Exploring ncRNA-mediated pathways in sepsis-induced pyroptosis.

Sepsis, a potentially fatal illness caused by an improper host response to infection, remains a serious problem in the world of healthcare. In recent years, the role of ncRNA has emerged as a pivotal aspect in the intricate landscape of cellular regulation. The exploration of ncRNA-mediated regulatory networks reveals their profound influence on key molecular pathways orchestrating pyroptotic responses during septic conditions. Through a comprehensive analysis of current literature, we navigate the diverse classes of ncRNAs, including miRNAs, lncRNAs, and circRNAs, elucidating their roles as both facilitators and inhibitors in the modulation of pyroptotic processes. Furthermore, we highlight the potential diagnostic and therapeutic implications of targeting these ncRNAs in the context of sepsis, aiming to cover the method for novel and effective strategies to mitigate the devastating consequences of septic pathogenesis. As we unravel the complexities of this regulatory axis, a deeper understanding of the intricate crosstalk between ncRNAs and pyroptosis emerges, offering promising avenues for advancing our approach to sepsis intervention. The intricate pathophysiology of sepsis is examined in this review, which explores the dynamic interaction between ncRNAs and pyroptosis, a highly regulated kind of programmed cell death.

Synthesis of novel (R)-carvone-tagged thiazolidinone as anticancer leads: characterization, in vitro antiproliferative evaluation and in silico studies.

This work describes the successful synthesis of a series of three novel thiazolidinone-carvone-O-alkyl hybrids through a two-step approach involving heterocyclization and O-alkylation reactions. Comprehensive structural characterization of the obtained products was achieved using NMR and HRMS spectroscopic techniques. This study assessed in vitro antiproliferative activity of synthesized thiazolidinone-carvone-O-alkyl hybrids (5a-c) against various human cancer cell lines, viz. HT-1080 (fibrosarcoma), A-549 (lung cancer), MCF-7 (breast cancer) and MDA-MB-231 (breast cancer). MTT assay revealed promising results for compounds 5b and 5c, demonstrating good antiproliferative activity against A-549 and MCF-7 cell lines comparable to the positive control, Doxorubicin. Compound 5a, harbouring an O-acetoxy group, displayed limited anticancer activity against MCF-7 and MDA-MB-231 cells, with IC50 values of 69.33 ± 0.42 µM and >100 µM, respectively. Docking results confirmed that the compounds 5a-c binds at the active site of p21 with docking scores -2.0, -4.8, and -7.0 kcal/mol, respectively. Compound 5a-c also showed good binding potential against Bcl2 protein with docking score of -4.9, -6.0, -5.5 kcal/mol, respectively. Furthermore, binding energy analysis and dynamics simulation studies of compounds towards p21 and Bcl2 yielded promising results. In PAK4 assay, compound 5c showed comparable potency (IC50 6.76 µM) with the standard control UC2288 (IC50 6.40 µM), while in BCL-2 TR-FRET assay, 5c exhibited good inhibition (IC50 1.78 µM) as compared to Venetoclax (IC50 0.016 µM). In conclusion, compounds 5a-c could be used as a structural framework for the discovery of novel therapeutics to combat different types of cancer.Communicated by Ramaswamy H. Sarma.

The hidden threat: Environmental toxins and their effects on gut microbiota.

The human gut microbiota (GM), which consists of a complex and diverse ecosystem of bacteria, plays a vital role in overall wellness. However, the delicate balance of this intricate system is being compromised by the widespread presence of environmental toxins. The intricate connection between contaminants in the environment and human well-being has garnered significant attention in recent times. Although many environmental pollutants and their toxicity have been identified and studied in laboratory settings and animal models, there is insufficient data concerning their relevance to human physiology. Consequently, research on the toxicity of environmental toxins in GM has gained prominence in recent years. Various factors, such as air pollution, chemicals, heavy metals, and pesticides, have a detrimental impact on the composition and functioning of the GM. This comprehensive review aims to comprehend the toxic effects of numerous environmental pollutants, including antibiotics, endocrine-disrupting chemicals, heavy metals, and pesticides, on GM by examining recent research findings. The current analysis concludes that different types of environmental toxins can lead to GM dysbiosis and have various potential adverse effects on the well-being of animals. We investigate the alterations to the GM composition induced by contaminants and their impact on overall well-being, providing a fresh perspective on research related to pollutant exposure.

Design, synthesis, molecular docking, and in vitro studies of 2-mercaptoquinazolin-4(3H)-ones as potential anti-breast cancer agents.

Triple-negative breast cancer (TNBC) comprises 10 % to 20 % of breast cancer, however, it is more dangerous than other types of breast cancer, because it lacks druggable targets, such as the estrogen receptors (ER) and the progesterone receptor (PR), and has under expressed receptor tyrosine kinase, ErbB2. Present targeted therapies are not very effective and other choices include invasive procedures like surgery or less invasive ones like radiotherapy and chemotherapy. This study investigated the potential anticancer activity of some novel quinazolinone derivatives that were designed on the structural framework of two approved anticancer drugs, Ispinesib (KSP inhibitor) and Idelalisib (PI3Kδ inhibitor), to find out solutions for TNBC. All the designed derivatives (3a-l) were subjected to extra precision molecular docking and were synthesized and spectrally characterized. In vitro enzyme inhibition assay of compounds (3a, 3b, 3e, 3 g and 3 h) revealed their nanomolar inhibitory potential against the anticancer targets, KSP and PI3Kδ. Using MTT assay, the cytotoxic potential of compounds 3a, 3b and 3e were found highest against MDA-MB-231 cells with an IC50 of 14.51 µM, 16.27 µM, and 9.97 µM, respectively. Remarkably, these compounds were recorded safe against the oral epithelial normal cells with an IC50 values of 293.60 µM, 261.43 µM, and 222 µM, respectively. The anticancer potential of these compounds against MDA-MB-231 cells was revealed to be associated with their apoptotic activity. This was established by examination with the inverted microscope that revealed the appearance of various apoptotic features like cell shrinkage, apoptotic bodies, and membrane blebbing. Using flow cytometry, the Annexin V/PI-stained cancer cells showed an increase in early and late apoptotic cells. In addition, DNA fragmentation was revealed to occur after treatment with the tested compounds by gel electrophoresis. The relative gene expression of pro-apoptotic and anti-apoptotic genes revealed an overexpression of the P53 and BAX genes and a downregulation of the BCL-2 gene by real-time PCR. So, this work proved that compounds 3a, 3b, and 3e could be developed as anticancer candidates, via their P53-dependent apoptotic activity.

Novel 2-Sulfanylquinazolin-4(3H)-one Derivatives as Multi-Kinase Inhibitors and Apoptosis Inducers: A Synthesis, Biological Evaluation, and Molecular Docking Study.

The discovery of multi-targeted kinase inhibitors emerged as a potential strategy in the therapy of multi-genic diseases, such as cancer, that cannot be effectively treated by modulating a single biological function or pathway. The current work presents an extension of our effort to design and synthesize a series of new quinazolin-4-one derivatives based on their established anti-cancer activities as inhibitors of multiple protein kinases. The cytotoxicity of the new derivatives was evaluated against a normal human cell line (WI-38) and four cancer lines, including HepG2, MCF-7, MDA-231, and HeLa. The most active compound, 5d, showed broad-spectrum anti-cancer activities against all tested cell lines (IC50 = 1.94-7.1 µM) in comparison to doxorubicin (IC50 = 3.18-5.57 µM). Interestingly, compound 5d exhibited lower toxicity in the normal WI-38 cells (IC50 = 40.85 µM) than doxorubicin (IC50 = 6.72 µM), indicating a good safety profile. Additionally, the potential of compound 5d as a multi-targeted kinase inhibitor was examined against different protein kinases, including VEGFR2, EGFR, HER2, and CDK2. In comparison to the corresponding positive controls, compound 5d exhibited comparable activities in nanomolar ranges against HER2, EGFR, and VEGFR2. However, compound 5d was the least active against CDK2 (2.097 ± 0.126 µM) when compared to the positive control roscovitine (0.32 ± 0.019 µM). The apoptotic activity investigation in HepG2 cells demonstrated that compound 5d arrested the cell cycle at the S phase and induced early and late apoptosis. Furthermore, the results demonstrated that the apoptosis pathway was provoked due to an upregulation in the expression of the proapoptotic genes caspase-3, caspase-9, and Bax and the downregulation of the Bcl-2 anti-apoptotic gene. For the in silico docking studies, compound 5d showed relative binding interactions, including hydrogen, hydrophobic, and halogen bindings, with protein kinases that are similar to the reference inhibitors.

Mechanisms of cancer cell death induction by triptolide.

Drug resistance is a hot topic issue in cancer research and therapy. Although cancer therapy including radiotherapy and anti-cancer drugs can kill malignant cells within the tumor, cancer cells can develop a wide range of mechanisms to resist the toxic effects of anti-cancer agents. Cancer cells may provide some mechanisms to resist oxidative stress and escape from apoptosis and attack by the immune system. Furthermore, cancer cells may resist senescence, pyroptosis, ferroptosis, necroptosis, and autophagic cell death by modulating several critical genes. The development of these mechanisms leads to resistance to anti-cancer drugs and also radiotherapy. Resistance to therapy can increase mortality and reduce survival following cancer therapy. Thus, overcoming mechanisms of resistance to cell death in malignant cells can facilitate tumor elimination and increase the efficiency of anti-cancer therapy. Natural-derived molecules are intriguing agents that may be suggested to be used as an adjuvant in combination with other anticancer drugs or radiotherapy to sensitize cancer cells to therapy with at least side effects. This paper aims to review the potential of triptolide for inducing various types of cell death in cancer cells. We review the induction or resistance to different cell death mechanisms such as apoptosis, autophagic cell death, senescence, pyroptosis, ferroptosis, and necrosis following the administration of triptolide. We also review the safety and future perspectives for triptolide and its derivatives in experimental and human studies. The anticancer potential of triptolide and its derivatives may make them effective adjuvants for enhancing tumor suppression in combination with anticancer therapy.

Baicalin-Loaded Lipid-Polymer Hybrid Nanoparticles Inhibiting the Proliferation of Human Colon Cancer: Pharmacokinetics and In Vivo Evaluation.

This research work is focused on pharmacokinetic and biochemical experiments to assess baicalin-loaded lipid-polymer hybrid nanoparticles (LPHNPs) with colon-targeting specificity. The nanoprecipitation method was used to develop the LPHNPs, and the characterized formulation revealed the 184.3 nm particle size, PDI of 0.177, spherical shape, and zeta potential of -19.8 mV. The baicalin LPHNPs are said to be poorly absorbed in the stomach and small intestine, and in vitro drug release tests have shown that the drug is released mostly in the caecal fluid. Additionally, the LPHNPs showed stability and nonsignificant drug loss at 25 °C for 3 months. The least viable population of baicalin-loaded LPHNPs was detected at a lower IC50 value after 48 h, and no cytotoxicity was observed by blank suspension and blank LPHNPs up to the concentration of 100 µg/mL. Apart from this, the pharmacokinetics study showed that baicalin from LPHNPs is much less absorbed and least available in the blood plasma and maximum available in the colon. Concurrently, organ distribution studies demonstrated that baicalin-loaded LPHNPs were distributed more widely in the colon compared to baicalin suspension. Moreover, baicalin-loaded LPHNPs were found to be superior to a baicalin suspension in reducing elevated liver enzyme levels. In a nutshell, baicalin-loaded LPHNPs show superior efficacy and can be maximally localized into the colon rectal cancer along with systemic availability of the drug.

An in silico quest for next-generation antimalarial drugs by targeting Plasmodium falciparum hexose transporter protein: a multi-pronged approach.

The emergence of artemisinin resistance by malaria parasites is a major challenge in the fight against malaria, thus posing serious threat to the public health across the world. To tackle this, antimalarial drugs with unconventional mechanisms are therefore urgently needed. It has been reported that selective starvation of Plasmodium falciparum by blocking the function of hexose transporter 1 (PfHT1) protein, the only known transporter for glucose uptake in P. falciparum, could provide an alternative approach to fight the drug resistant malaria parasites. In this study, three high affinity molecules (BBB_25784317, BBB_26580136 and BBB_26580144) that have shown the best docked conformation and least binding energy with PfHT1 were shortlisted. The docking energy of BBB_25784317, BBB_26580136 and BBB_26580144 with PfHT1 were -12.5, -12.1 and -12.0 kcal/mol, respectively. In the follow up simulation studies, the protein 3D structure maintains considerable stability in the presence of the compounds. It was also observed that the compounds produced a number of hydrophilic and hydrophobic interactions with the protein allosteric site residues. This demonstrates strong intermolecular interaction guided by close distance hydrogen bonds of compounds with Ser45, Asn48, Thr49, Asn52, Ser317, Asn318, Ile330 and Ser334. Revalidation of compounds binding affinity was conducted by more appropriate simulation based binding free energy techniques (MM-GB/PBSA and WaterSwap). Additionally, entropy assay was performed that further strengthen the predictions. In silico pharmacokinetics confirmed that the compounds would be suitable candidates for oral delivery due to their high gastrointestinal absorption and less toxic reaction. Overall, the predicted compounds are promising and could be further sought as antimalarial leads and subjected to thorough experimental investigations.Communicated by Ramaswamy H. Sarma.

High efficiency of Ag0 decorated Cu2MoO4 nanoparticles for heterogeneous photocatalytic activation, bactericidal system, and detection of glucose from blood sample.

The novel Ag0/Cu2MoO4 nanoparticles was simply synthesized via chemical method. Ag/Cu2MoO4 nanoparticles was characterized by FESEM image, XRD curve, UV-vis spectroscopy, BET analysis, and XPS spectrum. XRD pattern depicts that the cubic crystalline phase of particles. The band gap of Ag/Cu2MoO4 nanoparticles was achieved to 2.04 eV, which that depicted the best activity under visible light irradiation. Ag/Cu2MoO4 nanoparticles exhibits 99.74% degradation under light and persulfate ion which was higher response than Cu2MoO4 nanoparticles (83.56%) under this condition. The scavenging test indicates the important reactive species in removal process were •OH, and •SO4-. The Ag/Cu2MoO4 nanoparticles was indicated highly photo-stability for the MG degradation after 5th cycle. Ag/Cu2MoO4 exhibits substantial antibacterial properties against P. aeruginosa and S. pneumoniae. Moreover, Ag/Cu2MoO4 nanoparticles was experimented to peroxidase-like performance for the colorimetric detection of glucose with the Limit of Detection about 52.23 nM.

Apigenin Loaded Lipoid-PLGA-TPGS Nanoparticles for Colon Cancer Therapy: Characterization, Sustained Release, Cytotoxicity, and Apoptosis Pathways.

Colon cancer (CC) is one of major causes of mortality and affects the socio-economic status world-wide. Therefore, developing a novel and efficient delivery system is needed for CC management. Thus, in the present study, lipid polymer hybrid nanoparticles of apigenin (LPHyNPs) was prepared and characterized on various parameters such as particle size (234.80 ± 12.28 nm), PDI (0.11 ± 0.04), zeta potential (−5.15 ± 0.70 mV), EE (55.18 ± 3.61%), etc. Additionally, the DSC, XRD, and FT-IR analysis determined drug entrapment and affinity with the selected excipient, demonstrating a promising drug affinity with the lipid polymer. Morphological analysis via SEM and TEM exhibited spherical NPs with a dark color core, which indicated drug entrapment inside the core. In vitro release study showed significant (p < 0.05) sustained release of AGN from LPHyNPs than AGN suspension. Further, the therapeutic efficacy in terms of apoptosis and cell cycle arrest of developed LPHyNPs against CC was estimated by performing flow cytometry and comparing its effectiveness with blank LPHyNPs and AGN suspension, which exhibited remarkable outcomes in favor of LPHyNPs. Moreover, the mechanism behind the anticancer attribute was further explored by estimating gene expression of various signaling molecules such as Bcl-2, BAX, NF-κB, and mTOR that were involved in carcinogenic pathways, which indicated significant (p < 0.05) results for LPHyNPs. Moreover, to strengthen the anticancer potential of LPHyNPs against chemoresistance, the expression of JNK and MDR-1 genes was estimated. Outcomes showed that their expression level reduced appreciably when compared to blank LPHyNPs and AGN suspension. Hence, it can be concluded that developed LPHyNPs could be an efficient therapeutic system for managing CC.

Amphotericin B-PEG Conjugates of ZnO Nanoparticles: Enhancement Antifungal Activity with Minimal Toxicity.

Amphotericin B (AMB) is commonly used to treat life-threatening systemic fungal infections. AMB formulations that are more efficient and less nephrotoxic are currently unmet needs. In the current study, new ZnO-PEGylated AMB (ZnO-AMB-PEG) nanoparticles (NPs) were synthesized and their antifungal effects on the Candida spp. were investigated. The size and zeta potential values of AMB-PEG and ZnO-AMB-PEG NPs were 216.2 ± 26.9 to 662.3 ± 24.7 nm and -11.8 ± 2.02 to -14.2 ± 0.94 mV, respectively. The FTIR, XRD, and EDX spectra indicated that the PEG-enclosed AMB was capped by ZnO, and SEM images revealed the ZnO distribution on the surface NPs. In comparison to ZnO-AMB NPs and free AMB against C.albicans and C.neoformans, ZnO-AMB-PEG NPs significantly reduced the MIC and MFC. After a week of single and multiple dosage, the toxicity was investigated utilizing in vitro blood hemolysis, in vivo nephrotoxicity, and hepatic functions. ZnO-AMB-PEG significantly lowered WBC count and hematocrit concentrations when compared to AMB and ZnO-AMB. RBC count and hemoglobulin content, on the other hand, were unaltered. ZnO-AMB-PEG considerably lowered creatinine and blood urea nitrogen (BUN) levels when compared to AMB and ZnO-AMB. The difference in liver function indicators was determined to be minor by all formulae. These findings imply that ZnO-AMB-PEG could be utilized in the clinic with little nephrotoxicity, although more research is needed to determine the formulation's in vivo efficacy.

Nanomagnetic macrocyclic Schiff-base-Mn(ii) complex: an efficient heterogeneous catalyst for click approach synthesis of novel ß-substitued-1,2,3-triazoles.

In the present work, a novel symmetrical 15-membered macrocyclic Schiff base complex of manganese was prepared using the reaction of the synthetic 2,6-diacetylpyridine functionalized Fe3O4 MNPs with 2,2-(piperazine-1,4-diyl)dianiline and Mn(ii) bromide salt via a template approach. The resulting [Fe3O4@PAM-Schiff-base-Mn][ClO4] heterogenized complex was characterized using FT-IR, XRD, BET, TGA, EDX, Xray-mapping, SEM, TEM and VSM analysis. To demonstrate proof of concept, Huisgen 1,3-dipolar cycloaddition synthesis of 1,2,3-triazoles was selected to evaluate the activity and reusability of the catalyst. The ethanol as a green solvent proved to be an excellent reaction medium for this synthesis. Yields of up to 100% were obtained in some cases. Significantly, as demonstrated, [Fe3O4@PAM-Schiff-base-Mn][ClO4] catalyst was recycled for 8 cycles without losing catalytic activity under the optimized reaction conditions. The hot filtration and ICP-OES tests ratified that there was no leaching of metal during the catalytic reaction, indicating the heterogeneous manner of the catalyst.

Recent highlights on Omicron as a new SARS-COVID-19 variant: evolution, genetic mutation, and future perspectives.

COVID-19 has affected the lives of billions of people and is a causative agent for millions of deaths. After 23 months of the first reported case of COVID-19, on 25th November 2020, a new SARS-COVID-19 variant, i.e. Omicron was reported with a WHO tagline of VoC that trembled the world with its infectivity rate. This fifth VoC raised the concern about neutralising ability and adequate control of SARS-COVID-19 infection due to mass vaccination drive (nearly more than 4.7 billion individuals got vaccinated globally till December 2021). However, the present scenario of VoCs highlights the importance of vaccination and public health measures that need to be followed strictly to prevent the fatality from Omicron. The world still needs to overcome the hesitancy that poses a major barrier to the implementation of vaccination. This review highlights the SARS-COVID-19 situation and discusses in detail the mutational events that occurred at a cellular level in different variants over time. This article is dedicated to the scientific findings reported during the recent outbreak of 2019-2022 and describes their symptoms, disease, spread, treatment, and preventive action advised. The article also focuses on the treatment options available for Covid-19 and the update of Omicron by expert agencies.

Stimuli-Responsive Microneedles as a Transdermal Drug Delivery System: A Demand-Supply Strategy.

Microneedles are one of the most prominent approaches capable of physically disrupting the stratum corneum without devastating the deeper tissues to deliver both small molecules and macromolecules into the viable epidermis/dermis for local/systemic effects. Over the past two decades, microneedles have caught the attention of many researchers because of their outstanding advantages over oral and parenteral drug delivery systems such as self-administration, pain-free, steady-plasma concentration maintenance, avoidance of first-pass hepatic biotransformation, and so on. So far, scientists have reported various types of microneedle patches to deliver the loaded therapeutics as soon as the microneedles are inserted into the skin, regardless of the demand for therapeutics to treat a specific condition. This way of drug delivery can lead to potential risks such as poor therapeutic efficacy or drug overdose. The stimuli-responsive microneedles are the most predominant tool to achieve the on-demand/need-based drug delivery, leading to safe and effective treatment. Various natural and synthetic polymers that can undergo significant transitions such as swelling, shrinking, dissolution, or disintegration play a pivotal role in the development of stimuli-responsive microneedles. The current Review provides brief information about the history, emergence, type, and working principles of microneedles. Furthermore, it selectively discusses various exogenous and endogenous stimuli-responsive microneedles along with their mechanism of action involved in treating different disease conditions. Collaterally, the emergence of "closed-loop" combinatorial stimuli-responsive microneedle patches for precise delivery of therapeutics is meticulously canvassed. Subsequently, it covers the patents of different stimuli-responsive microneedles and further highlights the existing challenges and future perspectives concerning clinical application and large-scale production.

Development and Evaluation of Ginkgo biloba/Sodium Alginate Nanocomplex Gel as a Long-Acting Formulation for Wound Healing.

The aim of the study was to develop and evaluate the Ginkgo biloba nanocomplex gel (GKNG) as a long-acting formulation for the wound healing potential. Pharmaceutical analysis showed an average particle size of 450.14 ± 36.06 nm for GKNG, zeta potential +0.012 ± 0.003 mV, and encapsulation efficiency 91 ± 1.8%. The rheological analysis also showed the optimum diffusion rate and viscosity needed for topical drug delivery. Fourier transform infrared spectroscopy (FTIR), powder X-ray diffractometry (PXRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) analysis further confirmed the success of GKNG. The in vivo study showed increments in the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) and a lower level of lipid peroxidation (MDA) after GKNG treatment. The GKNG group showed upregulations in collagen type I, as alpha 1 collagen (COL1A1), and collagen type IV, as alpha 1 collagen (COL4A1). Furthermore, the in vivo study showed increments in hydroxyproline, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and transforming growth factor-beta 1 (TGF-ß1) after the GKNG. Additionally, GKNG effectively increased the wound contraction compared to GK gel and sodium alginate (SA) gel. Based on the in vitro and in vivo evaluation, GKNG effectively accelerated wound healing by modulation of antioxidant enzymes, collagens, angiogenic factors, and TGF-ß1.

Novel and Potential Small Molecule Scaffolds as DYRK1A Inhibitors by Integrated Molecular Docking-Based Virtual Screening and Dynamics Simulation Study.

The dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a novel, promising and emerging biological target for therapeutic intervention in neurodegenerative diseases, especially in Alzheimer's disease (AD). The molMall database, comprising rare, diverse and unique compounds, was explored for molecular docking-based virtual screening against the DYRK1A protein, in order to find out potential inhibitors. Ligands exhibiting hydrogen bond interactions with key amino acid residues such as Ile165, Lys188 (catalytic), Glu239 (gk+1), Leu241 (gk+3), Ser242, Asn244, and Asp307, of the target protein, were considered potential ligands. Hydrogen bond interactions with Leu241 (gk+3) were considered key determinants for the selection. High scoring structures were also docked by Glide XP docking in the active sites of twelve DYRK1A related protein kinases, viz. DYRK1B, DYRK2, CDK5/p25, CK1, CLK1, CLK3, GSK3ß, MAPK2, MAPK10, PIM1, PKA, and PKCα, in order to find selective DYRK1A inhibitors. MM/GBSA binding free energies of selected ligand-protein complexes were also calculated in order to remove false positive hits. Physicochemical and pharmacokinetic properties of the selected six hit ligands were also computed and related with the proposed limits for orally active CNS drugs. The computational toxicity webserver ProTox-II was used to predict the toxicity profile of selected six hits (molmall IDs 9539, 11352, 15938, 19037, 21830 and 21878). The selected six docked ligand-protein systems were exposed to 100 ns molecular dynamics (MD) simulations to validate their mechanism of interactions and stability in the ATP pocket of human DYRK1A kinase. All six ligands were found to be stable in the ATP binding pocket of DYRK1A kinase.

Nanocarrier mediated drug delivery as an impeccable therapeutic approach against Alzheimer's disease.

For the past several years, dementia, is one of the predominantly observed groups of symptoms in a geriatric population. Alzheimer's disease (AD) is a progressive memory related neurodegenerative disease, for which the current Food and drug administration approved therapeutics are only meant for a symptomatic management rather than targeting the root cause of AD. These therapeutics belong to two classes, Acetylcholine Esterase inhibitors and N-methyl D-aspartate antagonist. Furthermore, to facilitate neuroprotective action in AD, the drugs are majorly expected to reach the specific target area in the brain for the desired efficacy. Thus, there is a huge requirement for drug discovery and development for facilitating the entry of drugs more in brain to exert a specific action. The very first line of defense and the major limitation for the entry of drugs into the brain is the Blood Brain Barrier, followed by Blood-Cerebrospinal Fluid Barrier. More than a barrier, these mainly act as selectively permeable membranes, which allows entry of specific molecules into the brain. Furthermore, specific enzymes result in the degradation of xenobiotics. All these mechanisms pose as hurdles in the way of effective drug delivery in the brain. Thus, novel techniques need to be harbored for the facilitation of the delivery of such drugs into the brain. Nanocarriers are advantageous for facilitating the specific targeted drug treatment in AD. As nanomedicines are one of the novels and most useful approaches for AD, thus the present review mainly focuses on understanding the advanced use of nanocarriers for targeted drug delivery in the management of AD.

A green chemistry approach for oxidation of alcohols using novel bioactive cobalt composite immobilized on polysulfone fibrous network nanoparticles as a catalyst.

In this study, cobalt composite immobilized on polysulfone fibrous network nanoparticles (CCPSF NPs) were synthesized in a controllable and one-step way under microwave-assisted conditions. The structure of CCPSF NPs was characterized by SEM images (for morphology and size distribution), TGA (for thermal stability), BET technique (for the specific surface area), FT-IR spectroscopy (for relation group characterization), and XRD patterns (for crystal size). The oxidation of the primary and secondary alcohols to aldehyde and ketone was investigated using synthesized CCPSF NPs under solvent-free microwave-assisted conditions, and high oxidizing activity was observed. In addition to oxidation properties, the anticancer activity of the synthesized CCPSF NPs in breast cancer was evaluated by the MTT method , and significant results were obtained.

Synthesis, characterization, biological evaluation and molecular docking of a new quinazolinone-based derivative as a potent dual inhibitor for VEGFR-2 and EGFR tyrosine kinases.

An efficient process for the preparation of a new ethyl 2-((3-(4-fluorophenyl)-6-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio) acetate (5) was described. The prepared derivative was synthesized using the S-arylation method. Several analytical techniques, such as NMR, Raman and infrared spectroscopy, were used to characterize this compound. The compound was screened for cytotoxic activity against three human cancer cell lines: human cervical cancer (HeLa), human lung adenocarcinoma (A549) and triple negative breast cancer (MDA-MB-231) cells using an MTT assay. It exhibited potent cytotoxic activity against the tested cell lines with IC50 values in the low micromolar range when compared to a standard drug, docetaxel. It also displayed potent inhibitory activity towards VEGFR-2 and EGFR tyrosine kinases, reflecting its potential to act as an effective anti-cancer agent.Communicated by Ramaswamy H. Sarma.

Development, Characterization, and Evaluation of α-Mangostin-Loaded Polymeric Nanoparticle Gel for Topical Therapy in Skin Cancer.

The aim of this study was to prepare and evaluate α-mangostin-loaded polymeric nanoparticle gel (α-MNG-PLGA) formulation to enhance α-mangostin delivery in an epidermal carcinoma. The poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were developed using the emulsion-diffusion-evaporation technique with a 3-level 3-factor Box-Behnken design. The NPs were characterized and evaluated for particle size distribution, zeta potential (mV), drug release, and skin permeation. The formulated PLGA NPs were converted into a preformed carbopol gel base and were further evaluated for texture analysis, the cytotoxic effect of PLGA NPs against B16-F10 melanoma cells, and in vitro radical scavenging activity. The nanoscale particles were spherical, consistent, and average in size (168.06 ± 17.02 nm), with an entrapment efficiency (EE) of 84.26 ± 8.23% and a zeta potential of -25.3 ± 7.1 mV. Their drug release percentages in phosphate-buffered solution (PBS) at pH 7.4 and pH 6.5 were 87.07 ± 6.95% and 89.50 ± 9.50%, respectively. The release of α-MNG from NPs in vitro demonstrated that the biphasic release system, namely, immediate release in the initial phase, was accompanied by sustained drug release. The texture study of the developed α-MNG-PLGA NPs gel revealed its characteristics, including viscosity, hardness, consistency, and cohesiveness. The drug flux from α-MNG-PLGA NPs gel and α-MNG gel was 79.32 ± 7.91 and 16.88 ± 7.18 µg/cm2/h in 24 h, respectively. The confocal study showed that α-MNG-PLGA NPs penetrated up to 230.02 µm deep into the skin layer compared to 15.21 µm by dye solution. MTT assay and radical scavenging potential indicated that α-MNG-PLGA NPs gel had a significant cytotoxic effect and antioxidant effect compared to α-MNG gel (p < 0.05). Thus, using the developed α-MNG-PLGA in treating skin cancer could be a promising approach.