The fluorosis conundrum: bridging the gap between science and public health.

Fluorosis, a chronic condition brought on by excessive fluoride ingestion which, has drawn much scientific attention and public health concern. It is a complex and multifaceted issue that affects millions of people worldwide. Despite decades of scientific research elucidating the causes, mechanisms, and prevention strategies for fluorosis, there remains a significant gap between scientific understanding and public health implementation. While the scientific community has made significant strides in understanding the etiology and prevention of fluorosis, effectively translating this knowledge into public health policies and practices remains challenging. This review explores the gap between scientific research on fluorosis and its practical implementation in public health initiatives. It suggests developing evidence-based guidelines for fluoride exposure and recommends comprehensive educational campaigns targeting the public and healthcare providers. Furthermore, it emphasizes the need for further research to fill the existing knowledge gaps and promote evidence-based decision-making. By fostering collaboration, communication, and evidence-based practices, policymakers, healthcare professionals, and the public can work together to implement preventive measures and mitigate the burden of fluorosis on affected communities. This review highlighted several vital strategies to bridge the gap between science and public health in the context of fluorosis. It emphasizes the importance of translating scientific evidence into actionable guidelines, raising public awareness about fluoride consumption, and promoting preventive measures at individual and community levels.

Design of floating formulations and antiulcer activity of Desmostachya bipinnata.

The study aims to design and optimize the floating formulations of the aqueous extract of Desmostachya bipinnata (ADB) to treat peptic ulcers. The trial concentrations of HPMC E50, HPMC K4M, and Carbopol 940 were used as factors, and floating lag time, total floating time, and % drug release at 12 h were used as responses. The formulation underwent evaluation for different parameters: aspirin-induced ulcers in rats assessed the antiulcer activity, and X-ray studies in rabbits evaluated the gastroretentive nature. The optimized formulation has shown a floating lag time of 32 s and floated in the gastric medium for more than 9 h with a maximum drug release of 93% at the end of 12 h by following the Korsmeyer-Peppas drug release mechanism. The optimized formulation has good flow properties. The FT-IR, DSC, and XRD studies show ADB and excipients didn't show any incompatibility. The formulation has shown significant antiulcer activity against aspirin-induced ulcers in rats, with an ulcer index of 3.38 ± 0.24 and inhibition of 76.67 ± 0.56%. The in vivo X-ray imaging proved the gastric retention of the formulations for more than 8 h. The results of the formulations demonstrate the floating ability and sustained drug release of the tablet responsible for treating peptic ulcers to show a localized effect in the gastric region and to maintain the ROS levels.

Identification of potential Akt activators: a ligand and structure-based computational approach.

The Akt pathway plays a significant role in various diseases like Alzheimer's, Parkinson's, and Diabetes. Akt is the central protein whose phosphorylation controls many downstream pathways. Binding of small molecules to the PH domain of Akt facilitates its phosphorylation in the cytoplasm and upregulates the Akt pathway. In the current study, to identify Akt activators, ligand-based approaches like 2D QSAR, shape, and pharmacophore-based screening were used, followed by structure-based approaches such as docking, MM-GBSA, ADME prediction, and MD simulation. The top twenty-five molecules from the Asinex gold platinum database found to be active in most 2D QSAR models were used for shape and pharmacophore-based screening. Later docking was performed using the PH domain of Akt1 (PDB: 1UNQ), and 197105, 261126, 253878, 256085, and 123435 were selected based on docking score and interaction with key residues, which were druggable and formed a stable protein-ligand complex. MD simulations of 261126 and 123435 showed better stability and interactions with key residues. To further investigate the SAR of 261126 and 123435, derivatives were downloaded from PubChem, and structure-based approaches were employed. MD simulation of derivatives 12289533, 12785801, 83824832, 102479045, and 6972939 was performed, in which 83824832 and 12289533 showed interaction with key residues for a longer duration of time, proving that they may act as Akt activators.

Identification of phytochemical as a dual inhibitor of PI3K and mTOR: a structure-based computational approach.

Breast cancer is a common form of cancer that affects both men and women. One of the most common types of genomic flaws in cancer is the aberrations in the PI3K/AKT/mTOR pathway. The benefit of dual targeting PI3K as well as mTOR is that the kinase-positive feedback loops are more effectively inhibited. Therefore, in the current study, structure-based models like molecular docking, MM-GBSA, Qikprop, induced fit docking, simulated molecular dynamics (MD), and thermal MM-GBSA were used to identify the phytochemicals from the zinc 15 database, which may inhibit PI3K and mTOR. After docking the phytochemicals with PI3K (PDB 4FA6), ten ligands based on the docking score were selected, among which salvianolic acid C had the highest docking score. Hence, salvianolic acid A was also docked. All the ligands taken showed a binding energy of greater than - 30 kcal/mol. The predicted ADME showed that the ligands have druggable properties. By performing MD of the top five ligands and salvianolic acid A, it was found that ZINC000059728582, ZINC000257545754, ZINC000253532301, and salvianolic acid A form a stable complex with PI3K protein, among which ZINC000014690026 showed interaction with Val 882 for more than 89% of the time. Salvianolic acid A is already proven to suppress tumor growth in acute myeloid leukemia by inhibiting PI3K/AKT pathway, but the exact protein target is unknown. Therefore, the present study identifies new molecules and provides evidence for salvianolic acid A for dual inhibition. Further experiments must be performed both in vitro and in vivo to support the predictions of these computational tools.

Anticancer therapeutic potential of phosphorylated galactosylated chitosan against N-nitrosodiethyl amine-induced hepatocarcinogenesis.

Chitosan is a natural polyfunctional polymer that can be modified to achieve compounds with tailored properties for targeting and treating different cancers. In this study, we report the development and anticancer potential of phosphorylated galactosylated chitosan (PGC). The synthesized compound was characterized by FT-IR, NMR, and mass spectroscopy. The interaction of PGC with asialoglycoprotein receptors (ASGPR) and cellular internalization in HepG2 cells was studied using in silico and uptake studies respectively. PGC was evaluated for its metal chelating, ferric ion reducing, superoxide, and lipid peroxide (LPO) inhibiting potential. Further, anticancer therapeutic potential of PGC was evaluated against N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinoma in a mice model. After development of cancer, PGC was administered to the treatment group (0.5 mg/kg bw, intravenously), once a week for 4 weeks. Characterization studies of PGC revealed successful phosphorylation and galactosylation of chitosan. A strong interaction of PGC with ASGP-receptors was predicted by computational studies and cellular internalization studies demonstrated 98.76 ± 0.53% uptake of PGC in the HepG2 cells. A good metal chelating, ferric ion reducing, and free radical scavenging activity was demonstrated by PGC. The anticancer therapeutic potential of PGC was evident from the observation that PGC treatment increased number of tumor free animals (50%) (6/12) and significantly (p ≤ 0.05) lowered tumor multiplicity as compared to untreated tumor group.

Molecular dynamics and structure-based virtual screening and identification of natural compounds as Wnt signaling modulators: possible therapeutics for Alzheimer's disease.

Wnt signaling pathway is an evolutionarily conserved pathway responsible for neurogenesis, axon outgrowth, neuronal polarity, synapse formation, and maintenance. Downregulation of Wnt signaling has been found in patients with Alzheimer's disease (AD). Several experimental approaches to activate Wnt signaling pathway have proven to be beneficial in alleviating AD, which is one of the new therapeutic approaches for AD. The current study focuses on the computational structure-based virtual screening followed by the identification of potential phytomolecules targeting different markers of Wnt signaling like WIF1, DKK1, LRP6, GSK-3ß, and acetylcholine esterase. Initially, screening of 1924 compounds from the plant-based library of Zinc database was done for the selected five proteins using docking approach followed by MM-GBSA calculations. The top five hit molecules were identified for each protein. Based on docking score, and binding interactions, the top two hit molecules for each protein were selected as promising molecules for the molecular dynamic (MD) simulation study with the five proteins. Therefore, from this in silico based study, we report that Mangiferin could be a potential molecule targeting Wnt signaling pathway modulating the LRP6 activity, Baicalin for AChE activity, Chebulic acid for DKK1, ZINC103539689 for WIF1, and Morin for GSk-3ß protein. However, further validation of the activity is warranted based on in vivo and in vitro experiments for better understanding and strong claim. This study provides an in silico approach for the identification of modulators of the Wnt signaling pathway as a new therapeutic approach for AD.

Structure-based docking, pharmacokinetic evaluation, and molecular dynamics-guided evaluation of traditional formulation against SARS-CoV-2 spike protein receptor bind domain and ACE2 receptor complex.

There is an urgent need for reliable cure and preventive measures in this hour of the outbreak of SARS-CoV-2. Siddha- and Ayurvedic-based classical formulations have antiviral properties and great potential therapeutic choice in this pandemic situation. In the current study, in silico-based analysis for the binding potential of phytoconstituents from the classical formulations suggested by the Ministry of Ayush (Kabasura Kudineer, Shwas Kuthar Rasa with Kantakari and pippali churna, Talisadi churna) to the interface domain of the SARS-CoV-2 receptor-binding domain and angiotensin-converting enzyme 2 was performed. Maestro software from Schrodinger and tools like Glide Docking, induced fit docking, MM-GBSA, molecular dynamics (MD) simulation, and thermal MM-GBSA was used to analyze the binding of protein PDB ID:6VW1 and the selected 133 ligands in comparison with drug molecules like favipiravir and ribavirin. QikProp-based ADMET evaluation of all the phytoconstituents found them nontoxic and with drug-like properties. Selection of top ten ligands was made based on docking score for further MM-GBSA analysis. After performing IFD of top five molecules iso-chlorogenic acid, taxiphyllin, vasicine, catechin and caffeic acid, MD simulation and thermal MM-GBSA were done. Iso-chlorogenic acid had formed more stable interaction with key residue among all phytoconstituents. Computational-based study has highlighted the potential of the many constituents of traditional medicine to interact with the SARS-CoV-2 RBD and ACE2, which might stop the viral entry into the cell. However, in vivo experiments and clinical trials are necessary for supporting this claim. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11696-021-01917-z.

Prediction of volume of distribution in preclinical species and humans: application of simplified physiologically based algorithms.

The present study was aimed at developing simplified physiologically based semi-mechanistic algorithms to predict Vss and interspecies scaling factors to predict tissue-Kps which require minimum input parameters, diminish the computing complexity and have better predictability. Vss of 86 structurally diverse compounds in preclinical species and 27 compounds in humans were predicted using only lung- and muscle-Kp as inputs. Interspecies scaling factor (s) were developed based on fold-differences in individual tissue lipid contents, relative organ blood flow: relative organ weight ratio between two species. Tissue-Kps were predicted for 34 compounds using the newly developed interspecies scaling factors. The predicted-to-experimental Vss values for all the 113 compounds was 1.3 ± 0.9 with 83% values being within a factor of two. The tissue-Kps in rat, dog and human were predicted using experimental tissue-Kp data in rodents and interspecies scaling factors and here also, 83% of tissue-Kps were within two-fold of the experimental values. In conclusion, simplified physiologically based algorithms have been developed to predict both volume of distribution and tissue-Kps, in which required input parameters as well as computing complexity have been noticeably reduced.

Targeting HIV-TB coinfection by developing novel piperidin-4-substituted imines: Design, synthesis, in vitro and in silico studies.

Tuberculosis is the "Achilles heel" of the human immunodeficiency (HIV) ministration. HIV-positive people are 16-27 times more prone to contract tuberculosis. But the adverse interaction between antiretroviral drugs and antitubercular drugs has made it necessary to look for a single drug regimen for HIV-TB coinfection. Piperidine derivatives have been reported as anti-HIV and anti-TB agents. This inspired us to design, synthesize, and characterize a series of 3,5-bis(furan-2-ylmethylidene)-piperidin-4-substituted imines (R1-R25) and these were further screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv and anti-HIV activity. Molecular docking studies showed energetically favorable binding interactions with both EACP reductase (1ZID.pdb) and reverse-transcriptase (1REV.pdb) targets. The compounds R7, R12, R17, R18, R19, R20 were found to be more potent as anti-TB agents than ethambutol (MIC 3.125 µg/ml). Compound R7 was found to be moderately active with an IC50 of 2.1 ± 0.04 µM in multicycle infection assays, in comparison with the standard drug, zidovudine (IC50 = 5.7 ± 0.04 nM), used as anti-HIV drug. The cytotoxicity assay was done on Vero, MT-2, and TZM-bl cells to assess the safety of these compounds and they were found to be safe. From the above results, R7 seems to be a promising lead for anti-HIV and anti-TB activity.

Neuromodulatory potential of phenylpropanoids; para-methoxycinnamic acid and ethyl-p-methoxycinnamate on aluminum-induced memory deficit in rats.

Para-methoxycinnamic acid (PMCA) and Ethyl-p-methoxycinnamate (EPMC) are reported to possess neuroprotective effect in reversing an acute memory deficit. However, there is a dearth of evidence for their therapeutic effect in chronic memory deficit. Thus, there is a scope to study these derivatives against the chronic model of cognitive dysfunction. The present study was aimed to determine the cognitive enhancing activity of PMCA and EPMC in aluminum-induced chronic dementia. Cognitive enhancing property of PMCA and EPMC was assessed using Morris water maze by analyzing spatial memory parameters such as escape latency, D-quadrant latency, and island entries. To find a possible mechanism, the effect of test compounds on altered acetylcholinesterase (AChE) activity and oxidative stress was determined in the hippocampus and frontal cortex of rats. Docking interaction of these derivatives with acetylcholinesterase enzyme and glutamate receptors was also studied. Treatment with PMCA and EPMC showed a significant improvement in spatial memory markers and altered hippocampal AChE activity in rats with cognitive dysfunction. The implication of hippocampal and cortical oxidative stress in memory impairment was confirmed with decreased catalase/increased thiobarbituric acid reactive substances (TBARS) in rats. PMCA and EPMC reversed the oxidative stress in the brain by negatively affecting TBARS levels. Against depleted catalase levels, PMCA was more effective than EPMC in raising the depleted catalase levels. In silico analysis revealed poor affinity of EPMC and PMCA with AChE enzyme and glutamate receptor. To conclude, PMCA and EPMC exerted cognitive enhancing property independent of direct AChE and glutamate receptor inhibition.

An in silico drug repurposing approach to identify HDAC1 inhibitors against glioblastoma.

Despite considerable improvement in therapy and diagnosis, brain tumors remain a global public health concern. Among all brain tumors, 80% are due to Glioblastoma. The average survival rate of a patient once diagnosed with glioblastoma is 15 months. Lately, the role of peptidase enzymes, especially Neprilysin, a neutral endopeptidase, is gaining attention for its role in tumor growth regulation. Neprilysin expressions are positively correlated with several tumors including GBM and reduced expression of NEP protein is associated with the pathogenesis of multiple tumors. One of the main reasons for NEP protein downregulation is the action of Histone deacetylase (HDAC) enzymes, especially HDAC1. Additionally, studies have reported that increased levels of HDAC1 are responsible for downregulating NEP gene expression. Hence, HDAC1 inhibition can be a good target to elevate NEP levels, which can be a good therapeutic approach to GBM. This study utilizes the computational drug repurposing tool, Schrodinger Maestro to identify HDAC1 inhibitors from the ZINC15 database.1379 FDA-approved drugs from the ZINC15 database were screened through molecular docking. Based on docking score and ligand-protein interaction, the top ten molecules were selected which were then subjected to binding energy calculation and molecular dynamics (MD) simulations. The three most active drugs from the MD simulations- ZINC22010649 (Panobinostat), ZINC4392649 (Tasimelteon) and ZINC1673 (Melphalan), were tested on C6 and U87 MG glioblastoma cells for cytotoxicity and HDAC1 protein levels using western blot analysis. Among the three drugs, Panobinostat exhibited potent cytotoxic action and showed a significant reduction in the HDAC1 protein levels.Communicated by Ramaswamy H. Sarma.

In-silico lead identification of the pan-mutant IDH1 and IDH2 inhibitors to target glioblastoma.

Glioblastoma (GBM) is an aggressive malignant type of brain tumor. Targeting one single intracellular pathway might not alleviate the disease, rather it activates the other molecular pathways that lead to the worsening of the disease condition. Therefore, in this study, we attempted to target both isocitrate dehydrogenase 1 (IDH1) and IDH2, which are one of the most commonly mutated proteins in GBM and other cancer types. Here, standard precision and extra precision docking, IFD, MM-GBSA, QikProp, and molecular dynamics (MD) simulation were performed to identify the potential dual inhibitor for IDH1 and IDH2 from the enamine database containing 59,161 ligands. Upon docking the ligands with IDH1 (PDB: 6VEI) and IDH2 (PDB: 6VFZ), the top eight ligands were selected, based on the XP Glide score. These ligands produced favourable MMGBSA scores and ADME characteristics. Finally, the top four ligands 12953, 44825, 51295, and 53210 were subjected to MD analysis. Interestingly, 53210 showed maximum interaction with Gln 277 for 99% in IDH1 and Gln 316 for 100% in IDH2, which are the crucial amino acids for the inhibitory function of IDH1 and IDH2 to target GBM. Therefore, the present study attempts to identify the novel molecules which could possess a pan-inhibitory action on both IDH1 and IDH that could be crucial in the management of GBM. Yet further evaluation involving in vitro and in vivo studies is warranted to support the data in our current study.Communicated by Ramaswamy H. Sarma.

Inhibition of STAT3: A promising approach to enhancing the efficacy of chemotherapy in medulloblastoma.

Medulloblastoma is a type of brain cancer that primarily affects children. While chemotherapy has been shown to be effective in treating medulloblastoma, the development of chemotherapy resistance remains a challenge. One potential therapeutic approach is to selectively inhibit the inducible transcription factor called STAT3, which is known to play a crucial role in the survival and growth of tumor cells. The activation of STAT3 has been linked to the growth and progression of various cancers, including medulloblastoma. Inhibition of STAT3 has been shown to sensitize medulloblastoma cells to chemotherapy, leading to improved treatment outcomes. Different approaches to STAT3 inhibition have been developed, including small-molecule inhibitors and RNA interference. Preclinical studies have shown the efficacy of STAT3 inhibitors in medulloblastoma, and clinical trials are currently ongoing to evaluate their safety and effectiveness in patients with various solid tumors, including medulloblastoma. In addition, researchers are also exploring ways to optimize the use of STAT3 inhibitors in combination with chemotherapy and identify biomarkers that can predict treatment that will help to develop personalized treatment strategies. This review highlights the potential of selective inhibition of STAT3 as a novel approach for the treatment of medulloblastoma and suggests that further research into the development of STAT3 inhibitors could lead to improved outcomes for patients with aggressive cancer.

Oxyresveratrol-ß-cyclodextrin mitigates streptozotocin-induced Alzheimer's model cognitive impairment, histone deacetylase activity in rats: in silico & in vivo studies.

Alzheimer's disease (AD) is associated with cognitive deficits and epigenetic deacetylation that can be modulated by natural products. The role of natural oxyresveratrol-ß-cyclodextrin (ORV) on cognition and histone deacetylase activity in AD is unclear. Herein, in-silico docking and molecular dynamics simulation analysis determined that oxyresveratrol potentially targets histone deacetylase-2 (HDAC2). We therefore evaluated the in vivo ameliorative effect of ORV against cognitive deficit, cerebral and hippocampal expression of HDAC in experimental AD rats. Intracerebroventricular injection of STZ (3 mg/kg) induced experimental AD and the rats were treated with low dose (200 mg/kg), high dose (400 mg/kg) of ORV and donepezil (10 mg/kg) for 21 days. The STZ-induced AD caused cognitive and behavioural deficits demonstrated by considerable increases in acetylcholinesterase activity and escape latency compared to sham control. The levels of malondialdehyde (MDA) and HDAC activity were significantly increased in AD disease group comparison to the sham. Interestingly, the ORV reversed the cognitive-behavioural deficit and prominently reduced the MDA and HDAC levels comparable to the effect of the standard drug, donepezil. The findings suggest anti-AD role of ORV via antioxidant effect and inhibition of HDAC in the hippocampal and frontal cortical area of rats for AD.

Design of PI3K-mTOR Dual Inhibitors for Ovarian Cancer: Are We on the Right Track?

Ovarian cancer is one of the most familiar kinds of gynecological cancer seen in women. Though it is not as familiar as breast cancer, the survival rate for ovarian cancer is very low when compared with breast cancer. Even after being one among the familiar types, to date, there are no proper treatments available for ovarian cancer. All the treatments that are present currently show a high rate of recurrence after the treatment. Therefore, treating this silent killer from the roots is the need of the hour. PI3K/AKT/m- TOR pathway is one of the pathways that get altered during ovarian cancer. Studies are already going on for the inhibition of PI3K and mTOR separately. Efforts have been made to inhibit either PI3K or mTOR separately earlier. However, due to its side effects and resistance to the treatments available, current studies are based on the inhibition of PI3K and mTOR together. Inhibition of PI3K and mTOR simultaneously reduces the chances of negative feedback, thus decreasing the toxicity. This review contains the evolution of PI3K and mTOR drugs that are approved by the FDA and are in the trials for different cancer types, including Ovarian cancer. In this article, how a molecular targeted therapy can be made successful and free from toxicity for treating ovarian cancer is discussed. Therefore, this review paves the way for finding an effective scaffold rather than the clinical part. The scaffold thus selected can be further modified and synthesized in the future as dual PI3K/mTOR inhibitors specifically for OC.

Role of GSK-3ß Inhibitors: New Promises and Opportunities for Alzheimer's Disease.

Glycogen synthase kinase-3 (GSK-3) was discovered to be a multifunctional enzyme involved in a wide variety of biological processes, including early embryo formation, oncogenesis, as well cell death in neurodegenerative diseases. Several critical cellular processes in the brain are regulated by the GSK-3ß, serving as a central switch in the signaling pathways. Dysregulation of GSK-3ß kinase has been reported in diabetes, cancer, Alzheimer's disease, schizophrenia, bipolar disorder, inflammation, and Huntington's disease. Thus, GSK-3ß is widely regarded as a promising target for therapeutic use. The current review article focuses mainly on Alzheimer's disease, an age-related neurodegenerative brain disorder. GSK-3ß activation increases amyloid-beta (Aß) and the development of neurofibrillary tangles that are involved in the disruption of material transport between axons and dendrites. The drug-binding cavities of GSK-3ß are explored, and different existing classes of GSK-3ß inhibitors are explained in this review. Non-ATP competitive inhibitors, such as allosteric inhibitors, can reduce the side effects compared to ATP-competitive inhibitors. Whereas ATP-competitive inhibitors produce disarrangement of the cytoskeleton, neurofibrillary tangles formation, and lead to the death of neurons, etc. This could be because they are binding to a site separate from ATP. Owing to their interaction in particular and special binding sites, allosteric ligands interact with substrates more selectively, which will be beneficial in resolving drug-induced resistance and also helpful in reducing side effects. Hence, in this review, we focussed on the allosteric GSK-3ß inhibitors and discussed their futuristic opportunities as anti-Alzheimer's compounds.

MicroRNA (miR)-124: A Promising Therapeutic Gateway for Oncology.

MicroRNA (miR) are a class of small non-coding RNA that are involved in post-transcriptional gene regulation. Altered expression of miR has been associated with several pathological conditions. MicroRNA-124 (miR-124) is an abundantly expressed miR in the brain as well as the thymus, lymph nodes, bone marrow, and peripheral blood mono-nuclear cells. It plays a key role in the regulation of the host immune system. Emerging studies show that dysregulated expression of miR-124 is a hallmark in several cancer types and it has been attributed to the progression of these malignancies. In this review, we present a comprehensive summary of the role of miR-124 as a promising therapeutic gateway in oncology.

PAK4 inhibition significantly potentiates Gemcitabine activity in PDAC cells via inhibition of Wnt/ß-catenin, p-ERK/MAPK and p-AKT/PI3K pathways.

Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the most difficult to treat cancers. Gemcitabine is still the standard of care treatment for PDAC but with modest survival benefit and well reported resistance. Here we explored potential of inhibiting p21 activated kinase 4 (PAK4), a downstream protein of KRAS oncogenic pathway, in combination with Gemcitabine in PDAC cells. PAK4 inhibition by KPT-9274 led to significant potentiation of Gemcitabine activity in PDAC cells, with an increase in apoptosis, DNA damage and cell cycle arrest. At molecular level, PAK4 inhibition dose dependently inhibited Gemcitabine-induced ß-catenin, c-JUN and Ribonucleotide Reductase subunit 2 (RRM2) levels. PAK4 inhibition further inhibited levels of phosphorylated ERK (p-ERK); Gemcitabine-induced phosphorylated AKT (p-AKT), phosphorylated and total c-Myc. These results suggest possible role of ß-catenin, p-ERK and p-AKT, key effector proteins of Wnt/ß-catenin, MAPK and PI3K pathways respectively, in sensitisation of Gemcitabine activity with PAK4 inhibition. Our data unravel probable molecular mechanisms behind combination of PAK4 inhibition with Gemcitabine to counter PDAC, which may be unequivocally proved further with knock down of PAK4. Our findings provide a strong rationale to exploit the combination therapy of Gemcitabine and PAK4 inhibitor for PDAC at pre-clinical and clinical levels.

Expediting Molecular Translational Approach of Mesenchymal Stem Cells in COVID-19 Treatment.

Coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 with severe respiratory failure and organ damage that later appeared as a pandemic disease. Worldwide, people's mental and physical health and socioeconomic have been affected. Currently, with no promising treatment for COVID-19, the existing anti-viral drugs and vaccines are the only hope to boost the host immune system to reduce morbidity and mortality rate. Unfortunately, several reports show that people who are partially or fully vaccinated are still susceptible to COVID-19 infection. Evidence suggests that COVID-19 immunopathology may include dysregulation of macrophages and monocytes, reduced type 1 interferons (IFN-1), and enhanced cytokine storm that results in hypersecretion of proinflammatory cytokines, capillary leak syndrome, intravascular coagulation, and acute respiratory distress syndrome (ARDS) ultimately leading to the worsening of patient's condition and death in most cases. The recent use of cell-based therapies such as mesenchymal stem cells (MSCs) for critically ill COVID-19 patients has been authorized by the Food and Drug Administration (FDA) to alleviate cytokine release syndrome. It protects the alveolar epithelial cells by promoting immunomodulatory action and secreting therapeutic exosomes to improve lung function and attenuate respiratory failure. As a result, multiple clinical trials have been registered using MSCs that aim to use various cell sources, and dosages to promote safety and efficacy against COVID-19 infection. In this review, the possibility of using MSCs in COVID-19 treatment and its associated challenges in their use have been briefly discussed.

Biological, pathological, and multifaceted therapeutic functions of exosomes to target cancer.

Exosomes, small tiny vesicle contains a large number of intracellular particles that employ to cause various diseases and prevent several pathological events as well in the human body. It is considered a "double-edged sword", and depending on its biological source, the action of exosomes varies under physiological conditions. Also, the isolation and characterization of the exosomes should be performed accurately and the methodology also will vary depending on the exosome source. Moreover, the uptake of exosomes from the recipients' cells is a vital and initial step for all the physiological actions. There are different mechanisms present in the exosomes' cellular uptake to deliver their cargo to acceptor cells. Once the exosomal uptake takes place, it releases the intracellular particles that leads to activate the physiological response. Even though exosomes have lavish functions, there are some challenges associated with every step of their preparation to bring potential therapeutic efficacy. So, overcoming the pitfalls would give a desired quantity of exosomes with high purity.