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In the current study, three different carboxylic acids were incorporated as a cross-linker into the blend films of polyvinyl alcohol (PVA) and basmati rice starch (BRS) at a 70/30 ratio and plasticized with glycerol. The cross-linking succeeds through the creation of ester bonds between the free hydroxyl groups of PVA/BRS and the C = O groups. The effect of this cross-linking on physicochemical properties (film thickness, retraction ratio, moisture content, water absorption, and water vapor permeability) and optical (transmittance and color analysis), antimicrobial, and antioxidant properties was assessed. The current findings showed that COA incorporation into the PVA/BRS blend films demonstrated better hydrophobicity and excellent UV light-blocking properties. The incorporation of COA has no impact on radical scavenging activity; however, the cinnamic acid- and benzoic acid-containing films at higher percentages possess antimicrobial properties. FTIR studies confirm the existence of hydrogen bonding interactions among the PVA/BRS blend film and COA. The study encompasses the swelling properties of the blend film in water, brine, and seawater. The cast blend films can be utilized for the packaging purposes of foodstuffs. [ABSTRACT FROM AUTHOR]

Diabetes mellitus, a high‐morbidity endocrine disease, is typically treated with synthetic hypoglycemic drugs that are costly and have severe side effects. Natural products, like mushrooms, offer a cost‐effective, accessible, and eco‐friendly alternative. Current study intends to examine the antidiabetic potential of mushroom‐based herbal formulation (MHF) on streptozotocin‐induced diabetic rats. For this purpose, five different groups of Wister rats were established including one normal group. Among four diabetic groups, one group served as the diabetic control, while the remaining two groups were administrated with MHF 200 mg/kg and 400 mg/kg, respectively, and the fifth was administered with metformin for 28 days. On the last day of experiment, all rats were sacrificed, and samples were collected for different analysis. The study outcomes revealed that the administration of MHF to diabetic rats resulted in remarkable (p < 0.001) improvements in fasting blood glucose (FBG) levels and glycated hemoglobin along with other biochemical markers. The histopathological examination also showed the protective effect of MHF against diabetic‐induced damage in the pancreas, kidney, and liver. It also helps in the regeneration of β‐cells in the pancreas. These findings suggest MHF is a safer and more effective alternative for managing diabetes. [ABSTRACT FROM AUTHOR]

Protein inhibitors of activated STATs (PIAS) are proteins for cytokine signaling that activate activator-mediated gene transcription. These proteins, as versatile cellular regulators, have been described as regulators of approximately 60 proteins. Dysregulation of PIAS is associated with inappropriate gene expression that promotes oncogenic signaling in multiple cancers. Multiple lines of evidence have revealed that PIAS family members show modulated expressions in cancer cells. Most frequently reported PIAS family members in cancer development are PIAS1 and PIAS3. SUMOylation as post-translational modifier regulates several cellular machineries. PIAS proteins as SUMO E3 ligase factor promotes SUMOylation of transcription factors tangled cancer cells for survival, proliferation, and differentiation. Attenuated PIAS-mediated SUMOylation mechanism is involved in tumorigenesis. This review article provides the PIAS/SUMO role in the modulation of transcriptional factor control, provides brief update on their antagonistic function in different cancer types with particular focus on PIAS proteins as a bonafide therapeutic target to inhibit STAT pathway in cancers, and summarizes natural activators that may have the ability to cure cancer. [ABSTRACT FROM AUTHOR]

Molecular hybridization has emerged as the prime and most significant approach for the development of novel anticancer chemotherapeutic agents for combating cancer. In this pursuit, a novel series of indole–1,2,4-triazol-based N-phenyl acetamide structural motifs 8a–f were synthesized and screened against the in vitro hepatocellular cancer Hep-G2 cell line. The MTT assay was applied to determine the anti-proliferative potential of novel indole–triazole compounds 8a–f, which displayed cytotoxicity potential as cell viabilities at 100 µg/mL concentration, by using ellipticine and doxorubicin as standard reference drugs. The remarkable prominent bioactive structural hybrids 8a, 8c, and 8f demonstrated good-to-excellent anti-Hep-G2 cancer chemotherapeutic potential, with a cell viability of (11.72 ± 0.53), (18.92 ± 1.48), and (12.93 ± 0.55), respectively. The excellent cytotoxicity efficacy against the liver cancer cell line Hep-G2 was displayed by the 3,4-dichloro moiety containing indole–triazole scaffold 8b, which had the lowest cell viability (10.99 ± 0.59) compared with the standard drug ellipticine (cell viability = 11.5 ± 0.55) but displayed comparable potency in comparison with the standard drug doxorubicin (cell viability = 10.8 ± 0.41). The structure–activity relationship (SAR) of indole–triazoles 8a–f revealed that the 3,4-dichlorophenyl-based indole–triazole structural hybrid 8b displayed excellent anti-Hep-G2 cancer chemotherapeutic efficacy. The in silico approaches such as molecular docking scores, molecular dynamic simulation stability data, DFT, ADMET studies, and in vitro pharmacological profile clearly indicated that indole–triazole scaffold 8b could be the lead anti-Hep-G2 liver cancer therapeutic agent and a promising anti-Hep-G2 drug candidate for further clinical evaluations. [ABSTRACT FROM AUTHOR]

The major cause of hyperglycemia can generally be attributed to β-glucosidase as per its involvement in non-alcoholic fatty liver disease. This clinical condition leads to liver carcinoma (HepG2 cancer). The phthalimides and phthalamic acid classes possess inhibitory potential against glucosidase, forming the basis for designing new phthalimide and phthalamic acid analogs to test their ability as potent inhibitors of β-glucosidase. The study also covers in silico (molecular docking and MD simulations) and in vitro (β-glucosidase and HepG2 cancer cell line assays) analyses. The phthalimide and phthalamic acid derivatives were synthesized, followed by spectroscopic characterization. The mechanistic complexities associated with β-glucosidase inhibition were identified via the docking of the synthesized compounds inside the active site of the protein, and the results were analyzed in terms of the best binding energy and appropriate docking pose. The top-ranked compounds were subjected to extensive MD simulation studies to understand the mode of interaction of the synthesized compounds and binding energies, as well as the contribution of individual residues towards binding affinities. Lower RMSD/RMSF values were observed for 2c and 3c, respectively, in the active site, confirming more stabilized, ligand-bound complexes when compared to the free state. An anisotropic network model was used to unravel the role of loop fluctuation in the context of ligand binding and the dynamics that are distinct to the bound and free states, supported by a 3D surface plot. An in vitro study revealed that 1c (IC50 = 1.26 µM) is far better than standard acarbose (2.15 µM), confirming the potential of this compound against the target protein. Given the appreciable potential of the candidate compounds against β-glucosidase, the synthesized compounds were further tested for their cytotoxic activity against hepatic carcinoma on HepG2 cancer cell lines. The cytotoxicity profile of the synthesized compounds was performed against HepG2 cancer cell lines. The resultant IC50 value (0.048 µM) for 3c is better than the standard (thalidomide: IC50 0.053 µM). The results promise the hypothesis that the synthesized compounds might become potential drug candidates, given the fact that the β-glucosidase inhibition of 1c is 40% better than the standard, whereas compound 3c holds more anti-tumor activity (greater than 9%) against the HepG2 cell line than the known drug. [ABSTRACT FROM AUTHOR]

Cancer therapies based on nanoparticles with a loaded drug can overcome the problem of the drug's toxic effects in the traditional chemotherapeutic approach. In this study, we loaded LLY-507, a potent inhibitor of SMYD2, a methyltransferase enzyme, on iron oxide nanoparticles (IONPs). The prepared nanoparticles were characterized by microscopic analysis, loading efficiency, and drug release studies. Microscopic examination revealed an average grain size of 44 nm. The in vitro effect of LLY-507-IONPs, LLY-507, and IONPs was determined by MTT analysis (A549 cells) and hemolysis studies. IONPs have almost negative hemolytic activity in blood. The cell viability assay revealed IC50 values of both LLY-507 alone and LLY-507-loaded IONPs against A549; the lower value of the drug loaded on NPs (0.71 µg/mL alone and 0.53 µg/mL loaded on NPs) shows strong synergistic anticancer potential. We further tested the role of loaded NPs in a urethane-induced lung cancer mouse model (n = 40 mice in three independent trials, 20 mice in control group) to check the role of SMYD2 at various time points of lung cancer development. The loss of SMYD2 due to LLY-507 suppressed tumor growth, emphysema, hemorrhage, and congestion considerably. Hence, it can be concluded that the SMYD2 inhibitor has an anti-inflammatory effect on the mouse lung and suppresses tumor growth by inhibiting the SMYD2 protein. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries are one of those complex medical conditions for which a highly effective first‐line treatment is currently missing. The use of natural compound as medicines to treat various disorders has a long history. Our previous research explored that crude Cannabis sativa L. accelerated the recovery of sensorimotor functions following nerve injury. The purpose of the current study was to investigate the effects of n‐Hexane and ethyl acetate extracts of C. sativa L. leaves on the muscle function restoration in a mouse model after sciatic nerve injury. For this purpose, albino mice (n = 18) were equally divided into control and two treatment groups. The control group was fed on a plain diet while treatment groups were given a diet having n‐Hexane (treatment 1) and ethyl acetate (treatment 2) extracts of C. sativa L. (10 mg/kg body weight), respectively. The hot plate test (M = 15.61, SD = 2.61, p =.001), grip strength (M = 68.32, SD = 3.22, p <.001), and sciatic functional index (SFI) (M = 11.59, SD = 6.54, p =.012) assessment indicated significant amelioration in treatment 1 as compared to treatment 2 group. Furthermore, muscle fiber cross‐sectional area revealed a noticeable improvement (M = 182,319, SD = 35.80, p =.013) in treatment 1 while muscle mass ratio of Gastrocnemius (M = 0.64, SD = 0.08, p =.427) and Tibialis anterior (M = 0.57, SD = 0.04, p =.209) indicated nonsignificant change. A prominent increase in total antioxidant capacity (TAC) (M = 3.76, SD = 0.38, p <.001) and momentous decrease in total oxidant status (TOS) (M = 11.28, SD = 5.71, p <.001) along with blood glucose level indicated significant difference (M = 105.5, SD = 9.12, p < 0.001) in treatment 1 group. These results suggest that treatment 1 has the ability to speed up functional recovery after a peripheral nerve lesion. Further research is necessary, nevertheless, to better understand the extract's actual curative properties and the mechanisms that improve functional restoration. [ABSTRACT FROM AUTHOR]

The current study was designed to formulate ternary solid dispersions (TSDs) of dexibuprofen (Dex) by solvent evaporation to augment the solubility and dissolution profile, in turn providing gastric protection and effective anti-inflammatory activity. Initially, nine formulations (S1 to S9) of binary solid dispersions (BSDs) were developed. Formulation S1 comprising a 1:1 weight ratio of Dex and Syloid 244FP® was chosen as the optimum BSD formulation due to its better solubility profile. Afterward, 20 TSD formulations were developed using the optimum BSD. The formulation containing Syloid 244FP® with 40% Gelucire 48/16® (S18) and Poloxamer 188® (S23) successfully enhanced the solubility by 28.23 and 38.02 times, respectively, in pH 6.8, while dissolution was increased by 1.99- and 2.01-fold during the first 5 min as compared to pure drug. The in vivo gastroprotective study in rats suggested that the average gastric lesion index was in the order of pure Dex (8.33 ± 2.02) > S1 (7 ± 1.32) > S18 (2.17 ± 1.61) > S23 (1.83 ± 1.04) > control (0). The in vivo anti-inflammatory study in rats revealed that the percentage inhibition of swelling was in the order of S23 (71.47 ± 2.16) > S18 (64.8 ± 3.79) > S1 (54.14 ± 6.78) > pure drug (18.43 ± 2.21) > control (1.18 ± 0.64) after 6 h. ELISA results further confirmed the anti-inflammatory potential of the developed formulation, where low levels of IL-6 and TNF alpha were reported for animals treated with S23. Therefore, S23 could be considered an effective formulation that not only enhanced the solubility and bioavailability but also reduced the gastric irritation of Dex. [ABSTRACT FROM AUTHOR]

Triazole-based acetamides serve as important scaffolds for various pharmacologically active drugs. In the present work, structural hybrids of 1,2,4-triazole and acetamides were furnished by chemically modifying 2-(4-isobutylphenyl) propanoic acid (1). Target compounds 7a–f were produced in considerable yields (70–76%) by coupling the triazole of compound 1 with different electrophiles under different reaction conditions. These triazole-coupled acetamide derivatives were verified by physiochemical and spectroscopic (HRMS, FTIR, 13CNMR, and 1HNMR,) methods. The anti-liver carcinoma effects of all of the derivatives against a HepG2 cell line were investigated. Compound 7f, with two methyl moieties at the ortho-position, exhibited the highest anti-proliferative activity among all of the compounds with an IC50 value of 16.782 µg/mL. 7f, the most effective anti-cancer molecule, also had a very low toxicity of 1.190.02%. Molecular docking demonstrates that all of the compounds, especially 7f, have exhibited excellent binding affinities of −176.749 kcal/mol and −170.066 kcal/mol to c-kit tyrosine kinase and protein kinase B, respectively. Compound 7f is recognized as the most suitable drug pharmacophore for the treatment of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

In this work, BTEAC (benzyl triethylammonium chloride) was employed as a phase transfer catalyst in an improved synthesis (up to 88% yield) of S-alkylated bromobenzofuran-oxadiazole scaffolds BF1-9. These bromobenzofuran-oxadiazole structural hybrids BF1-9 were evaluated in vitro against anti-hepatocellular cancer (HepG2) cell line as well as for their in silico therapeutic potential against six key cancer targets, such as EGFR, PI3K, mTOR, GSK-3β, AKT, and Tubulin polymerization enzymes. Bromobenzofuran structural motifs BF-2, BF-5, and BF-6 displayed the best anti-cancer potential and with the least cell viabilities (12.72 ± 2.23%, 10.41 ± 0.66%, and 13.08 ± 1.08%), respectively, against HepG2 liver cancer cell line, and they also showed excellent molecular docking scores against EGFR, PI3K, mTOR, and Tubulin polymerization enzymes, which are major cancer targets. Bromobenzofuran-oxadiazoles BF-2, BF-5, and BF-6 displayed excellent binding affinities with the active sites of EGFR, PI3K, mTOR, and Tubulin polymerization enzymes in the molecular docking studies as well as in MMGBSA and MM-PBSA studies. The stable bindings of these structural hybrids BF-2, BF-5, and BF-6 with the enzyme targets EGFR and PI3K were further confirmed by molecular dynamic simulations. These investigations revealed that 2,5-dimethoxy-based bromobenzofuran-oxadiazole BF-5 (10.41 ± 0.66% cell viability) exhibited excellent cytotoxic therapeutic efficacy. Moreover, computational studies also suggested that the EGFR, PI3K, mTOR, and Tubulin polymerization enzymes were the probable targets of this BF-5 scaffold. In silico approaches, such as molecular docking, molecular dynamics simulations, and DFT studies, displayed excellent association with the experimental biological data of bromobenzofuran-oxadiazoles BF1-9. Thus, in silico and in vitro results anticipate that the synthesized bromobenzofuran-oxadiazole hybrid BF-5 possesses prominent anti-liver cancer inhibitory effects and can be used as lead for further investigation for anti-HepG2 liver cancer therapy. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy is one of the most prevalent complications of diabetes mellitus. It is the most common type of neuropathy characterized by decreased sensory functions in the lower extremities and substantial neuropathic pain. Based on clinical characterization, it is classified into symmetric and asymmetric neuropathy. The pathological changes and neuronal function impairment during diabetes are associated with various pathways, including polyol pathway activation, advanced glycation end-products formation, oxidative stress, protein kinase C activation, poly ADP-ribose polymerase, and hexosamine pathways. Demyelination, axonal atrophy, nerve fibre loss, reduced regeneration, and loss of neurovascular interactions are hallmarks. Although some symptomatic and supportive therapies, such as tricyclic agents, antiarrhythmics, opioid analgesics, incretin, aldose reductase, and protein kinase C inhibitors, are in practice, the outcome is not promising. To fill this gap, natural product-based therapy can prove prodigious as an effective alternative. This review aims to comprehend the available literature on the role of various biological molecules in ameliorating diabetic peripheral neuropathy. These molecules play a key role in reducing oxidative-nitrosative stress, aldose reductase activity, and neuronal apoptosis. They control glucose and HbA1c% levels and improve nerve conduction velocity, axonal regeneration, and antioxidant species (catalase, superoxide dismutase, malondialdehyde). They are known for their attenuating thermal and mechanical hyperalgesia and tactile allodynia. Therefore, there is a need to evaluate these molecules at the pre-clinical and clinical levels for efficacy. Hence, natural molecules may act as promising players against diabetic peripheral neuropathy and are a ray of hope for suffering individuals. [ABSTRACT FROM AUTHOR]

Targeting pentose phosphate pathway (PPP) enzymes has emerged as a promising strategy to combat cancer. 6-Phosphogluconate dehydrogenase (6-PGD), the third critical enzyme of the PPP, catalyzes oxidative decarboxylation of 6-phosphogluconate (6-PG) to produce ribulose-5-phosphate (Ru-5-P) and CO2. Overexpression of 6-PGD has been reported in multiple cancers and is recognized as a potential anticancer drug target. The current study is focused on the utilization of indispensable virtual screening tools for structure-based drug discovery. During the study, 17,000 natural compounds were screened against the 3-phosphoglycerate (3-PG) binding site of 6-PGD through a molecular operating environment (MOE), which revealed 115 inhibitors with higher selectivity and binding affinity. Out of the 115 best-fit compounds within the 6-PGD binding cavity, 15 compounds were selected and optimized through stringent in silico ADMET assessment models that justified the desirable pharmacokinetic, pharmacodynamic and physicochemical profiles of 5 ligands. Further protein–ligand stability assessment through molecular dynamics (MD) simulation illustrated three potential hits, secoisolariciresinol, syringaresinol and cleomiscosin A, with stable confirmation. Moreover, 6-PGD inhibitor validation was performed by an in vitro enzymatic assay using human erythrocytes purified 6-PGD protein and A549 cell lysate protein. The results of the in vitro assays supported the in silico findings. In order to gain insight into the anticancer activity of the aforementioned compounds, they were subjected to CLC-Pred, an in silico cytotoxicity browsing tool, which proved their anticancer activity against several cancer cell lines at Pa > 0.5. Additionally, a confirmation for in silico cytotoxicity was made by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for commercially available hits syringaresinol and cleomiscosin A against lung cancer (A549) cells. The results demonstrated that syringaresinol has an IC50 value of 36.9 μg/mL, while cleomiscosin A has an IC50 value of 133 μg/mL. After MTT, flow cytometry analysis confirmed that compounds induced apoptosis in A549 cells in a dose-dependent manner. This study suggested that the respective lignan compounds can serve as lead candidates for lung cancer therapy via 6-PGD inhibition. Furthermore, in vivo experiments need to be conducted to confirm their efficacy. [ABSTRACT FROM AUTHOR]

Novel azomethines derived from acefylline tethered triazole hybrids (7a-k) have been synthesized and evaluated against human liver cancer cell line (Hep G2) using MTT assay. The synthesized series of azomethines exhibited promising efficacy against liver cancer cell line. Screening of the synthesized series identified compound 7d with the least cell viability value (11.71 ± 0.39%) as the most potent anticancer agent in contrast to the reference drug acefylline (cell viability = 80 ± 3.87%). In this study, the potentials of the novel agents (7a-k) to inhibit liver cancer proteins were assessed. Subsequently, the structure-activity relationship of the potential drug candidates was assessed via ADME/T molecular screening. The cytotoxic potential of these derivatives was also investigated by hemolysis and thrombolysis. Their hemolytic and thrombolytic studies showed that all of these drugs had very low cytotoxicity and moderate clot lysis activity. Compound 7g (0.26% hemolysis) and 7k (52.1% clot lysis) were the least toxic and moderate thrombolytic agents respectively. [ABSTRACT FROM AUTHOR]

Axons in the peripheral nervous system have the ability to repair themselves after damage, whereas axons in the central nervous system are unable to do so. A common and important characteristic of damage to the spinal cord, brain, and peripheral nerves is the disruption of axonal regrowth. Interestingly, intrinsic growth factors play a significant role in the axonal regeneration of injured nerves. Various factors such as proteomic profile, microtubule stability, ribosomal location, and signalling pathways mark a line between the central and peripheral axons' capacity for self-renewal. Unfortunately, glial scar development, myelin-associated inhibitor molecules, lack of neurotrophic factors, and inflammatory reactions are among the factors that restrict axonal regeneration. Molecular pathways such as cAMP, MAPK, JAK/STAT, ATF3/CREB, BMP/SMAD, AKT/mTORC1/p70S6K, PI3K/AKT, GSK-3β/CLASP, BDNF/Trk, Ras/ERK, integrin/FAK, RhoA/ROCK/LIMK, and POSTN/integrin are activated after nerve injury and are considered significant players in axonal regeneration. In addition to the aforementioned pathways, growth factors, microRNAs, and astrocytes are also commendable participants in regeneration. In this review, we discuss the detailed mechanism of each pathway along with key players that can be potentially valuable targets to help achieve quick axonal healing. We also identify the prospective targets that could help close knowledge gaps in the molecular pathways underlying regeneration and shed light on the creation of more powerful strategies to encourage axonal regeneration after nervous system injury. [ABSTRACT FROM AUTHOR]

The development of an economical method for the synthesis of biologically active compounds was the major goal of this research. In the present study, we have reported the ultrasound-radiation-assisted synthesis of a series of novel N-substituted 1,2,4-triazole-2-thiol derivatives. The target compounds 6a–f were efficiently synthesized in significant yields (75–89%) by coupling 1,2,4-triazole of 2-(4-isobutylphenyl) propanoic acid 1 with different electrophiles using ultrasound radiation under different temperatures. The sonication process accelerated the rate of the reaction as well as yielded all derivatives compared to conventional methods. All derivatives were confirmed by spectroscopic (FTIR, 1HNMR, 13CNMR, HRMS) and physiochemical methods. All derivatives were further screened for their anticancer effects against the HepG2 cell line. Compound 6d containing two electron-donating methyl moieties demonstrated the most significant anti-proliferative activity with an IC50 value of 13.004 µg/mL, while compound 6e showed the lowest potency with an IC50 value of 28.399 µg/mL. The order of anticancer activity was found to be: 6d > 6b > 6f > 6a > 6c > 6e, respectively. The in silico modelling of all derivatives was performed against five different protein targets and the results were consistent with the biological activities. Ligand 6d showed the best binding affinity with the Protein Kinase B (Akt) pocket with the lowest ∆G value of −176.152 kcal/mol. Compound 6d has been identified as a promising candidate for treatment of liver cancer. [ABSTRACT FROM AUTHOR]

Polydatin or 3-O-β-d-resveratrol-glucopyranoside (PD), a stilbenoid component of Polygonum cuspicadum (Polygonaceae), has a variety of biological roles. In traditional Chinese medicine, P. cuspicadum extracts are used for the treatment of infections, inflammation, and cardiovascular disorders. Polydatin possesses a broad range of biological activities including antioxidant, anti-inflammatory, anticancer, and hepatoprotective, neuroprotective, and immunostimulatory effects. Currently, a major proportion of the population is victimized with cervical lung cancer, ovarian cancer and breast cancer. PD has been recognized as a potent anticancer agent. PD could effectively inhibit the migration and proliferation of ovarian cancer cells, as well as the expression of the PI3K protein. The malignancy of lung cancer cells was reduced after PD treatments via targeting caspase 3, arresting cancer cells at the S phase and inhibiting NLRP3 inflammasome by downregulation of the NF-κB pathway. This ceases cell cycle, inhibits VEGF, and counteracts ROS in breast cancer. It also prevents cervical cancer by regulating epithelial-to-mesenchymal transition (EMT), apoptosis, and the C-Myc gene. The objective of this review is thus to unveil the polydatin anticancer potential for the treatment of various tumors, as well as to examine the mechanisms of action of this compound. [ABSTRACT FROM AUTHOR]

The reliance of tumor cells on aerobic glycolysis is one of the emerging hallmarks of cancer. Pyruvate kinase M2 (PKM2), an important enzyme of glycolytic pathway, is highly expressed in a number of cancer cells. Tumor cells heavily depend on PKM2 to fulfill their divergent energetic and biosynthetic requirements, suggesting it as novel drug target for cancer therapies. Based on this context, we performed enzymatic-assay-based screening of the in-house phenolic compounds library for the identification of PKM2 inhibitors. This screening identified silibinin, curcumin, resveratrol, and ellagic acid as potential inhibitors of PKM2 with IC50 values of 0.91 µM, 1.12 µM, 3.07 µM, and 4.20 µM respectively. For the determination of Ki constants and the inhibition type of hit compounds, Lineweaver–Burk graphs were plotted. Silibinin and ellagic acid performed the competitive inhibition of PKM2 with Ki constants of 0.61 µM and 5.06 µM, while curcumin and resveratrol were identified as non-competitive inhibitors of PKM2 with Ki constants of 1.20 µM and 7.34 µM. The in silico screening of phenolic compounds against three binding sites of PKM2 provided insight into the binding pattern and functionally important amino residues of PKM2. Further, the evaluation of cytotoxicity via MTT assay demonstrated ellagic acid as potent inhibitor of cancer cell growth (IC50 = 20 µM). These results present ellagic acid, silibinin, curcumin, and resveratrol as inhibitors of PKM2 to interrogate metabolic reprogramming in cancer cells. This study has also provided the foundation for further research to validate the potential of identified bioactive entities for PKM2 targeted-cancer therapies. [ABSTRACT FROM AUTHOR]

The Covid-19, a threatening pandemic, was originated from China in December 2019 and spread quickly to all over the world. The pathogenesis of coronavirus is linked with the disproportionate response of the immune system. This involves the systemic inflammatory reaction which is characterized by marked pro-inflammatory cytokine release commonly known as cytokine release storm (CRS). The pro inflammatory cytokines are involved in cascade of pulmonary inflammation, hyper coagulation and thrombosis which may be lethal for the individual. That's why, it is very important to have understanding of pro inflammatory cytokines and their pathological role in SARS-CoV-2. The pathogenesis of Covid is not the same in every individual, it can vary due to the presence of pre-existing comorbidities like suffering from already an inflammatory disease such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), an immune-compromised patients suffering from Diabetes Mellitus (DM) and Tuberculosis (TB) are more vulnerable morbidity and complications following COVID-19. This review is particularly related to COVID-19 patients having comorbidity of other inflammatory diseases. We have discussed the brief pathogenesis of COVID-19 and cytokines release storm with reference to other co-morbidities including RA, IBD, COPD, DM and TB. The available therapeutic regimens for COVID-19 including cytokine inhibitors, anti-viral, anti-biotic, bronchodilators, JAK- inhibitors, immunomodulators and anti-fibrotic agents have also been discussed briefly. Moreover, newly emerging medicines in the clinical trials have also been discussed which are found to be effective in treating Covid-19. [ABSTRACT FROM AUTHOR]

Targeting the serine biosynthesis pathway enzymes has turned up as a novel strategy for anti-cancer therapeutics. 3- Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme that catalyzes the conversion of 3-Phosphoglyceric acid (3-PG) into 3-Phosphohydroxy pyruvate (3-PPyr) in the first step of serine synthesis pathway and perform a critical role in cancer progression. PHGDH has been reported to be overexpressed in different types of cancers and emerged as a novel target for cancer therapeutics. During this study, virtual screening tools were used for the identification of inhibitors of PHGDH. A library of phenolic compounds was docked against two binding sites of PHGDH using Molegro Virtual Docker (MVD) software. Out of 169 virtually tested compounds, Salvianolic acid C and Schizotenuin F possess good binding potential to co-factor binding site of PHGDH while Salvianolic acid I and Chicoric acid were identified as the best binding compounds toward the substrate binding site of PHGDH. The top selected compounds were evaluated for different physiochemical and ADMET properties, the obtained results showed that none of these hit compounds violated the Pfizer Rule and they possess acceptable ADMET profiles. Further, a commercially available hit compound, Chicoric acid, was evaluated for its anti-cancer potential against PHGDH-expressing gastric cancer cell lines (MGC-803 and SGC-7901) as well as cell lines with low expression of PHGDH (MCF-7 and MDA-MB2-31), which demonstrated that Chicoric acid possesses selective cytotoxicity toward PHGDH expressing cancer cell lines. Thus, this study has unveiled the potential of phenolic compounds, which could serve as novel candidates for the development of PHGDH inhibitors as anti-cancer agents. [ABSTRACT FROM AUTHOR]

Newcastle disease virus (NDV) is a highly contagious virus of domesticated (i.e. chickens, peacock, pet birds) and wild birds, which is excreted in the fecal material of infected birds. The house fly, Musca domestica L. can gain entry into the poultry flocks and will feed on poultry droppings and potentially serves as a mechanical vector for Newcastle disease. During the current study, houseflies were captured and examined for the presence of NDV. A total of 80 samples were collected from eight different poultry farms located around Faisalabad city with ten samples from each farm viz. Khurrianwala road, Shahkot road, Faisalabad road, Satyana road, Jhumra road, Nankana sahib road, Lahore road and Jaranwala road. Homogenate from house flies was first harvested in 11 day old embryonated chicken eggs to propagate the NDV, which was then titrated using haemagglutination inhibition assay for quantification of NDV. Polyclonal antibodies were produced in experimental rabbits followed by titration. These antibodies were then used to detect the presence of NDV. Sixteen samples were found positive (20%), 62 negative (77.5 %) and two unreactive (2.5 %) for NDV. All of the poultry farms around Faisalabad showed positive NDV (ranging from 1 to 4 samples). We conclud that house flies can play a role in the mechanical transmission of ND virus. Moreover, it is also suggested that positive poultry farms are likely to cause NDV infection to other farms in the vicinity due to the house fly flight range. [ABSTRACT FROM AUTHOR]

Piperazine-based dithiocarbamates serve as important scaffolds for numerous pharmacologically active drugs. The current study investigates the design and synthesis of a series of dithiocarbamates with a piperazine unit as well as their biological activities. Under ultrasound conditions, the corresponding piperazine-1-carbodithioates 5a–5j were synthesized from monosubstituted piperazine 2 and N-phenylacetamides 4a–4j in the presence of sodium acetate and carbon disulfide in methanol. The structures of the newly synthesized piperazines were confirmed, and their anti-lung carcinoma effects were evaluated. A cytotoxic assay was performed to assess the hemolytic and thrombolytic potential of the synthesized piperazines 5a–5j. The types of substituents on the aryl ring were found to affect the anticancer activity of piperazines 5a–5j. Piperazines containing 2-chlorophenyl (5b; cell viability = 25.11 ± 2.49) and 2,4-dimethylphenyl (5i; cell viability = 25.31 ± 3.62) moieties demonstrated the most potent antiproliferative activity. On the other hand, piperazines containing 3,4-dichlorophenyl (5d; 0.1%) and 3,4-dimethylphenyl (5j; 0.1%) rings demonstrated the least cytotoxicity. The piperazine with the 2,5-dimethoxyphenyl moiety (5h; 60.2%) showed the best thrombolytic effect. To determine the mode of binding, in silico modeling of the most potent piperazine (i.e., 5b) was performed, and the results were in accordance with those of antiproliferation. It exhibits a similar binding affinity to PQ10 and an efficient conformational alignment with the lipophilic site of PDE10A conserved for PQ10A. [ABSTRACT FROM AUTHOR]

The research was conducted to estimate the efficacy of Se nanoparticles on mineral absorption and carcass composition of C. mrigala fingerlings fed nano-Se particles supplemented sunflower meal based diets. The experiment was consisted on seven test diets on the basis of supplementation of nano Se graded levels (0, 0.5, 1, 1.5, 2, 2.5 and 3 mg/kg). Chromic oxide was added as an inert marker. Fingerlings were fed at the rate of 5% of their live wet weight. Maximum improvement in mineral absorption (Ca, Na, K, Cu, P and Al) was observed at test diet with 1.5 mg/kg supplementation of Se nanoparticles. Maximum Fe, Mn and Cr absorption was noted at 2 mg/kg supplementation of nano Se. The highest absorption of Mg and Zn was found in the fingerlings fed at test diet with 1 mg/kg supplementation of nano Se particles. The best results in regard of body composition (CP; 61% and EE; 14%) were noted in fingerlings when fed 1.5 mg/kg levels of Se-nano particles based diets. It was concluded from the results of current study that supplementation of Se NPs (1.5 mg/kg) in sunflower meal based diet improves the mineral absorption and body composition of C. mrigala fingerlings. [ABSTRACT FROM AUTHOR]

The research project was designed to check the effect of polyphenols supplemented canola meal-based diet on proximate composition, mineral absorption and hematology of Cyprinus carpio fingerlings. The diets were formulated in such a way that sufficient supply of all required nutrients were ensured for normal fish growth. Collection of feces from each tank was done twice a day. Impact of each treatment on the absorption of minerals, proximate analysis and hematology were determined using standard methods and formulae. Highest minerals absorption (Ca, Na, K, Fe, Cu, P, Mg and Al) was observed in the fish fed at 400mg/kg of polyphenols in canola meal based diets. Similarly, best hematological parameters (RBCs, WBCs, PLT, Hb, PCV, MCHC, MCH and MCV) as well as proximate composition (crude protein, crude fat, ash, moisture and carbohydrates) were noted in fish group fed on 400mg/kg of polyphenols in diet. Hence supplementation of polyphenols at 400mg/kg was found to be optimum for better hematology, minerals absorption and carcass composition of common carp. [ABSTRACT FROM AUTHOR]

The synthesis of novel acefyllines and exploring their biological activities attract researchers due to their medicinal applications. Therefore, the current work reports the successful synthesis of a series of novel acefyllines in good yields, and their structures wereconfirmed using various spectroscopic methods. The synthesized acefyllines demonstrated moderate activity (cell viability = 22.55 ± 0.95% − 57.63 ± 3.65%) compared with the starting drug acefylline (cell viability = 80 ± 3.87%) against the human liver carcinoma (Hep G2 cell line). N-(4-Chlorophenyl)-2-(4-(3,4-dichlorophenyl)-5-((1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)methyl)-4H-1,2,4-triazol-3-ylthio)acetamide exhibited the most potent activity (cell viability = 22.55 ± 0.95%) among the synthesized derivatives. The in silico modeling studies were performed to predict the binding of the most potent derivative with a binding site that agreed with the results of the antiproliferative activity. The newly synthesized heterocycles exhibited the least hemolytic and moderate clot lysis activity. [ABSTRACT FROM AUTHOR]

In the present work, nonwoven cotton fabric was modified for antibacterial applications using low-cost and eco-friendly precursors. The treatment of fabric with alkali leads to the formation of active sites for surface modification, followed by dip coating with silver nanoparticles and chitosan. The surface was chlorinated in the next step to transform amide (N–H) groups in chitosan into N-halamine (N-Cl). The modified and unmodified surfaces of the nonwoven cotton fabric have been characterized by FTIR, SEM, and XRD. The active chlorine loading is measured with iodine/sodium thiosulphate. The antimicrobial activity and cell toxicity assay were carried out with and without modifications of nonwoven cotton fabric. The antimicrobial efficacies of loaded fabric were evaluated against four bacterial species (Micrococcus luteus, Staphylococcus aureus, Enterobacter aerogenes, and E.coli). It was found that modified fabric exhibited superior efficiency against gram-positive and gram-negative bacterial strains as compared to their bulk counterparts upon exposure without affecting strength and integrity of fabric. The overall process is economical for commercial purposes. The modified fabric can be used for antimicrobial, health, and food packaging industries, and in other biomedical applications. [ABSTRACT FROM AUTHOR]

The study was intended to find in vitro antioxidant, cytotoxicity and safety profile of Polystichum braunii roots extracts and chemically characterise it by GC–MS and FTIR spectroscopy. Acute and sub-chronic (90-day oral repeated dose at 150, 300 and 600 mg/kg) toxicity studies of P. braunii methanol extract (PBME) were performed in Wistar rats by adopting OECD guidelines. The PBME exerted the highest in vitro antioxidant potential. There was no substantial change in blood parameters and body weight except a notable (p < 0.01) rise in ALT, ALP, MDA and HDL, and decrease in cholesterol and LDL (p < 0.05) in animals sub-chronically treated with PBME at 600 mg/kg dose. The IC50 in HepG2 was more than 1000 µg/ml. The GC–MS analysis revealed Pentadecanoic acid and 9,12-Octadecadienoic acid in PBME. The P. braunii might be safe in acute usage, however, monitoring of liver function tests should be carried out during long-term use. [ABSTRACT FROM AUTHOR]

The Hippo signaling pathway extorts several signals that concomitantly target the activity of transcriptional cofactor yes associated protein (YAP). YAP is a key regulator that elicits signature gene expression by coupling with transcriptional enhanced associate domain (TEAD) family of transcriptional factors. The YAP‐TEAD complex via target gene expression gets associated with the development, proliferation, and progression of cancerous cells. Moreover, YAP adorns cells with several oncogenic traits such as inhibition of apoptosis, enhanced proliferation, drug resistance, and immune response suppression, which later became associated with various diseases, particularly cancer. Therefore, inhibition of the YAP activity is an appealing and viable therapeutic target for cancer treatment. This review highlights the recent advances in existing and novel synthetic therapeutics targeting YAP inhibition and regulation. The synthetically produced YAPD93A belonging to cyclic peptides and DC‐TEADin02 and vinyl sulfonamide class of compounds are the most potent compounds to inhibit the YAP‐TEAD expression by targeting protein‐protein interaction (IC50 = 25 nM) and palmitate binding central pocket of TEAD (IC50 = 197 nM), respectively. On the other hand, Chlorpromazine belonging to phenothiazines class has the least potential to suppress YAP via proteasomal degradation (cell viability value of <20% at 40 µM). [ABSTRACT FROM AUTHOR]

The flare‐up in severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) that emerged in December 2019 in Wuhan, China, and spread expeditiously worldwide has become a health challenge globally. The rapid transmission, absence of anti‐SARS‐CoV‐2 drugs, and inexistence of vaccine are further exacerbating the situation. Several drugs, including chloroquine, remdesivir, and favipiravir, are presently undergoing clinical investigation to further scrutinize their effectiveness and validity in the management of COVID‐19. Natural products (NPs) in general, and plants constituents specifically, are unique sources for various effective and novel drugs. Immunostimulants, including vitamins, iron, zinc, chrysin, caffeic acid, and gallic acid, act as potent weapons against COVID‐19 by reinvigorating the defensive mechanisms of the immune system. Immunity boosters prevent COVID‐19 by stimulating the proliferation of T‐cells, B‐cells, and neutrophils, neutralizing the free radicals, inhibiting the immunosuppressive agents, and promoting cytokine production. Presently, antiviral therapy includes several lead compounds, such as baicalin, glycyrrhizin, theaflavin, and herbacetin, all of which seem to act against SARS‐CoV‐2 via particular targets, such as blocking virus entry, attachment to host cell receptor, inhibiting viral replication, and assembly and release. [ABSTRACT FROM AUTHOR]

Peripheral nerve damage is a debilitating condition that can result in partial or complete functional loss as a result of axonal degeneration, as well as lifelong dependence. Many therapies have been imbued with a plethora of positive features while posing little risks. It is worth noting that these biomolecules work by activating several intrinsic pathways that are known to be important in peripheral nerve regeneration. Although the underlying mechanism is used for accurate and speedy functional recovery, none of them are without side effects. As a result, it is believed that effective therapy is currently lacking. The dietary biomolecules‐based intervention, among other ways, is appealing, safe, and effective. Upregulation of transcription factors, neurotrophic factors, and growth factors such as NGF, GDNF, BDNF, and CTNF may occur as a result of these substances' dietary intake. Upregulation of the signaling pathways ERK, JNK, p38, and PKA has also been seen, which aids in axonal regeneration. Although several mechanistic approaches to understanding their involvement have been suggested, more work is needed to reveal the amazing properties of these biomolecules. We have discussed in this article that how different dietary biomolecules can help with functional recovery and regeneration after an injury. Practical applications: Based on the information known to date, we may conclude that treatment techniques for peripheral nerve injury have downsides, such as complications, donor shortages, adverse effects, unaffordability, and a lack of precision in efficacy. These difficulties cast doubt on their efficacy and raise severe concerns about the prescription. In this situation, the need for safe and effective therapeutic techniques is unavoidable, and dietary biomolecules appear to be a safe, cost‐efficient, and effective way to promote nerve regeneration following an injury. The information on these biomolecules has been summarized here. Upregulation of transcription factors, neurotrophic factors, and growth factors, such as NGF, GDNF, BDNF, and CTNF, as well as the ERK, JNK, p38, and PKA, signaling pathways, may stimulate axonal regeneration. [ABSTRACT FROM AUTHOR]

Objectives: Tramadol, an atypical opioid, is clinically efficacious in treating moderate to severe pain. The aim of current study was to find out the toxicological effects of tramadol exposure to pregnant rats and fetuses during the late phase of pregnancy. Methods: Wistar pregnant rats were exposed to 1.25, 2.5, or 5 mg/kg/day tramadol from 14th to 20th day of pregnancy. The same therapy was given to nonpregnant rats for 7 days. The body weight, oral glucose and lipid tolerance tests, and effect on complete blood parameters in both pregnant and nonpregnant rats were determined. On 20th day, maternal placentas were excised and weighed while fetuses were observed for any deformity and growth retardation. Oxidative stress biomarkers were estimated in the liver and kidney tissue homogenates of the pregnant and nonpregnant rats while the whole fetus homogenate was processed for the same. Moreover, histopathology of the liver and kidney of pregnant and nonpregnant rats were carried out. Results: Tramadol administration did not significantly alter the area under curve of the blood glucose and triglyceride levels in both the pregnant and nonpregnant rats. It reduced the live fetuses, placental weights, fetal length, and fetal weights. Tramadol treated pregnant rats showed significantly (p <.05) reduced red blood cells, hematocrit, hemoglobin, and platelets with reference to control group. Similarly, structural abnormalities and malfunctioning of the liver and kidney of pregnant rats were instituted; however, it did not affect the structural integrity of nonpregnant rats. A substantial (p <.001–.0001) altered glutathione and malondialdehyde levels in the fetuses, pregnant, and nonpregnant animals (tissue homogenates) at all dosage levels were indicative of tramadol induced oxidative stress. Furthermore, tramadol exposure resulted in more significant (p <.01–.001) alteration of lipid profile in the pregnant than the nonpregnant animals. Conclusion: Acquired results suggested the maternotoxic and fetotoxic effects of tramadol exposure during the late gestation period. [ABSTRACT FROM AUTHOR]

Nickel nanoparticles (Ni NPs) are utilized extensively in various industrial applications. However, there are increasing concerns about potential exposure to Ni NPs and consequent health effects. The aim of this study was to assess Ni NPs-induced liver toxicity in Sprague Dawley rats. Twenty-five rats were exposed to Ni NPs via intraperitoneal injection at doses of 15, 30, and 45 mg/kg per body weight for 28 days. Results from ICP-MS analysis showed an increase in the concentration of Ni NPs in a dose-dependent manner. The liver dysfunction was indicated by considerable production of ALT, AST, ALP, LDH, and TB in Ni NPs-treated rats. Histological examination demonstrated liver injuries (inflammatory cells, congestion, necrosis, and pyknosis) in exposed rats with dose-dependent severity of pathologies by semi-quantitative histograding system. To explore the toxicological pathways, we examined oxidative stress biomarkers and detected Ni NPs significantly elevated the levels of MDA and LPO while decreasing the levels of CAT and GSH. All the changes in biomarkers were recorded in a dose-dependent relationship. In addition, we found upregulated NF-kβ indicating activation of inflammatory cytokines. ELISA results of serum revealed a remarkable increase of nitrative stress markers (iNOS and NO), ATPase activity, inflammatory cytokine (IL-6, IL-1β, and TNF-α), and apoptotic mediators (caspase-3 and caspase-9) in Ni NPs-treated groups than the control. In summary, the result of this study provided evidence of hepatotoxicity of Ni NPs and insightful information about the involved toxic pathways, which will help in health risk assessment and management, related preventive measures for the use of Ni-NPs materials. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries are among those complicated medical conditions, which are still waiting for their highly effective first‐line therapies. In this study, the role of Calotropis procera crude leaves was evaluated at different doses for their effectiveness in improving functional recovery following sciatic nerve injury‐induced in the mouse model. Thirty‐two healthy albino mice were divided into four groups as Normal chow group (control, n = 8) and C. procera chow groups (50 mg/kg (n = 8), 100 mg/kg (n = 8) and 200 mg/kg (n = 8)). Behavioral analyses were performed to assess and compare improved functional recovery along with skeletal muscle mass measurement in all groups. Serum samples were analyzed for oxidative stress markers. Results showed that C. procera leaves at dose‐dependent manner showed statistically prominent (p <.05) increase in sensorimotor functions reclamation as confirmed by behavioral analyses along with muscle mass restoration and prominent decline in TOS and momentous increase in TAC along with the augmented activity of antioxidative enzymes. [ABSTRACT FROM AUTHOR]

The Dhok Pathan Formation of Middle Siwaliks is remarkably rich for the fossils of ungulates. The fauna consists of Cervidae, Giraffidae, Tragulidae and Suidae but the fossils of family bovidae are more abundant. The 23 collected and described specimens here belong to seven species which are Selenoportax vexillarius, Pachyportax latidens, Miotragocerus cf. gluten, Gazella lydekkeri, Dorcatherium majus, Propotamochoerus hysudricus and Tetraconodon cf. magnus. The described material consists of both upper and lower dentition. The fossil-bearing locality is located near Padhri village 55 km away from the tehsil Dina, district Jhelum. It is mainly composed of claystone, sand-stone and siltstone beds. The studied locality dated to Late Miocene. This Formation was deposited in subtropical condition. Bovids were predominant in Padhri, which indicate the highly moist conditions with small but numerous open standing water bodies. [ABSTRACT FROM AUTHOR]

At present, after extensive studies in the field of cancer, cancer stem cells (CSCs) have been proposed as a major factor in tumor initiation, progression, metastasis, and recurrence. CSCs are a subpopulation of bulk tumors, with stem cell-like properties and tumorigenic capabilities, having the abilities of self-renewal and differentiation, thereby being able to generate heterogeneous lineages of cancer cells and lead to resistance toward anti-tumor treatments. Highly resistant to conventional chemo- and radiotherapy, CSCs have heterogeneity and can migrate to different organs and metastasize. Recent studies have demonstrated that the population of CSCs and the progression of cancer are increased by the deregulation of different epigenetic pathways having effects on gene expression patterns and key pathways connected with cell proliferation and survival. Further, epigenetic modifications (DNA methylation, histone modifications, and RNA methylations) have been revealed to be key drivers in the formation and maintenance of CSCs. Hence, identifying CSCs and targeting epigenetic pathways therein can offer new insights into the treatment of cancer. In the present review, recent studies are addressed in terms of the characteristics of CSCs, the resistance thereof, and the factors influencing the development thereof, with an emphasis on different types of epigenetic changes in genes and main signaling pathways involved therein. Finally, targeted therapy for CSCs by epigenetic drugs is referred to, which is a new approach in overcoming resistance and recurrence of cancer. [ABSTRACT FROM AUTHOR]

Pyruvate kinase (PK), a key enzyme that determines glycolytic activity, has been known to support the metabolic phenotype of tumor cells, and specific pyruvate kinase isoform M2 (PKM2) has been reported to fulfill divergent biosynthetic and energetic requirements of cancerous cells. PKM2 is overexpressed in several cancer types and is an emerging drug target for cancer during recent years. Therefore, this study was carried out to identify PKM2 inhibitors from natural products for cancer treatment. Based on the objectives of this study, firstly, plant extract library was established. In order to purify protein for the establishment of enzymatic assay system, pET-28a-HmPKM2 plasmid was transformed to E. coli BL21 (DE3) cells for protein expression and purification. After the validation of enzymatic assay system, plant extract library was screened for the identification of inhibitors of PKM2 protein. Out of 51 plant extracts screened, four extracts Mangifera indica (leaf, seed, and bark) and Bombex ceiba bark extracts were found to be inhibitors of PKM2. In the current study, M. indica (leaf, seed, and bark) extracts were further evaluated dose dependently against PKM2. These extracts showed different degrees of concentration-dependent inhibition against PKM2 at 90-360 μg/ml concentrations. We have also investigated the anticancer potential of these extracts against MDA-MB231 cells and generated dose-response curves for the evaluation of IC50 values. M. indica (bark and seed) extracts significantly halted the growth of MDA-MB231 cells with IC50 values of 108 μg/ml and 33 μg/ml, respectively. Literature-based phytochemical analysis of M. indica was carried out, and M. indica-derived 94 compounds were docked against three binding sites of PKM2 for the identification of PKM2 inhibitors. The results of in silico based screening have unveiled various PKM2 modulators; however, further studies are recommended to validate their PKM2 inhibitory potential via in vitro biochemical assay. The results of this study provide novel findings for possible mechanism of action of M. indica (bark and seed) extracts against TNBC via PKM2 inhibition suggesting that M. indica might be of therapeutic interest for the treatment of TNBC. [ABSTRACT FROM AUTHOR]

The current study was designed to evaluate the anti-oxidant and anti-arthritic potential of a traditionally used herb, Monotheca buxifolia. The M. buxifolia methanolic extract (MBME) was prepared from the aerial parts of the plant followed by chemical characterization with GC–MS. The anti-oxidant potential of the MBME was demonstrated by DPPH scavenging activity. The effects of MBME on protein denaturation and membrane stabilization were determined by inhibition of egg albumin denaturation and RBC membrane stabilization assays, respectively. The in vivo anti-arthritic potential of the MBME at 50, 100, and 150 mg/kg/day was evaluated in Complete Freund's Adjuvant-induced polyarthritis in Wistar rats treated for 21 days. Phytochemicals, such as linolenic acid methyl ester, n-hexadecanoic acid, vitamin E, α-amyrin, and β-amyrin were detected in the GC–MS analysis. The plant extract exhibited a 55.20 ± 0.69% scavenging of free radicals at 100 µg/ml concentration. It significantly (p < 0.05) stabilized human RBC membrane (65.06 ± 0.22%) and inhibited protein denaturation (70.53 ± 0.34%) at 100 mg/ml concentration. The diclofenac sodium (DS) and MBME at 150,100, and 50 mg/kg reduced the paw edema, restored the body weight, and altered blood parameters including CRP. The MBME significantly reduced the MDA and increased the SOD, CAT, and GSH levels in liver tissue homogenate in treated rats. The serum concentration of TNF-α and PGE2 was remarkably (p < 0.01–< 0.0001) restored by the DS and MBME dose dependently. The histopathological study showed that MBME 150 mg/kg commendably restored the ankle joint inflammation, bone erosion, and cartilage damage in polyarthritic rats. It was concluded that the anti-oxidant, anti-inflammatory and anti-arthritic effects of MBME might be attributed to phenols, flavonoids, triterpenoids, vitamin E, phytol, and other fatty acids. This study showed the anti-arthritic potential of Monotheca buxifolia and thus validates its traditional claim. [ABSTRACT FROM AUTHOR]

Stress caused due to examinations during any degree program and at any educational level has been observed at all levels so the present study was conducted to investigate the stress related to final examination in undergraduate students with reference to their academic performance. Fifty-four volunteers were divided into three groups, (n = 18), according to their academic performance, that is, Group A with low CGPA (⩽2.99), Group B with average CGPA (⩾3.00–3.59) and Group C with high CGPA (⩾3.60) and blood samples (3 ml) were taken at three-time intervals, that is, pre-examination, during examination and post examination time interval, at the Department of Physiology, Government College University, Faisalabad. Anthropometric parameters like height, weight, blood pressure, heart rate and body mass index (BMI) were also determined. Blood cortisol and thyroid hormones (triiodothyronine, T3; thyroxine, T4) and thyroid stimulating hormone (TSH)) were measured using ELISA based technique. Arylesterase activity (ARE) and paraoxonase activity (PON-1) were also measured using colorimetric method. The results showed that overall cortisol level was increased at pre-examination and during examination time intervals as compared to the post examination time interval while PON-1 and ARE were significantly (p < 0.05) decreased. With regards to T4 and TSH, a non-significant (p < 0.05) difference was observed in pre and post examination time interval. It could be concluded from the current study that semester system examinations significantly (p < 0.05) imposed stress in all students group at pre-examination interval as compare to post examination interval and this examination related stress was find more in the students already obtained low CGPA as compared to the other studied groups. Although, a correlation between academic performance and examinations stress in semester system was found but a large scale trial in multiple institutions throughout the Pakistan is required to exclude any socioeconomic factors because Pakistan belongs to developing country. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury (PNI) is one of the major health concerns faced by the community at present. Till now, available therapeutic approaches are ineffective to fully heal a nerve injury and to assure the functional recovery entirely. Natural compounds can prove attractive and effective drug candidates to bridge up this gap. In this scenario, the present study was designed to explore the role of methanolic extract of Foeniculum vulgare (F. vulgare) seeds in accelerating the function regain following a sciatic nerve injury in a mouse model. For this purpose, 12 adult healthy albino mice (BALB/C), 8–10 weeks old, were grouped as control (Ctrl, n = 6) and treatment (Trt, n = 6). The treated group was given methanolic extract of F. vulgare (200 mg/kg per day) started from the day of nerve crush until the end of the study. The sensorimotor function regain assessed by hot plate test, grip strength, and SFI assessments was found significantly (p <.05) ameliorated in the F. vulgare‐treated group. A prominent improvement in the muscle mass of the treated group further affirmed these effects. Furthermore, morphometric analysis of muscle fiber cross‐sectional area of tibialis anterior muscle between groups revealed a noticeable improvement in muscle fibers' diameter of the treated group. Conclusively, these findings suggest that F. vulgare methanolic extract exhibits the potential to escalate functional recovery following a peripheral nerve injury. However, the real players of this extract and the mechanism involved in boosting functional restoration need to be dissected by further work. [ABSTRACT FROM AUTHOR]

Objective: The current study aimed to investigate the ABO and rhesus (Rh) blood group frequency in the people of District Faisalabad and Sheikhupura, Punjab Province, Pakistan. The retrospective study was conducted on more than thirty thousand people including both male and female patients admitted to the Tehsil Headquarter Hospital, Safdarabad and The Best Hospital, Faisalabad. Blood samples were taken from each subject and subsequently ABO and Rh blood groups were evaluated separately. The antigen antibody agglutination slide test for blood grouping (ABO) and Rh were used to assess the blood group frequencies. Results: The frequencies of ABO blood group distribution indicated that blood group B was predominant in the people of Safdarabad followed by O, A and AB respectively. While, among people of Faisalabad, blood group O was predominant followed B, A and AB respectively. Rh negative phenotype was found lesser distributed as compared to the positive Rh phenotype. [ABSTRACT FROM AUTHOR]

Probiotics are living micro-organism preparations which can vigorously inhibit the probable pathogens colonization in the gut microbial ecology. Current experiment was designed to investigate the efficacy of imported probiotic species compared with the indigenous probiotics species on the oxidative stress, enzymes, and hormones in animal model. Thirty Albino rats were equally divided into three groups with 10 rats (n = 10) in each group as Control (C), supplemented with imported probiotic species (IP), and supplemented with indigenous probiotics species (InP) for 21 days under controlled environment. The evaluation of treatments was done by testing the serum oxidative stress markers, liver enzymes (Aspartate transaminase and Alanine aminotransferase), lipid profile, and hormonal dynamics including Lutinizing hormone (LH), follicular stimulating hormone (FSH), and growth hormone (GH) in albino male rats. Results revealed that use of indigenous probiotic species significantly (p < 0.05) reduces the oxidative stress and improves the antioxidant capacity; liver enzymes, total cholesterol, and LDL-Cholesterol were also reduced significantly (p < 0.05) in InP as compared to IP group. Moreover, results of hormones including LH, FSH, and GH explored that indigenous probiotics have significant (p < 0.05) potential to improve these hormones as compared to imported probiotics. Although, it could be concluded that InP have beneficial role in preventing the body from oxidative stress as well as in improving the blood parameters but comprehensive studies are required to investigate the detail gut ecology of the indigenous species which will definitely a strong support in preparing a more suitable local probiotic supplement. [ABSTRACT FROM AUTHOR]

Stress caused due to examinations during any degree program and at any educational level has been observed at all levels so the present study was conducted to investigate the stress related to final examination in undergraduate students with reference to their academic performance. Fifty-four volunteers were divided into three groups, (n = 18), according to their academic performance, that is, Group A with low CGPA (⩽2.99), Group B with average CGPA (⩾3.00–3.59) and Group C with high CGPA (⩾3.60) and blood samples (3 ml) were taken at three-time intervals, that is, pre-examination, during examination and post examination time interval, at the Department of Physiology, Government College University, Faisalabad. Anthropometric parameters like height, weight, blood pressure, heart rate and body mass index (BMI) were also determined. Blood cortisol and thyroid hormones (triiodothyronine, T3; thyroxine, T4) and thyroid stimulating hormone (TSH)) were measured using ELISA based technique. Arylesterase activity (ARE) and paraoxonase activity (PON-1) were also measured using colorimetric method. The results showed that overall cortisol level was increased at pre-examination and during examination time intervals as compared to the post examination time interval while PON-1 and ARE were significantly (p < 0.05) decreased. With regards to T4 and TSH, a non-significant (p < 0.05) difference was observed in pre and post examination time interval. It could be concluded from the current study that semester system examinations significantly (p < 0.05) imposed stress in all students group at pre-examination interval as compare to post examination interval and this examination related stress was find more in the students already obtained low CGPA as compared to the other studied groups. Although, a correlation between academic performance and examinations stress in semester system was found but a large scale trial in multiple institutions throughout the Pakistan is required to exclude any socioeconomic factors because Pakistan belongs to developing country. [ABSTRACT FROM AUTHOR]

The study was planned to evaluate toxicity of M. oleifera leaf methanol extract in Wistar rats, cytotoxic potential and chemically characterize it. Acute toxicity study revealed no mortality at 2,000 mg/kg dose. In subchronic toxicity, 150, 300, and 600 mg/kg extract were administered in both sexes for 90 days. A decrease in body weight, cholesterol, and low‐density lipoproteins, as well as an increase in the platelet count were observed. The histology of heart, lung, and kidney was normal. The oxidative stress biomarkers were normal in the liver tissue. In vitro cytotoxicity assay revealed that IC50 of the plant extract was more than 1,000 µg/ml. FTIR explored various functional groups and HPLC analysis indicated the presence of kaempferol and quercetin in the plant extract. These results showed that the plant extract might be safe up to 2,000 mg/kg single dose. The long term use of the plant extract was mostly devoid of major system toxicities. Practical applications: M. oleifera is a multipurpose tree. It is a cruciferous plant that has nutritional as well as medicinal properties. It is exhibited a multitude of nutraceutical or pharmacological properties such as anti‐inflammatory, lipid‐lowering, anticancer, hypoglycemic, and antihypertensive activities. It is widely used by local inhabitants for their health, food, agriculture, and cosmetic purposes. Among other plant parts, its leaves are mostly used as a functional food because of abundant proteins, β‐carotene, polyphenol, vitamin C, and vitamin E. The current study was designed to validate its safety in acute and long term use. The data of this study suggested that the plant can be safely used as a nutraceutical as well as a nutritional food. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury (PNI) is an incapacitating situation and has no effective therapy until now. We examined the possible role of crude leaves of Moringa oleifera Lam. at 200 mg/kg body weight in accelerating the functional regain in the sciatic nerve lesion induced mouse model (Adult male albino mice (BALB/c). Motor functions were evaluated by using the sciatic functional index, muscle mass, and muscle grip strength measurement, whereas the sensory functions were evaluated by using the hot plate test. Blood glucose levels and blood cell composition were also analyzed. We found that the Moringa oleifera crude leaves endorse the sensory and motor functions reclamation following the PNI with a statistically significant difference (p <.05). It also revitalizes the gastrocnemius muscle by mass restoration with glycemic management perspective. Conclusively, the crude powder of Moringa oleifera leaves exhibited a function restoration boosting property and further detailed studies for its application as a therapeutic agent are strongly recommended. [ABSTRACT FROM AUTHOR]

Reprogrammed metabolism is key biochemical characteristic of malignant cells, which represents one of the emerging hallmarks of cancer. Currently, there is rising contemplation on oxidative pentose phosphate pathway (PPP) enzymes as potential therapeutic hits due to their affiliation with tumor metabolism. 6‐Phosphogluconate dehydrogenase (6PGD), third oxidative decarboxylase of PPP, has received a great deal of attention during recent years due to its critical role in tumorigenesis and redox homeostasis. 6PGD has been reported to overexpress in number of cancer types and its hyperactivation is mediated through post‐transcriptional and post‐translational modifications by YTH domain family 2 (YTHDF2), Nrf2 (nuclear factor erythroid 2‐related factor 2), EGFR (epidermal growth factor receptor) and via direct structural interactions with ME1 (malic enzyme 1). Upregulated expression of 6PGD provides metabolic as well as defensive advantage to cancer cells, thus, promoting their proliferative and metastatic potential. Moreover, enhanced 6PGD expression also performs key role in development of chemoresistance as well as radiation resistance in cancer. This review aims to discuss the historical timeline and cancer‐specific role of 6PGD, pharmacological and genetic inhibitors of 6PGD and 6PGD as prognostic biomarker in order to explore its potential for therapeutic interventions. We anticipate that targeting this imperative supplier of NADPH might serve as tempting avenue to combat the deadly disease like cancer. [ABSTRACT FROM AUTHOR]

Theophylline‐7‐acetic acid (acefylline) (3) and its derivatives are pharmacologically active compounds and generally recognized as bronchodilators for the treatment of respiratory diseases like acute asthma for over 70 years. In this article, synthesis of 2‐((5‐((1,3‐dimethyl‐2,6‐dioxo‐2,3‐dihydro‐1H‐purin‐7(6H)‐yl)methyl)‐1,3,4‐oxadiazol‐2‐yl)thio)‐N‐arylacetamides (10a‐j) has been reported. All the synthesized derivatives (10a‐j) were structurally verified by FT‐IR, 1H NMR, 13C NMR and evaluated for their anti‐cancer (using MTT assay), hemolytic and thrombolytic potential. N‐(4‐Chlorophenyl)‐2‐(5‐((1,3‐dimethyl‐2,6‐dioxo‐2,3‐dihydro‐1H‐purin‐7(6H)‐yl)methyl)‐1,3,4‐oxadiazol‐2‐ylthio)acetamide (10g) was found to be the most active against human liver cancer cell lines (Huh7) having cell viability 53.58 ± 1.28 using 100 μg/mL concentration of compound which was further in‐silico modelled to describe the possible mechanistic insights for its anti‐proliferative activity. The results of hemolytic and thrombolytic activities indicated that these derivatives were less toxic and hold considerable potential as a drug candidate. 2‐(5‐((1,3‐Dimethyl‐2,6‐dioxo‐2,3‐dihydro‐1H‐purin‐7(6H)‐yl)methyl)‐1,3,4‐oxadiazol‐2‐ylthio)‐N‐(2‐fluorophenyl)acetamide (10c) of the series was found to be least toxic with 0.1% hemolysis relative to ABTS (95.5%) as positive control. 2‐(5‐((1,3‐Dimethyl‐2,6‐dioxo‐2,3‐dihydro‐1H‐purin‐7(6H)‐yl)methyl)‐1,3,4‐oxadiazol‐2‐ylthio)‐N‐(tetrahydro‐2H‐pyran‐4‐yl)acetamide (10j) exhibited potent clot lysis activity (90%) as compared to negative control DMSO (0.57%). [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a male-predominant cancer. However, the relationship between 5α-dihydrotestosterone (DHT), the active form of testosterone, and HCC risk has not been established yet. Methods: We performed a serum epidemiological study in the Chinese population. From 2010 to 2012, 106 male HCC patients and 318 age-matched controls were detected for their serum DHT and estradiol (E2). The odds ratios (ORs) and 95% confidence interval (CI) were estimated by logistic regression analysis with adjustment for potential risk factors. Bivariate Pearson correlations between hormone concentrations and liver function index were investigated. Results: Serum DHT levels were lower (to 1/3 of control), and E2 levels were higher (to 1.5-fold of control) in HCC patients. Compared with the low DHT level, men with a medium level had an adjusted multiple OR of 0.15 (95% CI 0.05–0.43, p trend < 0.01), and men with a high level had an OR of 0.05 (95% CI 0.01–0.21, p trend < 0.01). Notably, DHT concentration, but not E2, is correlated with liver injury. Conclusion: The data suggest that serum DHT is closely associated with HCC risk, providing a reference in order to accurately predict liver cancer and study the pathogenesis of this disease. [ABSTRACT FROM AUTHOR]

Background: Peripheral nerve injury is a debilitating condition that may lead to partial or complete motor, sensory and autonomic function loss and lacks effective therapy until date. Therefore, it is quite imperative to explore impending remedies for rapid and accurate functional retrieval following such conditions. Natural product-based intervention can prove effective to facilitate the process of functions regain. Methods: Here, we investigated the effect of processed Strychnos nux-vomica seeds at a dose of 250 mg/kg body weight in a mouse model of induced Sciatic nerve lesion in promoting the recovery of the functions. A compression injury was induced in the Sciatic nerve of the right leg in the mice. Sensory function recovery was evaluated by hot-plate and formalin tests, whereas the motor function retrieval was assessed by measuring muscle grip strength, sciatic functional index, and muscle mass restoration. Oxidative stress and blood cell count were measured by biochemistry and haematological analyses. Results: This study indicates that Strychnos nux-vomica seeds enhance the rate of recovery of both sensory and motor functions. It helps restore the muscle mass, attenuates total oxidant status and enhances the total anti-oxidant capacity of the biological system. Moreover, the treated animals manifested an enhanced glucose tolerance aptitude and augmented granulocyte and platelet counts. Improved oxidant control, enhanced glucose sensitivity and amended granulocyte and platelet counts are likely to contribute to the advantageous effects of Strychnos nux-vomica, and warrant further in-depth studies for deciphering possible mechanisms and identification of active constituent(s) responsible for these effects. Conclusion: Strychnos nux-vomica seed offers functional recovery promoting effects following a mechanical injury to the Sciatic nerve and the possible reasons behind this effect can be reduced oxidative stress and improved glycaemic control. Further and detailed investigations can unravel this mystery. [ABSTRACT FROM AUTHOR]

Five different weed plants viz. Convulvulus arvensis, Chenopodium murale, Tribulus terrestris, Trianthema portulacastrum, and Achyranthes aspera were investigated for their entomocidal and genotoxic effects against Culex quinquefasciatus mosquitoes. High mortality was observed at 72 hours in a dose dependent manner. Among all the tested plants, A. aspera was found highly significant which showed 100% mortality at 250 ppm after 72 hours with LC50 of 87.46, 39.08 and 9.22 ppm at 24, 48, respectively. In combination with Bacillus thuringiensis israelensis (Bti); A. aspera also caused 100% mortality at 250 ppm concentration after 72 hours (LC50 8.29 ppm). Phytochemical analysis of all the tested weed plants showed the presence of flavonoids, saponins, tannins, steroids, cardiac glycosides, alkaloids, anthrequinones and terpenoids. Random Amplification of Polymorphic DNA-Polymerase chain reaction (RAPD-PCR) and comet assay were performed to assess the genotoxic effect of A. aspera but no change in DNA profile was observed. Furthermore, FTIR showed the presence of phenolic compounds in A. aspera extract. It is suggested that certain phenolic compounds such as flavonoids modulate the enzymatic activity and, hence, cause the death of larvae of Cx. quinquefasciatus. Altogether, current study would serve as an initial step towards replacement of synthetic insecticides to plant-microbe based biopesticide against Culex mosquitoes in future. [ABSTRACT FROM AUTHOR]