed fibroblast cell proliferation, migration and adhesion properties, implying their wound-healing potentials. Thus, the developed in situ gel-forming powders could be employed as promising dressings for wound management., Competing Interests: Declaration of competing interest All authors declare no personal relationships or conflicting interests, which have influenced the research activities presented in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

HDAC3 is an emerging target for the identification and discovery of novel drug candidates against several disease conditions including cancer. Here, a fragment-based non-linear machine learning (ML) method along with chemical space exploration followed by a structure-based binding mode of interaction analysis study was carried out on some HDAC3 inhibitors to obtain the key structural features modulating HDAC3 inhibition. Both the ML and chemical space analysis identified several physicochemical and structural properties namely lipophilicity, polar and relative polar surface area, arylcarboxamide moiety, bulky fused aromatic group, n -alkyl, and cinnamoyl moieties, the higher number of oxygen atoms, π-electrons for the substituted tetrahydrofuronaphthodioxolone moiety favorable for higher HDAC3 inhibition. Moreover, hydrogen bond forming capabilities, the length and substitution position of the linker moiety, the importance of phenyl ring in the linker motif, the contribution of heterocyclic cap moieties for effective inhibitor binding at the HDAC3 catalytic site that correspondingly affects the HDAC3 inhibitory potency. Again, macrocyclic ring structure and cyclohexyl cap moiety are responsible for lower HDAC3 inhibition. The MD simulation study of selected compounds explained strong binding patterns at the HDAC3 active site as evidenced by the lower RMSD and RMSF values. Nevertheless, it also explained the importance of the crucial structural fragments derived from the fragment-based analysis during ligand-enzyme interactions. Therefore, the outcomes of this current structural analysis will be a useful tool for fragment-based drug discovery of effective HDAC3 inhibitors for clinical therapeutics in the future.Communicated by Ramaswamy H. Sarma.

Climate change represents a considerable threat to aquatic ecosystems, potentially affecting various water quality parameters.The study aims to assess the impacts climatic factors on the water quality parameters in tilapia broodfish pond and forecasting of water temperature in a tilapia broodfish pond using the ARIMAX model. Daily longitudinal time series data on water quality parameters were collected from the pond, while monthly climatic data were obtained from the Bangladesh Meteorological Department. Water temperature exhibited seasonal variation, peaking at 31.23 °C in October and dropping to 20.8 °C in December. pH levels ranged from 7.36 to 10.32, with the lowest recorded in December and the highest in August. Dissolved oxygen levels varied from 7.09 mg/L to 10.65 mg/L, with the lowest in September and the highest in January. Ammonia levels were highest in February at 0.33 mg/L. Water transparency ranged from 15.37 to 28 inches, with the highest in January and the lowest in June. Climatic factors significantly influenced these variations, as specified by Canonical correlation analysis (CCA). The best-fitting model, ARIMAX (1, 0, 1), indicated a fluctuating trend influenced by important exogenous factors like air temperature and solar intensity. By the end January 2025, the water temperature is expected to rise to 27.93 °C. This is a noticeable increase started from November to January. These higher temperatures may improve tilapia broodfish growth and development earlier. But the temperatures are predicted to drop started from February to March, which could negatively affect tilapia growth and development. A clear seasonal fluctuating pattern is exhibited in the future. These findings provide important insights for researchers, policymakers, academics, and those involved in tilapia farming. By considering air temperature and solar intensity in planning, stakeholders can better anticipate future pond conditions. Developing adaptive management strategies to reduce negative impacts and make the most of favorable conditions will be essential for sustainable tilapia production in the context of climate change., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Protein-based hydrogels are appealing materials for a variety of therapeutic uses because they are compatible, biodegradable, and adaptable to biological and chemical changes. Therefore, adherent varieties of hydrogels have received significant study; nevertheless, the majority of them show weak mechanical characteristics, transient adherence, poor biocompatibility activity, and low tensile strength. Here we are reporting, a two-component (BSA-gelatin) protein solution crosslinked with Tetrakis (hydroxymethyl) phosphonium chloride (THPC) to form a novel hydrogel. Compared with classical adhesive hydrogels, this hydrogel showed enhanced mechanical properties, was biocompatible with L929 cells, and had minimal invasive injectability. A considerable, high tensile strength of 73.33 ± 11.54 KPa and faultless compressive mechanical properties of 173 KPa at 75% strain were both demonstrated by this adhesive hydrogel. Moreover, this maximum tissue adhesion strength could reach 18.29 ± 2.22 kPa, significantly higher than fibrin glue. Cell viability was 97.09 ± 6.07%, which indicated that these hydrogels were non-toxic to L929. The fastest gelation time of the BSA-gelatin hydrogel was 1.25 ± 0.17 min at physiological pH and 37 °C. Therefore, the obtained novel work can potentially serve as a tissue adhesive hydrogel in the field of biomedical industries.

Overexpression of matrix metalloproteinase-2 (MMP-2) possesses a correlation with leukemia especially chronic myeloid leukemia (CML). However, no such MMP-2 inhibitor has come out in the market to date for treating leukemia. In this study, synthesis, biological evaluation, and molecular modeling studies of a set of biphenylsulfonamide derivatives as promising MMP-2 inhibitors were performed, focusing on their potential applications as antileukemic therapeutics. Compounds DH-18 and DH-19 exerted the most effective MMP-2 inhibition (IC 50 of 139.45 nM and 115.16 nM, respectively) with potent antileukemic efficacy against the CML cell line K562 (IC 50 of 0.338 µM and 0.398 µM, respectively). The lead molecules DH-18 and DH-19 reduced the MMP-2 expression by 21.3% and 17.8%, respectively with effective apoptotic induction (45.4% and 39.8%, respectively) in the K562 cell line. Moreover, both these compounds significantly arrested different phases of the cell cycle. Again, both these molecules depicted promising antiangiogenic efficacy in the ACHN cell line. Nevertheless, the molecular docking and molecular dynamics (MD) simulation studies revealed that DH-18 formed strong bidentate chelation with the catalytic Zn 2+ ion through the hydroxamate zinc binding group (ZBG). Apart from that, the MD simulation study also disclosed stable binding interactions of DH-18 and MMP-2 along with crucial interactions with active site amino acid residues namely His120, Glu121, His124, His130, Pro140, and Tyr142. In a nutshell, this study highlighted the importance of biphenylsulfonamide-based novel and promising MMP-2 inhibitors to open up a new avenue for potential therapy against CML., (© 2024 Wiley Periodicals LLC.)

Any pathogenic attack, infection, or disease can initiate inflammation. It results in significant adverse consequences like inflammatory bowel disease, rheumatoid arthritis, etc. TNFα is one of the major pro-inflammatory cytokines for the progression of inflammation-the present study designed a series of hybrid compounds consisting of the pyrazole-pyridine moiety. Virtual screening was performed utilizing the e-pharmacophore hypothesis with the co-ligand of TNFα, screening, docking, and ADMET study. Induced fit docking, DFT analysis, and molecular dynamic simulation showed that the four best molecules - Dh1- Dh4-showed crucial interaction with Tyrosine, higher dock scores, and better stability than Diclofenac. Following the synthesis of hit molecules, an in vitro albumin denaturation IC 50 of Dh1 was found to be 118.01 μM. Further in-depth in vitro and in vivo analyses of these pyrazole-pyridine small compounds may serve as potential space for creating new anti-inflammatory leads., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Among various matrix metalloproteinases (MMPs), MMP-12 is one of the potential targets for cancer and other diseases. However, none of the MMP-12 inhibitors has passed the clinical trials to date. Therefore, designing potential MMP-12 inhibitors as new drug molecules can provide effective therapeutic strategies for several diseases. In this study, a series of dibenzofuran and dibenzothiophene derivatives were subjected to different 2D and 3D-QSAR techniques to point out the crucial structural contributions highly influential toward the MMP-12 inhibitory activity. These techniques identified some structural attributes of these compounds that are responsible for influencing their MMP-12 inhibition. The carboxylic group may enhance proper binding with catalytic Zn 2+ ion at the MMP-12 active site. Again, the i -propyl sulfonamido carboxylic acid function contributed positively toward MMP-12 inhibition. Moreover, the dibenzofuran moiety conferred stable binding at the S1' pocket for higher MMP-12 inhibition. The steric and hydrophobic groups were found favourable near the furan ring substituted at the dibenzofuran moiety. Besides these ligand-based approaches, molecular docking and molecular dynamic (MD) simulation studies not only elucidated the importance of several aspects of these MMP-12 inhibitors while disclosing the significance of the finding of these QSAR studies and their influences toward MMP-12 inhibition. The MD simulation study also revealed stable and compact binding between such compounds at the MMP-12 active site. Therefore, the findings of these validated ligand-based and structure-based molecular modeling studies can aid the development of selective and potent lead molecules that can be used for the treatment of MMP-12-associated diseases.Communicated by Ramaswamy H. Sarma.

Accurate detection of bacterial antibiotic sensitivity is crucial for theranostics and the containment of antibiotic-resistant infections. However, the intricate task of detecting and quantifying the antibiotic-induced changes in the bacterial cytoplasmic membrane, and their correlation with other metabolic pathways leading to antibiotic resistance, poses significant challenges. Using a novel class of 4-aminophthalimide (4AP)-based fluorescent dyes with precisely tailored alkyl chains, namely 4AP-C9 and 4AP-C13, we quantify stress-mediated alterations in E. coli membranes. Leveraging the unique depth-dependent positioning and environment-sensitive fluorescence properties of these dyes, we detect antibiotic-induced membrane damage through single-cell imaging and monitoring the fluorescence peak maxima difference ratio (PMDR) of the dyes within the bacterial membrane, complemented by other methods. The correlation between the ROS-induced cytoplasmic membrane damage and the PMDR of dyes quantifies sensitivity against bactericidal antibiotics, which correlates to antibiotic-induced lipid peroxidation. Significantly, our findings largely extend to clinical isolates of E. coli and other ESKAPE pathogens like K. pneumoniae and Enterobacter subspecies. Our data reveal that 4AP-Cn probes can potentially act as precise scales to detect antibiotic-induced membrane damage ("thinning") occurring at a subnanometer scale through the quantification of dyes' PMDR, making them promising membrane dyes for rapid detection of bacterial antibiotic resistance, distinguishing sensitive and resistant infections with high specificity in a clinical setup.

Chronic myeloid leukemia (CML) is a global issue and the available drugs such as tyrosine kinase inhibitors (TKIs) comprise various toxic effects as well as resistance and cross-resistance. Therefore, novel molecules targeting specific enzymes may unravel a new direction in antileukemic drug discovery. In this context, targeting gelatinases (MMP-2 and MMP-9) can be an alternative option for the development of novel molecules effective against CML. In this article, some D(-)glutamine derivatives were synthesized and evaluated through cell-based antileukemic assays and tested against gelatinases. The lead compounds, i.e., benzyl analogs exerted the most promising antileukemic potential showing nontoxicity in normal cell line including efficacious gelatinase inhibition. Both these lead molecules yielded effective apoptosis and displayed marked reductions in MMP-2 expression in the K562 cell line. Not only that, but both of them also revealed effective antiangiogenic efficacy. Importantly, the most potent MMP-2 inhibitor, i.e., benzyl derivative of p-tosyl D(-)glutamine disclosed stable binding interaction at the MMP-2 active site correlating with the highly effective MMP-2 inhibitory activity. Therefore, such D(-)glutamine derivatives might be explored further as promising MMP-2 inhibitors with efficacious antileukemic profiles for the treatment of CML in the future., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Herein, we report the synthesis and anticancer properties of 21 new 1,3,4-thiadiazole-2-yl-imino-thiazolidine-4-one containing binary heterocyclic molecules. Cytotoxicity of the synthesized molecules was evaluated on various in vitro cancer cell lines (MCF-7, PC3, 4T1, MDA-MB-231, and MOC2) and normal human embryonic cell lines (HEK-293) via MTT assay. The cytotoxicity data of developed compounds was compared with the reference anticancer molecule BG45, a selective inhibitor of the HDAC3 enzyme. All compounds showed a significant cytotoxic effect higher than BG45 on tested cancer cell lines. Moreover, the compounds exhibited better selectivity on cancer cells than on normal cells. Among the molecules, compound 6e is the most potent in cytotoxic activity on MCF-7 cell lines (IC 50 value of 3.85 μM). Additional mechanistic investigation revealed that compound 6e promotes apoptosis (25.3%) and G0/G1 phase cell cycle arrest of MCF-7 cells. Also, compound 6e induces intracellular ROS accumulation and subsequent nuclear fragmentation. Hence, this research finds new hybrid molecules active against in vitro cancer cells., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (This journal is © The Royal Society of Chemistry.)

A 3 adenosine receptor (A 3 AR) positive allosteric modulators (PAMs) (2,4-disubstituted-1 H -imidazo[4,5- c ]quinolin-4-amines) allosterically increase the E max of A 3 AR agonists, but not potency, due to concurrent orthosteric antagonism. Following mutagenesis/homology modeling of the proposed lipid-exposed allosteric binding site on the cytosolic side, we functionalized the scaffold, including heteroatom substitutions and exocyclic phenylamine extensions, to increase allosteric binding. Strategically appended linear alkyl-alkynyl chains with terminal amino/guanidino groups improved allosteric effects at both human and mouse A 3 ARs. The chain length, functionality, and attachment position were varied to modulate A 3 AR PAM activity. For example, 26 (MRS8247, p -alkyne-linked 8 methylenes) and homologues increased agonist Cl-IB-MECA's E max and potency ([ 35 S]GTPγS binding). The putative mechanism involves a flexible, terminally cationic chain penetrating the lipid environment for stable electrostatic anchoring to cytosolic phospholipid head groups, suggesting "lipid trolling", supported by molecular dynamic simulation of the active-state model. Thus, we have improved A 3 AR PAM activity through rational design based on an extrahelical, lipidic binding site.

A novel Schiff base moiety, ( E )-4-(1-hydrazonoethyl)benzene-1,3-diol (2), and 2,4-dihydroxybenzaldehyde were condensed in a 1 : 1 molar ratio to generate 4-(( E )-1-((( Z )-2,4dihydroxybenzylidene)hydrazono)ethyl)benzene-1,3-diol (L), which was then characterized using high-resolution mass spectrometry (HRMS), 1 H-NMR, 13 C NMR, and single-crystal XRD techniques. UV-vis absorbance measurements were used to determine whether the Schiff base could detect the cupric ions more effectively than the other transition metal ions. When Cu 2+ ions were involved, a new band was observed at 462 nm. From the Job plot, the binding stoichiometry for the anticipated L : Cu 2+ partnership is determined to be 1 : 1. For the purpose of validating structural correlations and absorption data, DFT simulations were performed. Further, docking studies for L indicated high binding affinity for human hemoglobin, providing vital information about the ligand's favorable binding locations inside hemoglobin binding sites and the consequent interactions with HHb. The binding coefficient and limit of detection were found to be 3.02 × 10 4 M -1 and 42.09 nM, respectively. Reversibility of the complex was seen upon the addition of EDTA to the L-Cu 2+ solution, and a colorimetric variation simulating the "INHIBIT" molecular logic gate was seen upon the addition of Cu 2+ and EDTA to L. Furthermore, the chemosensor's potential application in the detection of Cu 2+ in the solid state by chemosensor L also confirms its usefulness in real-world applications emphasizing its versatility and practical utility., Competing Interests: The authors declare that they have no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Background: Sailors undergo anxiety and sleep disturbances due to prolonged journeys and the nature of their work on ships. Earlier studies indicate Cyclic Meditation (CM) being beneficial for managing anxiety and improving sleep quality. Thus, the current study was designed to investigate the effect of CM on anxiety and sleep quality among sailors., Materials and Methods: Fifty sailors were assigned to experimental ( n  = 25) and control ( n  = 25) groups. The experimental group received 45 min of CM, 7 days a week for 3 weeks. Control group continued with their routine activities and were offered CM practice the following 3 weeks. Hamilton Anxiety Scale for anxiety (HAM-A) and the Pittsburg Sleep Quality Index (PSQI) for sleep along with blood pressure and pulse rate were taken at baseline and by the end of 3 weeks. Data were analyzed using Repeated Measures Analysis of Variance (RM ANOVA) for within and between group effects., Results: Significant differences were found between the groups following 3 weeks for all the variables. Experimental group demonstrated reduced anxiety ( p  < 0.001) and improved sleep ( p  < 0.001) along with improvements in blood pressure and pulse rate. The control group did not show any significant changes following 3 weeks., Conclusion: CM could be incorporated as a routine for sailors to manage their anxiety and improve sleep quality during the period on board ships., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Paranthatta, George, Vinaya, Swathi, Pandey, Pradhan, Babu and Saoji.)

Introduction: HER2, a tyrosine kinase receptor, is amplified in HER2-positive breast cancer, driving cell signaling and growth. Aim: This study aimed to combat multidrug resistance in Dox-insensitive breast adenocarcinoma by creating a nanoformulation therapy with a tyrosine kinase inhibitor. Methodology: Human serum albumin (HSA) was conjugated with α-D-tocopherol succinate to form nanoaggregates loaded with lapatinib (Lapa). Results: The resulting Lapa@HSA(VE) NPs were 117.2 nm in size and demonstrated IC50 values of 10.25 μg/ml on MCF7 (S) and 8.02 μg/ml on MCF7 (R) cell lines. Conclusion: Lapa@HSA(VE) NPs showed no hepatotoxicity, unlike free Lapa, as seen in acute toxicity studies in rats.

Nowadays, Nanoparticle-based immunotherapeutic research has invoked global interest due to their unique properties. The immune system is a shielding structure that defends living things from external threats. Before the use of any materials in drug design, it is essential to study the immunological response to avoid triggering undesirable immune responses in the body. This review tries to summarize the properties, various applications, and immunotherapeutic aspects of NP-induced immunomodulation relating to therapeutic development and toxicity in human health. The role of NPs in the immune system and their modulatory functions, resulting in immunosuppression or immunostimulation, exerts benefits or dangers depending on their compositions, sizes, surface chemistry, and so forth. After NPs enter into the body, they can interact with body fluid exposing, them to different body proteins to form protein corona particles and other bio-molecules (DNA, RNA, sugars, etc.), which may alter their bioactivity. Phagocytes are the first immune cells that can interact with foreign materials including nanoparticles. Immunostimulation and immunosuppression operate in two distinct manners. Overall, functionalized nanocarriers optimized various therapeutic implications by stimulating the host immune system and regulating the tranquility of the host immune system. Among others, toxicity and bio-clearance of nanomaterials are always prime concerns at the preclinical and clinical stages before final approval. The interaction of nanoparticles with immune cells causes direct cell damage via apoptosis and necroses as well as immune signaling pathways also become influenced., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The metal intoxication and its associated adverse effects to humans have led to the research for development of water treatment technologies from pollution hazards. Therefore, development of cheaper water remediation technologies is more urgent than ever. Clays and clay minerals are naturally occurring, inexpensive, non-toxic materials possessing interesting chemical and physical properties. As a result of interesting surface properties, these have been developed as efficient absorbent in water remediation. Recently, clay-polymer nanocomposites have provided a cost-effective technological platform for removing contaminants from water. Covering research advancements from past 25 years, this review highlights the developments in clay-polymer nanocomposites and their advanced technical applications are evaluated with respect to the background and issues in remediation of toxic metals and organic compounds from water. The extensive analysis of literature survey of more than two decades suggests that future work need to highlight on advancement of green and cost-effective technologies. The development of understanding of the interaction and exchange between toxin and clay-polymer composites would provide new assembly methods of nanocomposites with functional molecules or nanomaterials need to be extended to increase the detection and extraction limit to parts per trillion., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Herein we report the design and synthesis of a series of fully-substituted 4-(trifluoromethyl)isoxazoles and evaluation of their anti-cancer activities against MCF-7, 4T1 and PC-3 cell lines as a proof of concept study. 4-(Trifluoromethyl)isoxazole is a synthetically challenging class of molecules and very few synthetic methods have been developed so far and all of them suffered from several serious limitations. Recently we developed a novel, metal-free, and general synthetic strategy to access synthetically challenging 4-(trifluoromethyl)isoxazoles starting from readily available chalcones using cheap CF 3 SO 2 Na as the source of the -CF 3 group and multitasking t BuONO as an oxidant as well as the source of N and O and thus we have overcome the limitations of the previous methods. Based on the structure of an isoxazole-based anti-cancer agent, 3-(3,4-dimethoxyphenyl)-5-(thiophen-2-yl)isoxazole 14, we designed a set of 4-(trifluoromethyl)isoxazoles for synthesis and further anti-cancer evaluation. Among various molecules, 3-(3,4-dimethoxyphenyl)-5-(thiophen-2-yl)-4-(trifluoromethyl)isoxazole 2g (IC 50 = 2.63 μM) and 3-(thiophen-2-yl)-5-(4-(thiophen-2-yl)-1 H -pyrrol-3-yl)-4-(trifluoromethyl)isoxazole 5 (IC 50 = 3.09 μM) exhibited the best anti-cancer activity against the human breast cancer cell-lines (MCF-7), 2g being the lead molecule among all. Interestingly, 2g is found to be almost 8 times more active compared to its non-trifluoromethylated analogue, i.e. , 3-(3,4-dimethoxyphenyl)-5-(thiophen-2-yl)isoxazole 14 (IC 50 = 19.72 μM) which revealed the importance of a 'CF 3 ' moiety in enhancing the anti-cancer activity of 14. Further studies such as apoptosis induction, cell cycle analysis, and nuclear staining revealed an apoptotic cell death mechanism. The in silico molecular docking, induced fit analysis, and ADME studies further supported the effect of a -CF 3 moiety on the enhancement of anti-cancer activity of isoxazole-based anti-cancer molecules. Further exploration of the biodistribution and therapeutic efficacy of lead 2g in vivo holds significant promise, positioning it as a potential candidate for anticancer therapy., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Amidst the Zn 2+ -dependant isoforms of the HDAC family, HDAC6 has emerged as a potential target associated with an array of diseases, especially cancer and neuronal disorders like Rett's Syndrome, Alzheimer's disease, Huntington's disease, etc. Also, despite the availability of a handful of HDAC inhibitors in the market, their non-selective nature has restricted their use in different disease conditions. In this situation, the development of selective and potent HDAC6 inhibitors will provide efficacious therapeutic agents to treat different diseases. In this context, this study has been carried out to evaluate the potential structural contributors of quinazoline-cap-containing HDAC6 inhibitors via machine learning (ML), conventional classification-dependant QSAR, and MD simulation-based binding mode of interaction analysis toward HDAC6 binding. This combined conventional and modern molecular modeling study has revealed the significance of the quinazoline moiety, substitutions present at the quinazoline cap group, as well as the importance of molecular property, number of hydrogen bond donor-acceptor functions, carbon-chlorine distance that significantly affects the HDAC6 binding of these inhibitors, subsequently affecting their potency . Interestingly, the study also revealed that the substitutions such as the chloroethyl group, and bulky quinazolinyl cap group can affect the binding of the cap function with the amino acid residues present in the loops proximal to the catalytic site of HDAC6. Such contributions of cap groups can lead to both stabilization and destabilization of the cap function after occupying the hydrophobic catalytic site by the aryl hydroxamate linker-ZBG functions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that can influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Bleeding causes ∼5.8 million deaths globally; half of the patients die if rapid hemostasis is not achieved. Here, we report a chitosan-casein (CC)-based nanofibrous polyelectrolyte complex (PEC) that could clot blood within 10 s in the rat femoral artery model in vivo. The nanofiber formation by self-assembly was also optimized for process parameters (concentration, mixing ratio, pH, and ultrasonication). Results showed that increasing the concentration of chitosan from 10 % to 90 % in the formulation increased the productivity (r = 0.99) of PECs but led to increased blood clotting time (r = 0.90) due to an increase in zeta potential (r = 0.98), fiber diameter (r = 0.93), and decreased surface porosity (r = -0.99), absorption capacity (r = -0.99). The pH also influenced the zeta potential of PEC, with an optimized pH of 8.0 ± 0.1 yielding clear nanofibers. Sonication improved the segregation of nanofibers by promoting water removal. The optimized PECs containing chitosan and casein in the ratio of 30:70 (CC30) at a pH of 8.0 and dehydration under sonication could clot the blood within 9 ± 2 s in vitro and 9 ± 2 s in rat femoral artery puncture model. The CC30 formulation did not cause any irritation or corrosion on rat skin. Histopathology and immunohistochemistry of various organs showed that CC30 was biocompatible and non-immunogenic under in vivo conditions., Competing Interests: Declaration of competing interest BM, DP, and MKG declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. DV holds a patent related to this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Photodynamic Therapy (PDT) is a promising paradigm for treating cancer, especially superficial cancers, including skin and oral cancers. However, the effectiveness of PDT is hindered by the hydrophobicity of photosensitizers. Here, chlorin e6 (Ce6), a hydrophobic photosensitizer, was loaded into pluronic F127 micelles to enhance solubility and improve tumor-specific targeting efficiency. The resulting Ce6@F127 Ms demonstrated a significant increase in solubility and singlet oxygen generation (SOG) efficiency in aqueous media compared to free Ce6. The confocal imaging and fluorescence-activated cell sorting (FACS) analysis confirmed the enhanced internalization rate of Ce6@F127 Ms in murine melanoma cell lines (B16F10) and human oral carcinoma cell lines (FaDu). Upon laser irradiation (666 nm), the cellular phototoxicity of Ce6@F127 Ms against B16F10 and FaDu was approximately three times higher than the free Ce6 treatment. The in vivo therapeutic investigations conducted on a murine model of skin cancer demonstrated the ability of Ce6@F127 Ms, when combined with laser treatment, to penetrate solid tumors effectively, which resulted in a significant reduction in tumor volume compared to free Ce6. Further, the Ce6@F127 Ms demonstrated upregulation of TUNEL-positive cells, downregulation of proliferation markers in tumor tissues, and prevention of lung metastasis with insignificant levels of proliferating cells and collagenase, as validated through immunohistochemistry. Subsequent analysis of serum and blood components affirmed the safety and efficacy of Ce6@F127 Ms in mice. Consequently, the developed Ce6@F127 Ms exhibits significant potential for concurrently treating solid tumors and preventing metastasis. The photodynamic formulation holds great clinical translation potential for treating superficial tumors., (© 2024. Controlled Release Society.)

Interleukin-1-beta (IL-1β) one of the biomarkers for oral squamous cell carcinoma (OSCC), is upregulated in tumor-microenvironment (TME) and associated with poor patient survival. Thus, a novel modulator of IL-1β would be of great therapeutic value for OSCC treatment. Here we report regulation of IL-1β and TME by histone deacetylase-6 (HDAC6)-inhibitor in OSCC. We observed significant upregulation of HDAC6 in 4-nitroquniline (4-NQO)-induced OSCC in mice and 4-NQO & Lipopolysaccharide (LPS) stimulated OSCC and fibroblast cells. Tubastatin A (TSA)-attenuated the OSCC progression in mice as observed improvement in the histology over tongue and esophagus, with reduced tumor burden. TSA treatment to 4-NQO mice attenuated protein expression of HDAC6, pro-and-mature-IL-1β and pro-and-cleaved-caspase-1 and ameliorated acetylated-tubulin. In support of our experimental work, human TCGA analysis revealed HDAC6 and IL-1β were upregulated in the primary tumor, with different tumor stages and grades. We found TSA modulate TME, indicated by downregulation of CD11b + Gr1 + -Myeloid-derived suppressor cells, CD11b + F4/80 + CD206 + M2-macrophages and increase in CD11b + F4/80 + MHCII + M1-macrophages. TSA significantly reduced the gene expression of HDAC6, IL-1β, Arginase-1 and iNOS in isolated splenic-MDSCs. FaDu-HTB-43 and NIH3T3 cells stimulated with LPS and 4-NQO exhibit higher IL-1β levels in the supernatant. Interestingly, immunoblot analysis of the cell lysate, we observed that TSA does not alter the expression as well as activation of IL-1β and caspase-1 but the acetylated-tubulin was found to be increased. Nocodazole pre-treatment proved that TSA inhibited the lysosomal exocytosis of IL-1β through tubulin acetylation. In conclusion, HDAC6 inhibitors attenuated TME and cancer progression through the regulation of IL-1β in OSCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

DNA methyl transferases (DNMTs) are one of the crucial epigenetic modulators associated with a wide variety of cancer conditions. Among the DNMT isoforms, DNMT1 is correlated with bladder, pancreatic, and breast cancer, as well as acute myeloid leukemia and esophagus squamous cell carcinoma. Therefore, the inhibition of DNMT1 could be an attractive target for combating cancers and other metabolic disorders. The disadvantages of the existing nucleoside and non-nucleoside DNMT1 inhibitors are the main motive for the discovery of novel promising inhibitors. Here, pharmacophore modeling, 3D-QSAR, and e-pharmacophore modeling of DNMT1 inhibitors were performed for the large fragment database screening. The resulting fragments with high dock scores were combined into molecules. The current study revealed several constitutional pharmacophoric features that can be essential for selective DNMT1 inhibition. The fragment docking and virtual screening identified 10 final hit molecules that exhibited good binding affinities in terms of docking score, binding free energies, and acceptable ADME properties. Also, the modified lead molecules (GL1b and GL2b) designed in this study showed effective binding with DNMT1 confirmed by their docking scores, binding free energies, 3D-QSAR predicted activities and acceptable drug-like properties. The MD simulation studies also suggested that leads (GL1b and GL2b) formed stable complexes with DNMT1. Therefore, the findings of this study can provide effective information for the development/identification of novel DNMT1 inhibitors as effective anticancer agents., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Bacterial keratitis (BK) causes visual morbidity/blindness if not treated effectively. Here, ciprofloxacin (CIP)-loaded nanoparticles (NPs) using glycol chitosan (GC) and poly(lactic acid) (PLA) conjugate at three different ratios (CIP@GC(PLA) NPs (1:1,5,15)) were fabricated. CIP@GC(PLA) NPs (1:1) were more effective than other tested ratios, indicating the importance of optimal hydrophobic/hydrophilic balance for corneal penetration and preventing bacterial invasion. The CIP@GC(PLA) (NPs) (1:1) realized the highest association with human corneal epithelial cells, which were nonirritant to the hen's egg-chorioallantoic membrane test (HET-CAM test) and demonstrated significant antibacterial response in the in vitro minimum inhibitory, bactericidal, live-dead cells, zone of inhibition, and biofilm inhibition assays against the keratitis-inducing pathogen Pseudomonas aeruginosa . The antiquorum sensing activity of GC has been explored for the first time. The NPs disrupted the bacterial quorum sensing by inhibiting the production of virulence factors, including acyl homoserine lactones, pyocyanin, and motility, and caused significant downregulation of quorum sensing associated genes. In the in vivo studies, CIP@GC(PLA) NPs (1:1) displayed ocular retention in vivo (∼6 h) and decreased the opacity and the bacterial load effectively. Overall, the CIP@GC(PLA) NP (1:1) is a biofilm-disrupting antiquorum sensing treatment regimen with clinical translation potential in BK.

Mono or dual chitosan oligosaccharide lactate (COL)-conjugated pluronic F127 polymers, FCOL1 and FCOL2 were prepared, self-assembled to form micelles, and loaded with gatifloxacin. The Gati@FCOL1/Gati@FCOL2 micelles preparation process was optimized by QbD analysis. Micelles were characterized thoroughly for size, CMC, drug compatibility, and viscosity by GPC, DLS, SEM, IR, DSC, and XRD. The micelles exhibited good cellular uptake in both monolayers and spheroids of HCEC. The antibacterial and anti-biofilm activities of the micelles were evaluated on P. aeruginosa and S. aureus. The anti-quorum sensing activity was explored in P. aeruginosa by analyzing micelles' ability to produce virulence factors, including AHLs, pyocyanin, and the motility behavior of the organism. Gati@FCOL2 Ms was mucoadhesive, cornea-penetrant, antibacterial, and inhibited the biofilm formation by P. aeruginosa and S. aureus significantly more than Gati@FCOL1. A significant reduction in bacterial load in mice cornea was observed after Gati@FCOL2 Ms-treatment to the P. aeruginosa-induced bacterial keratitis-infected mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in the paper., (Copyright © 2024. Published by Elsevier Ltd.)

Carbon nanodots (CNDs), a fascinating carbon-based nanomaterial (typical size 2-10 nm) owing to their superior optical properties, high biocompatibility, and cell penetrability, have tremendous applications in different interdisciplinary fields. Here, in this Review, we first explore the superiority of CNDs over other nanomaterials in the biomedical, optoelectronics, analytical sensing, and photocatalysis domains. Beginning with synthesis, characterization, and purification techniques, we even address fundamental questions surrounding CNDs such as emission origin and excitation-dependent behavior. Then we explore recent advancements in their applications, focusing on biological/biomedical uses like specific organelle bioimaging, drug/gene delivery, biosensing, and photothermal therapy. In optoelectronics, we cover CND-based solar cells, perovskite solar cells, and their role in LEDs and WLEDs. Analytical sensing applications include the detection of metals, hazardous chemicals, and proteins. In catalysis, we examine roles in photocatalysis, CO 2 reduction, water splitting, stereospecific synthesis, and pollutant degradation. With this Review, we intend to further spark interest in CNDs and CND-based composites by highlighting their many benefits across a wide range of applications.

A mucoadhesive polyelectrolyte complex (PEC) nanoparticles were developed for ocular moxifloxacin (Mox) delivery in Bacterial Keratitis (BK). Moxifloxacin-loaded G/CG-Alg NPs were prepared by an amalgamation of cationic polymers (gelatin (G)/cationized gelatin (CG)), and anionic polymer (sodium alginate (Alg)) along with Mox respectively. Mox@CG-Alg NPs were characterized for physicochemical parameters such as particle size (DLS technique), morphology (SEM analysis), DSC, XRD, encapsulation efficiency, drug loading, mucoadhesive study (by texture analyzer), mucin turbidity, and viscosity assessment. The NPs uptake and toxicity of the formulation were analyzed in the Human Corneal Epithelial (HCE) cell line and an ocular irritation study was performed on the HET-CAM. The results indicated that the CG-Alg NPs, with optimal size (217.2 ± 4 nm) and polydispersity (0.22 ± 0.05), have shown high cellular uptake in monolayer and spheroids of HCE. The drug-loaded formulation displayed mucoadhesiveness, trans-corneal permeation, and sustained the release of the Mox. The anti-bacterial efficacy studied on planktonic bacteria/biofilms of P. aeruginosa and S. aureus (in vitro) indicated that the Mox@CG-Alg NPs displayed low MIC, higher zone of bacterial growth inhibition, and cell death compared to free Mox. A significant reduction of bacterial load was observed in the BK-induced mouse model., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2024. Published by Elsevier B.V.)

Delivery of therapeutic agents through contact lenses-like patches is a promising strategy to achieve significant bioavailability with negligible eye drainage. The present study investigates the preparation and 3D printing of mucoadhesive gelatin methacryloyl (GelMA)/chitosan methacryloyl (ChiMA) hydrogels to fabricate them as contact lens-like patches (CLP) loaded with antimicrobial peptide, S100A12 (AMP) for treating bacterial keratitis (BK). Extrusion technology is used to print the patches layer by layer to form a hemispherical scaffold suitable for eyewear, and 3D-printed CLP is crosslinked using Irgacure 2959 under UV light. The results from the in vivo experiment conducted on Pseudomonas aeruginosa-infected BK rabbit model after the treatment with AMP-loaded CLP have shown a significant decrease in bacterial load when plated for CFU. The newly developed delivery system containing AMP has great potential to overcome the treatment challenges of multidrug resistance (MDR) in bacteria and eliminate the frequent dosing associated with eye drops. The presence of chitosan in the formulation provides a synergetic effect on the AMP in disrupting bacterial biofilms. The ease of using 3D printing will open new avenues for optimizing the dosage depending on the severity of the BK in the patients, which can be used as personalized medicine., (© 2024 Wiley‐VCH GmbH.)

Chemical synthesis of the tetrasaccharide repeating unit of the O-specific polysaccharide from Enterobacter cloacae G3422 is reported. The synthesis of the target tetrasaccharide is achieved through a convergent [2 + 2]-block strategy. The conjugation ready target oligosaccharide is attractive for further glycoconjugate formation with a suitable aglycon. Synthesis of the challenging 6-deoxy-L-talose moiety is reported using two different approaches and the obvious difficulties are discussed.

The human immune defensesystem routinely expresses the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which is the most prevalent element for antitumor immunity. TRAIL associates with its death receptors (DRs), DR4 (TRAIL-R1), and DR5 (TRAIL-R2), in cancer cells to initiate the intracellular apoptosis cascade. Accordingly, numerous academic institutions and pharmaceutical companies havetried to exploreTRAIL's capacity to kill tumourcells by producing recombinant versions of it (rhTRAIL) or TRAIL receptor agonists (TRAs) [monoclonal antibody (mAb), synthetic and natural compounds, etc.] and molecules that sensitize TRAIL signalling pathway for therapeutic applications. Recently, several microRNAs (miRs) have been found to activate or inhibit death receptor signalling. Therefore, pharmacological regulation of these miRs may activate or resensitize the TRAIL DRs signal, and this is a novel approach for developing anticancer therapeutics. In this article, we will discuss TRAIL and its receptors and molecular pathways by which it induces various cell death events. We will unravel potential innovative applications of TRAIL-based therapeutics, and other investigated therapeutics targeting TRAIL-DRs and summarize the current preclinical pharmacological studies and clinical trials. Moreover, we will also emphasizea few situations where future efforts may be addressed to modulate the TRAIL signalling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study describes the localization and computational prediction of a binding site for the A 3 adenosine receptor (A 3 AR) positive allosteric modulator 2-cyclohexyl-1 H -imidazo[4,5-c]quinolin-4-(3,4-dichlorophenyl)amine (LUF6000). The work reveals an extrahelical lipid-facing binding pocket disparate from the orthosteric binding site that encompasses transmembrane domain (TMD) 1, TMD7, and Helix (H) 8, which was predicted by molecular modeling and validated by mutagenesis. According to the model, the nearly planar 1 H -imidazo[4,5-c]quinolinamine ring system lies parallel to the transmembrane segments, inserted into an aromatic cage formed by π-π stacking interactions with the side chains of Y284 7.55 in TMD7 and Y293 8.54 in H8 and by π-NH bonding between Y284 7.55 and the exocyclic amine. The 2-cyclohexyl group is positioned "upward" within a small hydrophobic subpocket created by residues in TMDs 1 and 7, while the 3,4-dichlorophenyl group extends toward the lipid interface. An H-bond between the N - 1 amine of the heterocycle and the carbonyl of G29 1.49 further stabilizes the interaction. Molecular dynamics simulations predicted two metastable intermediates, one resembling a pose determined by molecular docking and a second involving transient interactions with Y293 8.54 ; in simulations, each of these intermediates converges into the final bound state. Structure-activity-relationships for replacement of either of the identified exocyclic or endocyclic amines with heteroatoms lacking H-bond donating ability were consistent with the hypothetical pose. Thus, we characterized an allosteric pocket for 1 H -imidazo[4,5-c]quinolin-4-amines that is consistent with data generated by orthogonal methods, which will aid in the rational design of improved A 3 AR positive allosteric modulators. SIGNIFICANCE STATEMENT: Orthosteric A 3 AR agonists have advanced in clinical trials for inflammatory conditions, liver diseases, and cancer. Thus, the clinical appeal of selective receptor activation could extend to allosteric enhancers, which would induce site- and time-specific activation in the affected tissue. By identifying the allosteric site for known positive allosteric modulators, structure-based drug discovery modalities can be enabled to enhance the pharmacological properties of the 1 H -imidazo[4,5-c]quinolin-4-amine class of A 3 AR positive allosteric modulators., (U.S. Government work not protected by U.S. copyright.)

A series of new 2,5-disubstituted arylidene derivatives of thiazolidinedione ( 16a-e, 17a-d, 18a-c ) designed using molecular hybridization approach were synthesized, structurally characterized, and explored for their anti-obesity potential via inhibition of Pancreatic Lipase (PL). Compound 18a presented the most potent PL inhibitory activity with IC 50 = 2.71 ± 0.31 µM, as compared to the standard drug, Orlistat (IC 50 = 0.99 µM). Kinetic study revealed reversible competitive mode of enzyme inhibition by compound 18a with an inhibitory constant value of 1.19 µM. The most promising compound 18a revealed satisfactory binding mode within the active site of the target protein (human PL, PDB ID: 1LPB). Also, MM/PBSA binding free energy and molecular dynamics (MD) simulation analysis were performed for the most promising compound 18a , which showed potent inhibition according to the results of in vitro studies. Furthermore, a stable conformation of the 1LPB-ligand suggested the stability of this compound in the dynamic environment. The ADME and toxicity analysis of the compounds were examined using web-based online platforms. Results of in vivo studies confirmed the anti-obesity efficacy of compound 18a , wherein oral treatment with compound 18a (30 mg/kg) resulted in a significant reduction in the body weight, BMI, Lee index, feed intake (in Kcal), body fat depots and serum triglycerides. Compound 18a significantly decreased the levels of serum total cholesterol (TC) to 128.6 ± 0.59 mg/dl and serum total triglycerides (TG) to 95.73 ± 0.67 mg/dl as compared to the HFD control group. The present study identified disubstituted TZD derivatives as a new promising class of anti-obesity agents.Communicated by Ramaswamy H. Sarma.

Purpose: The aim of this study was to assess and compare the likelihood of relapse one year after LeFort I advancement surgery in patients with and without cleft lip and palate., Methods: A retrospective observational study which included two groups of participants who underwent LeFort I maxillary advancement was performed. Group 1 included 10 non-cleft subjects and Group 2 included 21 subjects with cleft palate. These maxillary deficient patients were chosen and operated using a technique where only a sagittal displacement was intended. Patients who underwent additional mandibular surgery, significant vertical or transverse alterations, or both were excluded. Pre-operative (T1), immediately post-operative (T2), and minimum one-year follow-up (T3) lateral cephalograms were studied for each group. Skeletal stability and dental stability after LeFort I surgery at a minimum of one-year follow-up in cleft palate and non-cleft patients were evaluated., Results: For the given sample size, relapse tendencies showed statistically significant differences between cleft palate patients and non-cleft palate patients after maxillary advancement. The sella nasion angle and horizontal overlap of the maxillary and mandibular incisors (overjet) decreased by 2 degrees and 0.9 mm respectively in the cleft palate group while decreasing by 1.10 degrees and 0.40 mm in the non-cleft group., Conclusions: After maxillary advancement with LeFort I osteotomy and miniplate fixation in patients with cleft palate and non-cleft patients, some degree of relapse was detected in both groups for the given sample size after one year post-operatively. The cleft palate group displayed additional relapse tendencies when compared to the non-cleft group., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Patil et al.)

Human meprin β is a Zn 2+ -containing multidomain metalloprotease enzyme that belongs to the astacin family of the metzincin endopeptidase superfamily. Meprin β, with its diverse tissue expression pattern and wide substrate specificity, plays a significant role in various biological processes, including regulation of IL-6R pathways, lung fibrosis, collagen deposition, cellular migration, neurotoxic amyloid β levels, and inflammation. Again, meprin β is involved in Alzheimer's disease, hyperkeratosis, glomerulonephritis, diabetic kidney injury, inflammatory bowel disease, and cancer. Despite a crucial role in diverse disease processes, no such promising inhibitors of meprin β are marketed to date. Thus, it is an unmet requirement to find novel promising meprin β inhibitors that hold promise as potential therapeutics. In this study, a series of arylsulfonamide and tertiary amine-based hydroxamate derivatives as meprin β inhibitors has been analyzed through ligand-based and structure-based in silico approaches to pinpoint their structural and physiochemical requirements crucial for exerting higher inhibitory potential. This study identified different crucial structural features such as arylcarboxylic acid, sulfonamide, and arylsulfonamide moieties, as well as hydrogen bond donor and hydrophobicity, inevitable for exerting higher meprin β inhibition, providing valuable insight for their further future development.Communicated by Ramaswamy H. Sarma.

Nanomedicines have emerged as a potential strategy to reduce the toxic effect of drugs administered via conventional approaches. Nanomedicines undergo passive and active targeting of the tumor tissues, thereby causing localized drug delivery and reducing drug demand and side effects. Here, we prepared reduction-sensitive oxaliplatin-conjugated human serum albumin nanoparticles with a small size, uniform surfaces, and a satisfactory encapsulation coefficient. The findings of cellular studies demonstrate that utilizing human serum albumin is effective for active tumor targeting. The presence of glutathione-sensitive disulfide linkers in the crosslinking agent and between Pt(IV) and HSA provided dual reduction sensitivity. Cytotoxicity and cell death were enhanced compared to free Oxaliplatin. The outcomes demonstrate that the approach maximized Oxaliplatin's ability to control tumor growth, induced apoptosis, and reduced drug resistance. Therefore, for the first time, our results imply that OXA-SS-HSA NPs were biocompatible, smart, and effective anticancer nanomedicine for triple-negative breast cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Angiogenesis is mediated by the vascular endothelial growth factor (VEGF) that plays a key role in the modulation of progression, invasion and metastasis, related to solid tumors and hematological malignancies. Several small-molecule VEGFR-2 inhibitors are marketed, but their usage is restricted to specific cancers due to severe toxicities. Therefore, cost-effective novel small molecule VEGFR-2 inhibitors may be an alternative to overcome these adverse effects. Here, a set of thiourea-based VEGFR-2 inhibitors were considered for a combined fragment-based QSAR technique, structure-based molecular docking followed by molecular dynamics simulation studies to acquire insights into the key structural attributes and the binding pattern of enzyme-ligand interactions. Noticeably, amine-substituted quinazoline phenyl ring and a higher number of nitrogen atoms, and the hydrazide function in the molecular structure are crucial for VEGFR-2 inhibition whereas methoxy groups are detrimental to VEGFR-2 inhibition. The MD simulation study of sorafenib and thiourea derivatives explored the significance of urea and thiourea moiety binding at VEGFR-2 active site that can be utilized further in the future to design molecules for greater binding stability and better VEGFR-2 selectivity. Therefore, such findings can be beneficial for the development of newer VEGFR-2 inhibitors for further refinement to acquire better therapeutic efficacy.Communicated by Ramaswamy H. Sarma.

Matrix metalloproteinases (MMPs) are belonging to the Zn 2+ -dependent metalloenzymes. These can degenerate the extracellular matrix (ECM) that is entailed with various biological processes. Among the MMP family members, MMP-9 is associated with several pathophysiological circumstances. Apart from wound healing, remodeling of bone, inflammatory mechanisms, and rheumatoid arthritis, MMP-9 has also significant roles in tumor invasion and metastasis. Therefore, MMP-9 has been in the spotlight of anticancer drug discovery programs for more than a decade. In this present study, classification-based QSAR techniques along with fragment-based data mining have been carried out on divergent MMP-9 inhibitors to point out the important structural attributes. This current study may be able to elucidate the importance of several pivotal molecular fragments such as sulfonamide, hydroxamate, i-butyl, and ethoxy functions for imparting potential MMP-9 inhibition. These observations are in correlation with the ligand-bound co-crystal structures of MMP-9. Therefore, these findings are beneficial for the design and discovery of effective MMP-9 inhibitors in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)