Phytoconstituents as modulators of NF-κB signalling: Investigating therapeutic potential for diabetic wound healing.

The NF-κB pathway plays a pivotal role in impeding the diabetic wound healing process, contributing to prolonged inflammation, diminished angiogenesis, and reduced proliferation. In contrast to modern synthetic therapies, naturally occurring phytoconstituents are well-studied inhibitors of the NF-κB pathway that are now attracting increased attention in the context of diabetic wound healing because of lower toxicity, better safety and efficacy, and cost-effectiveness. This study explores recent research on phytoconstituent-based therapies and delve into their action mechanisms targeting the NF-κB pathway and potential for assisting effective healing of diabetic wounds. For this purpose, we have carried out surveys of recent literature and analyzed studies from prominent databases such as Science Direct, Scopus, PubMed, Google Scholar, EMBASE, and Web of Science. The classification of phytoconstituents into various categorie such as: alkaloids, triterpenoids, phenolics, polyphenols, flavonoids, monoterpene glycosides, naphthoquinones and tocopherols. Noteworthy phytoconstituents, including Neferine, Plumbagin, Boswellic acid, Genistein, Luteolin, Kirenol, Rutin, Vicenin-2, Gamma-tocopherol, Icariin, Resveratrol, Mangiferin, Betulinic acid, Berberine, Syringic acid, Gallocatechin, Curcumin, Loureirin-A, Loureirin-B, Lupeol, Paeoniflorin, and Puerarin emerge from these studies as promising agents for diabetic wound healing through the inhibition of the NF-κB pathway. Extensive research on various phytoconstituents has revealed how they modulate signalling pathways, including NF-κB, studies that demonstrate the potential for development of therapeutic phytoconstituents to assist healing of chronic diabetic wounds.

Exploring anticancer properties of the phytoconstituents and comparative analysis of their chemical space parameters with USFDA-approved synthetic anticancer agents.

The present review article thoroughly analyses natural products and their derived phytoconstituents as a rich source of plausible anticancer drugs. The study thoroughly explores the chemical components derived from various natural sources, thus emphasizing their unique structural characteristics and therapeutic potential as an anticancer agent. The review contains the critical chemical constituents' in-depth molecular mechanisms, their source's chemical structures and the categories. The review also comprises an exhaustive and comprehensive analysis of different chemical spacing parameters of the anticancer agents derived from natural products. It compares them with USFDA-approved synthetic anticancer drugs up to 2020, thus providing a meaningful understanding of the relationship between natural and synthetic compounds portraying the anticancer assets. The review also delves more deeply into the chemical analysis of the heterocyclic moieties from the natural product arena, illustrating the anticancer mechanisms. The present article is, therefore, expected to serve as a valuable resource for natural product and medicinal chemists, encouraging and promoting an integrated approach to exploit the potential of natural products in drug discovery development and translational research, which have a prerequisite of bench to bedside approach. The work could guide researchers toward innovative approaches for the ever-evolving field of anticancer drug discovery.

Natural autophagy activators: A promising strategy for combating photoaging.

BACKGROUND: Photodamage to the skin stands out as one of the most widespread epidermal challenges globally. Prolonged exposure to sunlight containing ultraviolet radiation (UVR) instigates stress, thereby compromising the skin's functionality and culminating in photoaging. Recent investigations have shed light on the importance of autophagy in shielding the skin from photodamage. Despite the acknowledgment of numerous phytochemicals possessing photoprotective attributes, their potential to induce autophagy remains relatively unexplored. PURPOSE: Diminished autophagy activity in photoaged skin underscores the potential benefits of restoring autophagy through natural compounds to enhance photoprotection. Consequently, this study aims to highlight the role of natural compounds in safeguarding against photodamage and to assess their potential to induce autophagy via an in-silico approach. METHODS: A thorough search of the literature was done using several databases, including PUBMED, Science Direct, and Google Scholar, to gather relevant studies. Several keywords such as Phytochemical, Photoprotection, mTOR, Ultraviolet Radiation, Reactive oxygen species, Photoaging, and Autophagy were utilized to ensure thorough exploration. To assess the autophagy potential of phytochemicals through virtual screening, computational methodologies such as molecular docking were employed, utilizing tools like AutoDock Vina. Receptor preparation for docking was facilitated using MGLTools. RESULTS: The initiation of structural and functional deterioration in the skin due to ultraviolet radiation (UVR) or sunlight-induced reactive oxygen species/reactive nitrogen species (ROS/RNS) involves the modulation of various pathways. Natural compounds like phenolics, flavonoids, flavones, and anthocyanins, among others, possess chromophores capable of absorbing light, thereby offering photoprotection by modulating these pathways. In our molecular docking study, these phytochemicals have shown binding affinity with mTOR, a negative regulator of autophagy, indicating their potential as autophagy modulators. CONCLUSION: This integrated review underscores the photoprotective characteristics of natural compounds, while the in-silico analysis reveals their potential to modulate autophagy, which could significantly contribute to their anti-photoaging properties. The findings of this study hold promise for the advancement of cosmeceuticals and therapeutics containing natural compounds aimed at addressing photoaging and various skin-related diseases. By leveraging their dual benefits of photoprotection and autophagy modulation, these natural compounds offer a multifaceted approach to combatting skin aging and related conditions.

Photoprotective efficacy of Sunset Yellow via inhibition of type-I and type-II pathway under exposure of sunlight.

Exposure to phototoxicants and photosensitizers can result in the generation of reactive oxygen species (ROS), leading to oxidative stress, DNA damage, and various skin-related issues such as aging, allergies, and cancer. While several photo-protectants offer defense against ultraviolet radiation (UV-R), their effectiveness is often limited by photo-instability. Sunset Yellow (SY), an FDA-approved food dye, possesses significant UV-R and visible light absorption properties. However, its photoprotective potential has remained unexplored. Our investigation reveals that SY exhibits remarkable photostability for up to 8 h under both UV-R and sunlight. Notably, SY demonstrates the ability to quench ROS, including singlet oxygen (1O2), superoxide radicals ( O 2 · - $$ {\mathrm{O}}_2^{\cdotp -} $$ ), and hydroxyl radicals (·OH) induced by rose bengal, riboflavin and levofloxacin, respectively. Moreover, SY proves effective in protecting against the apoptotic and necrotic cell death induced by the phototoxicant chlorpromazine (CPZ) in HaCaT cells. Further, it was observed that SY imparts photoprotection by inhibiting intracellular ROS generation and calcium release. Genotoxicity evaluation provides additional evidence supporting SY's photoprotective effects against CPZ-induced DNA damage. In conclusion, these findings underscore the potential of SY as a promising photoprotective agent against the toxic hazards induced by phototoxicants, suggesting its prospective application in the formulation of broad-spectrum sunscreens.

In Vitro and In Vivo Investigations of Chromone Derivatives as Potential Multitarget-Directed Ligands: Cognitive Amelioration Utilizing a Scopolamine-Induced Zebrafish Model.

Alzheimer's disease is a complex neurological disorder linked with multiple pathological hallmarks. The interrelation of therapeutic targets assists in the enhancement of cognitive decline through interference with overall neuronal transmission. We have synthesized and screened various chromone derivatives as potential multitarget-directed ligands for the effective treatment of Alzheimer's disease. The synthesized compounds exhibited multipotent activity against AChE, BuChE, MAO-B, and amyloid ß aggregation. Three potent compounds, i.e., VN-3, VN-14, and VN-19 were identified that displayed remarkable activities against different targets. These compounds displayed IC50 values of 80 nM, 2.52 µM, and 140 nM against the AChE enzyme, respectively, and IC50 values of 2.07 µM, 70 nM, and 450 nM against the MAO-B isoform, respectively. VN-3 displayed potent activity against self-induced Aß1-42 aggregation with inhibition of 58.3%. In the ROS inhibition studies, the most potent compounds reduced the intracellular ROS levels up to 80% in SH-SY5Y cells at 25 µM concentration. The compounds were found to be neuroprotective and noncytotoxic even at a concentration of 25 µM against SH-SY5Y cells. In silico studies showed that the compounds were nicely accommodated in the active sites of the receptors along with thermodynamically stable orientations. Compound VN-19 exhibited a balanced multitargeting profile against AChE, BuChE, MAO-B, and Aß1-42 enzymes and was further evaluated for in vivo activities on the scopolamine-induced zebrafish model. VN-19 was found to ameliorate the cognitive decline in zebrafish brains by protecting them against scopolamine-induced neurodegeneration. Thus, VN-3, VN-14, and VN-19 were identified as potent multitarget-directed ligands with a balanced activity profile against different targets and can be developed as therapeutics for AD.

Phyto-Fabrication of Moringa Oleifera Peel-Sourced Silver Nanoparticles: A Promising Approach for Combating Hepatic Cancer by Targeting Proinflammatory Cytokines and Mitigating Cytokine Storms.

Hepatocellular carcinoma (HCC) arises from precancerous nodules, leading to liver damage and inflammation, which triggers the release of proinflammatory cytokines. Dysregulation of these cytokines can escalate into a cytokine storm, causing severe organ damage. Interestingly, Moringa oleifera (M. oleifera) fruit peel, previously discarded as waste, contains an abundance of essential biomolecules and high nutritional value. This study focuses on the eco-friendly synthesis of silver nanoparticles infused with M. oleifera peel extract biomolecules and their impact on regulating proinflammatory cytokines, as well as their potential anticancer effects against Wistar rats. The freshly synthesized nanoformulation underwent comprehensive characterization, followed by antihepatic cancer evaluation using a diethyl nitrosamine-induced model (at a dose of 200 mg kg-1 BW). The study demonstrates a significant reduction in proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6, interleukin-1ß, and nuclear factor kappa beta (NF-κB). Furthermore, it confirms that the newly biosynthesized silver nanoparticles exhibit additional potential against hepatic cancer due to their capped biomolecules.

Facile Fabrication of Sandalwood Oil-Based Nanoemulsion to Intensify the Fatty Acid Composition in Burned and Rough Skin.

The restoration process of burned and rough skin takes a long time and remains a critical challenge. It can be repaired through a combination of proper care, hydration, and topical therapies. In this study, a novel nanoemulsion was synthesized through the high-energy ultrasonication method. A total of five nanoemulsions (NE1-5) were prepared with varying concentrations of sandalwood oil, a nonionic surfactant (polysorbate 80), and water. Among them, NE3 had a number of appropriate physicochemical characteristics, such as physiological pH (5.58 ± 0.09), refractive index (∼1.34), electrical conductivity (115 ± 0.23 mS cm-1), and transmittance (∼96.5%), which were suitable for skin care applications. The NE3 had a strong surface potential of -18.5 ± 0.15 mV and a hydrodynamic size of 61.99 ± 0.22 nm with a polydispersity index of 0.204. The structural integrity and a distinct droplet size range between 50 and 100 nm were confirmed by transmission electron microscopic analysis. The skin regeneration and restoration abilities of synthesized nanoemulsions were examined by conducting an in vivo study on Sprague-Dawley rats. Exposure to NE3 significantly increased the healing process in burned skin as compared to untreated control and nonemulsified sandalwood oil. In another set of experiments, the NE3-treated rough skin became softer, smoother, and less scaly than all other treatments. Enhanced fatty acids, i.e., palmitic acid, stearic acid, and cholesterol, were recorded in NE3-supplemented burned and rough skin compared to the untreated control. The NE3 had outstanding compatibility with key components of skincare products without any stability issues. Its biocompatibility with the cellular system was established by the negligible generation of reactive oxygen species (ROS) and a lack of genotoxicity. Considering these results, NE3 can be used in cosmetic products such as creams, lotions, and serums, allowing industries to achieve improved product formulations and provide better healthcare benefits to humanity.

Iodine-PEG as a unique combination for the metal-free synthesis of flavonoids through iodonium-triiodide ion-pair complexation.

An efficient metal-free single-step protocol has been developed for the direct synthesis of flavones from 2-hydroxyacetophenone and substituted benzaldehydes. This chemical transformation is exclusively promoted by the iodonium-triiodide ion couple formed through iodine and PEG-400 complexation. The triiodide anion not only helps in the abstraction of a proton from the acetophenone but also promotes the cyclization of intermediate chalcone to the corresponding flavones. The flavones were obtained in very high yields without using any toxic metal catalysts or harsh reaction conditions. The reaction mechanism was established through a series of test reactions and entrapping of reaction intermediates. The developed protocol provides direct access to flavones in high yields under milder reaction conditions with great substrate compatibility, including hydroxylated derivatives.

Smart Nanofibrous Hydrogel Wound Dressings for Dynamic Infection Diagnosis and Control: Soft but Functionally Rigid.

Chronic wounds, such as burns and diabetic foot ulcers, pose significant challenges to global healthcare systems due to prolonged hospitalization and increased costs attributed to susceptibility to bacterial infections. The conventional use of antibiotic-loaded and metal-impregnated dressings exacerbates concerns related to multidrug resistance and skin argyrosis. In response to these challenges, our research introduces a unique approach utilizing antibiotic-free smart hydrogel wound dressings with integrated infection eradication and diagnostic capabilities. Electrospinning stands out as a method capable of producing hydrogel nanofibrous materials possessing favorable characteristics for treating wounds and detecting infections under conditions utilizing sustainable materials. In this study, innovative dressings are fabricated through electrospinning polycaprolactone (PCL)/gelatin (GEL) hybrid hydrogel nanofibers, incorporating pDA as a cross-linker, εPL as a broad-spectrum antimicrobial agent, and anthocyanin as a pH-responsive probe. The developed dressings demonstrate exceptional antioxidant (>90% radical scavenging) and antimicrobial properties (95-100% killing). The inclusion of polyphenols/flavonoids and εPL leads to absolute bacterial eradication, and in vitro assessments using HaCaT cells indicate increased cell proliferation, decreased reactive oxygen species (ROS) production, and enhanced cell viability (100% Cell viability). The dressings display notable alterations in color that correspond to different wound conditions. Specifically, they exhibit a red/violet hue under healthy wound conditions (pH 4-6.5) and a green/blue color under unhealthy wound conditions (pH > 6.5). These distinctive color changes provide valuable insights into the versatile applications of the dressings in the care and management of wounds. Our findings suggest that these antibiotic-free smart hydrogel wound dressings hold promise as an effective and sustainable solution for chronic wounds, providing simultaneous infection control and diagnostic monitoring. This research contributes to advancing the field of wound care, offering a potential paradigm shift in the development of next-generation wound dressings.

Virtual screening and molecular dynamics simulation approach for the identification of potential multi-target directed ligands for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial neurological disorder characterized by memory loss and cognitive impairment. The currently available single-targeting drugs have miserably failed in the treatment of AD, and multi-target directed ligands (MTDLs) are being explored as an alternative treatment strategy. Cholinesterase and monoamine oxidase enzymes are reported to play a crucial role in the pathology of AD, and multipotent ligands targeting these two enzymes simultaneously are under various phases of design and development. Recent studies have revealed that computational approaches are robust and trusted tools for identifying novel therapeutics. The current research work is focused on the development of potential multi-target directed ligands that simultaneously inhibit acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) enzymes employing a structure-based virtual screening (SBVS) approach. The ASINEX database was screened after applying pan assay interference and drug-likeness filter to identify novel molecules using three docking precision criteria; High Throughput Virtual Screening (HTVS), Standard Precision (SP), and Extra Precision (XP). Additionally, binding free energy calculations, ADME, and molecular dynamic simulations were employed to get structural insights into the mechanism of protein-ligand binding and pharmacokinetic properties. Three lead molecules viz. AOP19078710, BAS00314308 and BDD26909696 were successfully identified with binding scores of -10.565, -10.543 & -8.066 kcal/mol against AChE and -11.019, -12.357 & -10.068 kcal/mol against MAO-B, better score as compared to the standard inhibitors. In the near future, these molecules will be synthesized and evaluated through in vitro and in vivo assays for their inhibition potential against AChE and MAO-B enzymes.

Toxic potential assessment of hair dye developer 2,4,5,6-tetraaminopyrimidine sulfate exposed under ambient UVB radiation.

Synthetic cosmetics, particularly hair dyes, are becoming increasingly popular among people of all ages and genders. 2,4,5,6-tetraaminopyrimidine sulfate (TAPS) is a key component of oxidative hair dyes and is used as a developer in several hair dyes. TAPS has previously been shown to absorb UVB strongly and degrade in a time-dependent manner, causing phototoxicity in human skin cells. However, the toxic effects of UVB-degraded TAPS are not explored in comparison to parent TAPS. Therefore, this research work aims to assess the toxicity of UVB-degraded TAPS than TAPS on two different test systems, that is, HaCaT (mammalian cell) and Staphylococcus aureus (a bacterial cell). Our result on HaCaT has illustrated that UVB-degraded TAPS is less toxic than parent TAPS. Additionally, UVB-exposed TAPS and parent TAPS were given to S. aureus, and the bacterial growth and their metabolic activity were assessed via CFU and phenotype microarray. The findings demonstrated that parent TAPS reduced bacterial growth via decreased metabolic activity; however, bacteria easily utilized the degraded TAPS. Thus, this study suggests that the products generated after UVB irradiation of TAPS is considered to be safer than their parent TAPS.

Caesium carbonate promoted regioselective O-functionalization of 4,6-diphenylpyrimidin-2(1H)-ones under mild conditions and mechanistic insight.

A facile one-step catalyst free methodology has been developed for the regioselective functionalization of 4,6-diphenylpyrimidin-2(1H)-ones under mild conditions. Selectivity towards the O-regioisomer was achieved by using Cs2CO3 in DMF without use of any coupling reagents. A total of 14 regioselective O-alkylated 4,6-diphenylpyrimidines were synthesized in 81-91% yield. In the DFT studies it was observed that the transition state for the formation of the O-regioisomer is more favourable with Cs2CO3 as compared to K2CO3. Furthermore, this methodology was extended to increase the O/N ratio for the alkylation of 2-phenylquinazolin-4(3H)-one derivatives.

Benzo(ghi)perylene (BgP) a black tattoo ingredient induced skin toxicity via direct and indirect mode of DNA damage under UVA irradiation.

Tattooing is a very common fashion trend across all the ages and gender of the society worldwide. Although skin inflammatory diseases are very frequent among tattoo users because of the active chemical ingredients used in tattoo ink, yet no ingredient-specific toxicity study has been performed. Benzo(ghi)perylene (BgP) is one of the PAHs and an important ingredient of black tattoo ink that shows strong absorption in UVA and UVB radiation of sunlight. Therefore, understanding the hazardous potential of BgP especially under UVA exposure is important for the safety of skin of tattoo users by considering the fact that penetration of UVA is in the dermis region where tattoo ingredients reside. To evaluate the hazardous potential of BgP on human skin under UVA exposure, different experimental tools i.e., in-chemico, in-silico and in-vitro were utilized. Our results illustrated that BgP photosensitized under UVA (1.5 mW/cm2) irradiation shows a degradation pattern till 4 h exposure. Photosensitized BgP reduced significant cell viability (%) at 1 µg/ml concentration. However, the pretreatment of singlet and hydroxyl radical quenchers, restoration of cell viability observed, confirmed the role of type-I and type-II photodynamic reactions in phototoxicity of BgP. Further, intracellular uptake of BgP in HaCaT cells was estimated and confirmed by UHPLC analysis. Molecular docking of BgP with DNA and formation of γ-H2AX foci demonstrated the DNA intercalation and double-stranded DNA damaging potential of BgP. Furthermore, acridine orange and ethidium bromide (AO/EB) dual staining showed apoptotic cell death via photosensitized BgP under UVA irradiation. The above findings suggest that BgP reached the human skin cell and induced dermal toxicity via direct and indirect mode of DNA damage under UVA exposure finally promoting the skin cell death. Thus, BgP-containing tattoo ink may be hazardous and may induce skin damage and diseases, especially in presence of UVA radiation of sunlight. To minimize the risk of skin diseases from synthetic ingredients in tattoo ink, the study highlights the importance of developing eco-friendly and skin-friendly tattoo ingredients by companies.

Involvement of type-1 pathway in phototoxicity of benzo[ghi]perylenean ingredient of tattoo ink at ambient exposure of UVR and sunlight.

Tattooing on different parts of the body is a very common fashion trend in all sections of society globally. Skin allergies and other related skin diseases are very common among tattoo users. Benzo[ghi]perylene (BP) is a PAH and an important component of tattoo ink that showed prominent absorption under ultraviolet radiation (UVR) region. Therefore, to provide safety to the skin, a thorough safety study of BP exposed under UVR and Sunlight is very essential to understand their hazardous impact on the skin. BP showed a strong absorption of UVA and UVB radiation of sunlight. It is photolabile and degraded under UVA, UVB, and Sunlight in progressing order of time (1-4 h) without generating any novel photoproducts. Further, BP showed a specific generation of O2.- and OH radicals via activation of type I photodynamic reaction under exposure to UVA, UVB and Sunlight. Photocytotoxicity results illustrated concentration-dependent cell viability reduction in all exposure conditions of UVA, UVB, and Sunlight, respectively. Fluorescent probes (2',7'-dichlorofluorescein diacetate and dihydroethidium) for intracellular reactive oxygen species (ROS) generation supported the involvement of ROS in the phototoxicity of BP in the HaCaT cell line. Hoechst staining showed significant genomic insult induced by BP under UVA and UVB. Photoexcited BP promoted cell cycle arrest in the G1 phase and induced apoptosis confirmed via acridine orange/ethidium bromide staining. The findings of gene expression also supported apoptotic cell death in photoexcited BP via an increase in the level of pro-apoptotic gene (Bax) and a decrease in the level of anti-apoptotic gene (Bcl-2). The aforementioned finding indicates that tattoo users should avoid using BP since it can cause skin damage/diseases if they are exposed to UVR or Sunlight while tattooing on the body.

Post-COVID green supply chain management of used products: a study towards awareness for vaccination.

In the era of digital media, there is rapid spread of information. During coronavirus (COVID-19) pandemic situation, the government and other administrative bodies were highly dependent on media outlets, as direct contact was not feasible. Visual communication tools are used to spread awareness and encourage people towards vaccination. The circulation of wrong information may lead to confusion, which may cause denying the vaccine. There was a need to know the extent for contribution of visual communication tools for spreading correct information and motivating the society towards vaccination in post COVID times. In the present study, survey questionnaires were framed specific to which media (print or digital) was more effective to deliver the correct information to the targeted audience. The present study objectives to answer the questions through a survey of 312 people of different age groups, and the data was collected about their families. The obtained data was tested through hypothesis, and fact-checked was performed adopting analysis of variance (ANOVA). The results from the study highlighted that different age groups prefer different mediums of communication. The reach and adoption of digital media have tremendously increased, and it helped to achieve the sustainable development goals (SDGs) by efficient green supply chain management (GSCM) of daily plastic and paper wastage during post-pandemic.

Benzotriazole Substituted 2-Phenylquinazolines as Anticancer Agents: Synthesis, Screening, Antiproliferative and Tubulin Polymerization Inhibition Activity.

AIMS: Development of anticancer agents targeting tubulin protein. BACKGROUND: Tubulin protein is being explored as an important target for anticancer drug development. Ligands binding to the colchicine binding site of the tubulin protein act as tubulin polymerization inhibitors and arrest the cell cycle in the G2/M phase. OBJECTIVE: Synthesis and screening of benzotriazole-substituted 2-phenyl quinazolines as potential anticancer agents. METHODS: A series of benzotriazole-substituted quinazoline derivatives have been synthesized and evaluated against human MCF-7 (breast), HeLa (cervical) and HT-29 (colon) cancer cell lines using standard MTT assays. RESULTS: ARV-2 with IC50 values of 3.16 µM, 5.31 µM, 10.6 µM against MCF-7, HELA and HT29 cell lines, respectively displayed the most potent antiproliferative activities in the series while all the compounds were found non-toxic against HEK293 (normal cells). In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, ARV-2 and ARV-3 were found to induce mitochondria-mediated apoptosis. CONCLUSION: The benzotriazole-substituted 2-phenyl quinazolines have the potential to be developed as potent anticancer agents.

Therapeutic potential of short-chain fatty acid production by gut microbiota in neurodegenerative disorders.

Dietary fibers are a major source of short-chain fatty acids (SCFAs) in the body, and the fermentation products of SCFAs induced by intestinal microbiota affect energy metabolism. Apart from serving as an energy source in the intestines, SCFAs also inhibit autophagy, nucleotide-binding oligomerization domain-containing protein, LRR, and pyrin domain-containing protein 3 inflammasome. SCFAs provide numerous therapeutic benefits through their influence on cognitive functioning and neurodegenerative diseases (NDD) pathophysiology. Additionally, NDDs are associated with abnormalities in the gut microbiota, including an increased load of pathogens and opportunistic microbes. SCFAs maintain the healthy mitochondrial function and stimulate the maturation of microglia, which consequently suppresses the progression of NDD and cognitive decline by regulating inflammation and oxidative stress. Basically, SCFAs function as cofactors for the host's mitochondrial enzymes and are being studied for their ability to reverse the alteration in the gut microbiota seen in many NDDs and cardiac diseases. In the present review, the focus is on the detrimental and beneficial roles of SCFAs in NDD, emphasizing the effects of SCFA on following phenomenon: (1) alteration in gut microbiota profile associated with NDD, (2) the molecular mechanism of metabolic regulation by SCFA's, and its co-relation with NDD, (3) use of mitochondrial antioxidants as a strategy for maintaining microbiota diversity in the gut, and (4) the future direction of metabolism and neurodegeneration in the gut-brain axis. In addition, the interplay between gut microbiota, SCFAs, epithelial barrier, and neuroimmune signaling in neurodegeneration has been reviewed.

Synthesis and screening of novel 4-N-heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines as antiproliferative and tubulin polymerization inhibitors.

Colchicine binding site represent a crucial target for the anticancer drug development especially in view of emerging drug resistance from the currently available chemotherapeutics. A total of 16 novel 4-N-heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines were synthesized and screened for antiproliferative and tubulin polymerization inhibition potential. The synthesized compounds were evaluated against MCF-7, HeLa and HT-29 cancer cell lines and normal cell line HEK-293 T. In the series, 2­aryl group with 4­bromophenyl substitution displayed IC50 values of 6.37 µM, 17.43 µM, 6.76 µM and 4­chlorophenyl substitution displayed IC50 values of 2.16 µM, 8.53 µM, 10.42 µM against MCF-7, HELA and HT29 cancer cell lines, respectively. In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, both the lead compounds were found to induce mitochondria mediated apoptosis and lead molecule with 4­chlorophenyl substitution displayed significant tubulin polymerization inhibition activity. In the computation studies, lead molecule displayed significant binding affinites in the colchicine domain and showed good thermodynamic stability during 100 ns MD simulation studies. 4-N-Heterocyclic-2-aryl-6,7,8-trimethoxyquinazolines showed appreciable drug like characteristics and can be developed as potent anticancer agents.

Phenotype microarray analysis reveals the biotransformation of Fusarium oxysporum f.sp. lycopersici influenced by Bacillus subtilis PBE-8 metabolites.

Herein, Bacillus subtilis PBE-8's biocontrol efficacy was evaluated through physiological and metabolic approaches against Fusarium oxysporum f.sp. lycopersici (FOL). The study elaborates on PBE-8's cell-free filtrate (CFF) antifungal activity through mycelial growth inhibition, metabolite profiling, and substrates utilization patterns. Additionally, under different CFF concentrations, reduction in spore count (94%-55%), biomass (50%), and cytoplasmic bulbous protrusions in mycelia were also observed. Furthermore, the effect of bacterial CFF on FOL metabolism was confirmed through GC-MS. CFF suppresses the concentration of aliphatic amino acids like L-valine, L-leucine, L-Isoleucine, glycine, and fatty acids such as linoleic acid and α- linolenic acid during the co-culturing conditions, which are essential for pathogenicity and resistance against host's systemic acquired resistance. The phenotype microarray assay revealed that CFF-treated FOL shows phenotype loss in 507 (56.58%) out of 896 substrates. Among 507, twenty-seven substrates showed significant phenotype loss, among which four substrates such as L-glutamic acid, L-glutamine, ammonia, and L-arginine are common in different crucial metabolic pathways of FOL, like alanine, aspartate, and glutamate metabolism, arginine and proline, carbon metabolism, arginine biosynthesis, nitrogen metabolism, amino-acyl tRNA synthesis, and biosynthesis of amino acids. The results suggest that PBE-8 CFF has certain antifungal metabolites that hinder the fungal metabolic pathways.

Design, Synthesis, and Pharmacological Evaluation of N-Propargylated Diphenylpyrimidines as Multitarget Directed Ligands for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD), a multifactorial complex neural disorder, is categorized with progressive memory loss and cognitive impairment as main clinical features. The multitarget directed ligand (MTDL) strategy is explored for the treatment of multifactorial diseases such as cancer and AD. Herein, we report the synthesis and screening of 24 N-propargyl-substituted diphenylpyrimidine derivatives as MTDLs against acetylcholine/butyrylcholine esterases and monoamine oxidase enzymes. In this series, VP1 showed the most potent MAO-B inhibitory activity with an IC50 value of 0.04 ± 0.002 µM. VP15 with an IC50 value of 0.04 ± 0.003 µM and a selectivity index of 626 (over BuChE) displayed the most potent AChE inhibitory activity in this series. In the reactive oxygen species (ROS) inhibition studies, VP1 reduced intercellular ROS levels in SH-SY5Y cells by 36%. This series of compounds also exhibited potent neuroprotective potential against 6-hydroxydopamine-induced neuronal damage in SH-SY5Y cells with up to 90% recovery. In the in vivo studies in the rats, the hydrochloride salt of VP15 was orally administered and found to cross the blood-brain barrier and reach the target site. VP15·HCl significantly attenuated the spatial memory impairment and improved the cognitive deficits in the mice. This series of compounds were found to be irreversible inhibitors and showed no cytotoxicity against neuronal cells. In in silico studies, the compounds attained thermodynamically stable orientation with complete occupancy at the active site of the receptors. Thus, N-propargyl-substituted diphenylpyrimidines displayed drug-like characteristics and have the potential to be developed as MTDLs for the effective treatment of AD.