Immunopathology of herpes simplex virus-associated neuroinflammation: Unveiling the mysteries.

The immunopathology of herpes simplex virus (HSV)-associated neuroinflammation is a captivating and intricate field of study within the scientific community. HSV, renowned for its latent infection capability, gives rise to a spectrum of neurological expressions, ranging from mild symptoms to severe encephalitis. The enigmatic interplay between the virus and the host's immune responses profoundly shapes the outcome of these infections. This review delves into the multifaceted immune reactions triggered by HSV within neural tissues, intricately encompassing the interplay between innate and adaptive immunity. Furthermore, this analysis delves into the delicate equilibrium between immune defence and the potential for immunopathology-induced neural damage. It meticulously dissects the roles of diverse immune cells, cytokines, and chemokines, unravelling the intricacies of neuroinflammation modulation and its subsequent effects. By exploring HSV's immune manipulation and exploitation mechanisms, this review endeavours to unveil the enigmas surrounding the immunopathology of HSV-associated neuroinflammation. This comprehensive understanding enhances our grasp of viral pathogenesis and holds promise for pioneering therapeutic strategies designed to mitigate the neurological ramifications of HSV infections.

The potential neuroprotective effects of Spirulina platensis in a valproic acid-induced experimental model of autism in the siblings of albino rats: targeting PIk3/AKT/mTOR signalling pathway.

Introduction: Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with poor social interaction, communication issues, aberrant motor movements, and limited repetitive interests and behaviour. Spirulina platensis (SP) contains several multi-nutrients and has a wide range of neuroprotective properties.Aim: The target of the current experiment is to detect the protective effects of S. platensis on valproic-induced autism in adult female albino rats' siblings for the first time.Materials and Methods: Twelve Pregnant rats were separated into four main groups; Group I (control); Group II (S. platensis); Group III (autistic group); and Group IV (autistic SP-treated group). Fifteen offspring pups from each group were sacrificed, brain was divided for biochemical analysis as superoxide dismutase and malondialdehyde were evaluated spectrophotometrically while interleukin-6, interleukin-12, Bcl-2-associated X protein, B-cell lymphoma-2, Beclin-1, brain-derived neurotrophic factor were assessed by ELISA, other division of brain were used for gene expression of PI3k, Akt and mTOR pathway, last division of brain were stained using (H&E) and Giemsa stains. Tumour necrosis factor alpha (TNF-α) and Synaptophysin (SYN) markers were used for immunohistochemical staining.Results: Autistic Group (III) showed an increment in levels of MDA, IL-6, IL12 and BAX while showing a decrement in SOD, Bcl-2 and Beclin-1 as well as increased PI3k, Akt and mTOR gene expression. Autistic Group (III) also exhibited hypocellularity and disorganization of hippocampal and prefrontal cortex cells. The autistic SP-treated group (IV) showed improvement in these biochemical markers and pathological changes. Our findings suggest that Spirulina platensis will be significant in managing autism.

Molecular overlay-guided design of new CDK2 inhibitor thiazepinopurines: Synthesis, anticancer, and mechanistic investigations.

Adopting the molecular overlay approach, three novel sets of thiazepinopurines with expected cytotoxicity and CDK2 inhibition potential were designed and synthesized. This was accomplished through the heteroannelation of purines, for the first time, with thiazepine. The obtained thiazepinopurines derivatives were assessed for their cytotoxicity toward tumor cells of three different types, HepG2, MCF-7, and PC-3 as well as one normal cell (WI38). Among the studied compounds, 3b and 3c exhibited significant antiproliferative activity against tumor cells presenting IC50 range of 5.52-17.09 µM in comparison with Roscovitine (9.32-13.82 µM). Additionally, both compounds displayed superior selectivity indices (SI = 3.00-7.15) toward tested cancer cells. The 4-chlorophenyl analog 3b has shown the best selectivity index, and hence it has been subjected to additional investigations to determine its proper mechanistic effect. Accordingly, the CDK2 inhibition potential, apoptosis induction, and cell cycle analysis of MCF-7 were evaluated. Results revealed that this analog displayed a potent CDK2 inhibition potential with an IC50 value of 0.219 µM. Findings also showed that 3b was thought to arrest MCF-7 cell cycle at S phase together with apoptosis induction by the increased expression of Bax, Caspase-8, and -9 markers with a concomitant decrease in Bcl-2 expression. Besides, the probable interaction of 3b with CDK2 binding pocket was investigated by molecular docking.

Development of novel cyanopyridines as PIM-1 kinase inhibitors with potent anti-prostate cancer activity: Synthesis, biological evaluation, nanoparticles formulation and molecular dynamics simulation.

Recently, inhibition of PIM-1 enzyme is found as an effective route in the fight against proliferation of cancer. Herein, new cyano pyridines that target PIM-1 kinase were designed, synthesized, and biologically evaluated. Two prostate cell lines were used to examine each of the new compounds in vitro for anticancer activity, namely, PC-3 and DU-145. The cyanopyridine derivatives 2b, 3b, 4b, and 5b with an N,N-dimethyl phenyl group at the pyridine ring's 4-position showed considerable antitumor effect on the tested cell lines. Additionally, the high selectivity index revealed that these compounds were less cytotoxic to normal WI-38 cells. Furthermore, they exhibited strong inhibitory effect on PIM-1 having IC50 = 0.248, 0.13, 0.326 and 0.245 µM, respectively. The most powerful derivatives2b, 3b, 4b, and 5b, were chosen for further examination of their inhibitory potential on both kinases (PIM-2 and PIM-3). Interestingly, upon loading compound 3b in a cubosomes formulation with nanometric size, improvements in cytotoxicity and inhibitory effect on PIM-1 kinase were observed. In silico ADME parameters study revealed that compound 3b is orally bioavailable without penetration to the blood-brain barrier. Further, the docking simulations revealed the ability of our potent compounds to well accommodate the PIM-1 kinase active site forming stable complexes. In a 150 ns MD simulation, the most powerful PIM-1 inhibitor 3b produced stable complex with the PIM-1 enzyme (RMSD = 1.76). Furthermore, the 3b-PIM-1 complex has the low binding free energy (-242.2 kJ/mol) according to the MM-PBSA calculations.

Antidiarrheal and Antibacterial Activities of Monterey Cypress Phytochemicals: In Vivo and In Vitro Approach.

Monterey cypress (Cupressus macrocarpa) is a decorative plant; however, it possesses various pharmacological activities. Therefore, we explored the phytochemical profile of C. macrocarpa root methanol extract (CRME) for the first time. Moreover, we investigated its antidiarrheal (in vivo), antibacterial, and antibiofilm (in vitro) activities against Salmonella enterica clinical isolates. The LC-ESI-MS/MS analysis of CRME detected the presence of 39 compounds, besides isolation of 2,3,2″,3″-tetrahydro-4'-O-methyl amentoflavone, amentoflavone, and dihydrokaempferol-3-O-α-l-rhamnoside for the first time. Dihydrokaempferol-3-O-α-l-rhamnoside presented the highest antimicrobial activity and the range of values of MICs against S. enterica isolates was from 64 to 256 µg/mL. The antidiarrheal activity of CRME was investigated by induction of diarrhea using castor oil, and exhibited a significant reduction in diarrhea and defecation frequency at all doses, enteropooling (at 400 mg/kg), and gastrointestinal motility (at 200, 400 mg/kg) in mice. The antidiarrheal index of CRME increased in a dose-dependent manner. The effect of CRME on various membrane characters of S. enterica was studied after typing the isolates by ERIC-PCR. Its impact on efflux and its antibiofilm activity were inspected. The biofilm morphology was observed using light and scanning electron microscopes. The effect on efflux activity and biofilm formation was further elucidated using qRT-PCR. A significant increase in inner and outer membrane permeability and a significant decrease in integrity and depolarization (using flow cytometry) were detected with variable percentages. Furthermore, a significant reduction in efflux and biofilm formation was observed. Therefore, CRME could be a promising source for treatment of gastrointestinal tract diseases.

Elucidation of the Metabolite Profile of Yucca gigantea and Assessment of Its Cytotoxic, Antimicrobial, and Anti-Inflammatory Activities.

The acute inflammation process is explained by numerous hypotheses, including oxidative stress, enzyme stimulation, and the generation of pro-inflammatory cytokines. The anti-inflammatory activity of Yucca gigantea methanol extract (YGME) against carrageenan-induced acute inflammation and possible underlying mechanisms was investigated. The phytochemical profile, cytotoxic, and antimicrobial activities were also explored. LC-MS/MS was utilized to investigate the chemical composition of YGME, and 29 compounds were tentatively identified. In addition, the isolation of luteolin-7-O-ß-d-glucoside, apigenin-7-O-ß-d-glucoside, and kaempferol-3-O-α-l-rhamnoside was performed for the first time from the studied plant. Inflammation was induced by subcutaneous injection of 100 µL of 1% carrageenan sodium. Rats were treated orally with YGME 100, 200 mg/kg, celecoxib (50 mg/kg), and saline, respectively, one hour before carrageenan injection. The average volume of paws edema and weight were measured at several time intervals. Levels of NO, GSH, TNF-α, PGE-2, serum IL-1ß, IL-6 were measured. In additionally, COX-2 immunostaining and histopathological examination of paw tissue were performed. YGME displayed a potent anti-inflammatory influence by reducing paws edema, PGE-2, TNF-α, NO production, serum IL-6, IL-1ß, and COX-2 immunostaining. Furthermore, it replenished the diminished paw GSH contents and improved the histopathological findings. The best cytotoxic effect of YGME was against human melanoma cell line (A365) and osteosarcoma cell line (MG-63). Moreover, the antimicrobial potential of the extract was evaluated against bacterial and fungal isolates. It showed potent activity against Gram-negative, Gram-positive, and fungal Candida albicans isolates. The promoting multiple effects of YGME could be beneficial in the treatment of different ailments based on its anti-inflammatory, antimicrobial, and cytotoxic effects.

Ehrlich ascites carcinoma as model for studying the cardiac protective effects of curcumin nanoparticles against cardiac damage in female mice.

While clinical innovation has improved, cancer or malignant growth stays a genuine medical issue and has been perceived as a significant factor in mortality and morbidity. Current work aimed to define the cardiac defensive effects of curcumin nanoparticles (Cur Nps) against EAC induced cardiac toxicity, injury, and alterations in apoptosis, proliferation, and cytokines immunoreactivity. Forty female mice were aimlessly and equally divided into four groups [Gp1, Control; Gp2, Cur NPs; Gp3, Ehrlich ascites carcinoma (EAC); Gp4, Co-treatment of EAC with Cur NPs (Cur NPs + EAC)]. Serum lactate dehydrogenase (LDH), phosphocreatine kinase (CPK), creatine kinase myoglobin (CK-MB), alkaline phosphatase (ALP), glutamic oxaloacetic transaminase (GOT), cholesterol, triglycerides, potassium ions, cardiac injury, P53, vascular endothelial growth factor protein (VEGF), Bax, and tumor necrosis factor alpha (TNFα) expressions were significantly elevated while sodium ions levels were significantly depleted in EAC when compared to control. Co-treatment of EAC with Cur NPs (Cur NPs + EAC) improved these parameters as compared with EAC group. So, our results indicate that; Cur NPs induced protection to the blood and heart tissue during Ehrlich ascites carcinoma.

Dual EGFR/VEGFR2 inhibitors and apoptosis inducers: Synthesis and antitumor activity of novel pyrazoline derivatives.

Novel derivatives of the pyrazoline scaffold were synthesized and investigated for their cytotoxicity against prostate (PC-3), hepatocellular (HepG2), and breast (MDA-MB-231) carcinoma cells. The most active compounds, 4a, 4b, 5b, and 7c, revealed significant and broad-spectrum anticancer activities with IC50 values of 1.30-7.18 µM in comparison with doxorubicin (IC50 = 5.12-7.33 µM). Additionally, they exhibited lower cytotoxicity against normal WI-38 cells, indicating their high safety profiles. Aiming to enlighten the inhibitory potential on receptor tyrosine kinases (RTKs), compounds 4a, 4b, 5b, and 7c were assessed for their activities against four different RTKs (EGFR, FGFR2, HER2, and VEGFR2) and their apoptotic potencies on PC-3 cells. The results revealed that compounds 5b and 7c are potent dual EGFR and VEGFR2 inhibitors (IC50 = 0.21 and 0.23 µM, respectively, against EGFR; 0.22 and 0.21 µM, respectively, against VEGFR2), whereas they displayed moderate inhibitory activities against HER2 and FGFR2. Besides, compounds 4a, 4b, 5b, and 7c prompted apoptosis via the upregulation of Bax, p53, and caspase-3, together with the downregulation of the levels of Bcl-2. Also, it was found that compounds 5b and 7c are more potent as apoptosis inducers than the other tested derivatives. Furthermore, molecular docking analyses of compounds 4a, 4b, 5b, and 7c in the EGFR and VEGFR ATP binding sites were performed, to confirm the in vitro assays.

Design and Synthesis of New Thiophene/Thieno[2,3-d]pyrimidines along with Their Cytotoxic Biological Evaluation as Tyrosine Kinase Inhibitors in Addition to Their Apoptotic and Autophagic Induction.

This work describes the synthesis and anticancer activity against kinase enzymes of newly designed thiophene and thieno[2,3-d]pyrimidine derivatives, along with their potential to activate autophagic and apoptotic cell death in cancer cells. The designed compounds were scanned for their affinity for kinases. The results were promising with affinity ranges from 46.7% to 13.3%. Molecular docking studies were performed, and the compounds were then screened for their antiproliferative effects. Interestingly, compounds 8 and 5 resulted in higher cytotoxic effects than the reference standard against MCF-7 and HepG-2. The compounds were evaluated for their induction of apoptosis and/or necrosis on HT-29 and HepG-2. Three compounds induced significant early apoptosis compared to untreated control HT-29 cells, and four derivatives were more significant compared to untreated HepG-2 cells. We further investigated the effect of four compounds on the autophagy process within HT-29, HepG-2, and MCF-7 cells with flow cytometry. Similar to the apoptosis results, compound 5 showed the highest autophagic induction among all compounds. The potential inhibitory activity of the synthesized compounds on kinases was assessed. Screened compounds showed inhibition activity ranging from 41.4% to 83.5%. Compounds recorded significant inhibition were further investigated for their specific FLT3 kinase inhibitory activity. Noticeably, Compound 5 exhibited the highest inhibitory activity against FLT3.

In Vitro and In Vivo Antitumor Activity of Indolo[2,3-b] Quinolines, Natural Product Analogs from Neocryptolepine Alkaloid.

Neocryptolepine (5-methyl-5H-indolo[2,3-b] quinoline) analogs were synthesized and evaluated in vitro and in vivo for their effect versus Ehrlich ascites carcinoma (EAC). The analogs showed stronger cytotoxic activity against EAC cells than the reference drug. The in vivo evaluation of the target compounds against EAC-induced solid tumor in the female albino Swiss mice revealed a remarkable decrease in the tumor volume (TV) and hepatic lipid peroxidation. A noticeable increase of both superoxide dismutase (SOD) and catalase (CAT) levels was reported (p < 0.001), which set-forth proof of their antioxidant effect. In addition, the in vitro antioxidant activity of the neocryptolepine analogs was screened out using the DPPH method and showed promising activities activity. The histopathological investigations affirmed that the tested analogs have a remarkable curative effect on solid tumors with minimal side-effect on the liver. The study also includes illustrated mechanism of the antitumor activity at the cell level by flow cytometry. The cell cycle analysis showed that the neocryptolepine analogs extensively increase the aggregation of tumor cells in three phases of the cell cycle (G0/G1, S and G2/M) with the emergence of a hypo-diploid DNA content peak (sub-G1) in the cell cycle experiments, which is a clear-cut for the apoptotic cell population. Furthermore, the immunological study manifested a significant elevation in splenic lymphocyte count (p < 0.001) with the elevation of the responsiveness of lymphocytes to phytohemagglutinin (PHA). These results indicate that these naturally-based neocryptolepine alkaloids exhibit marked antitumor activity in vivo and represent an important lead in the development of natural-based anticancer drugs.

Potential therapeutic effects of avenanthramide-C against lung toxicity caused by silver nanoparticles injection in rats.

Most clinical investigations about the impact of nanoparticles on cells and tissues show that nanoparticles may enter the human body by means of respiratory tracts. Humans, animals, plants and environments are continually presented to a wide scope of business items containing silver nanoparticles (Ag NPs) in their piece. Ag NPs, utilized in various consumer products as room showers, surface cleaners, wound dressings, food storage containers and many textiles. The current examination planned to explore the defensive role of Avenanthramide-C (Avns) contrary to the lung toxicity initiated by Ag NPs injection in rats. 40 male Wistar rats were separated into 4 groups (Gp1, control; Gp2, Avns; Gp3, Ag NPs; Gp4, Ag NPs+Avns). Current results revealed that; Ag NPs induced a significant depletion in RBCs count, hemoglobin, platelets counts and a significant increase in total WBCs, lung injury, cyclooxygenase-2 (COX2) and TNFα expressions as compared to control. Treatments of Ag NPs with Avenanthramide-C extract (Ag NPs+Avns) improved the lung structure and blood complete pictures as compared to Ag NPs group.

Therapeutic effects of rocket seeds (Eruca sativa L.) against testicular toxicity and oxidative stress caused by silver nanoparticles injection in rats.

Silver nanoparticles (AgNPs), one of the most well-known nanomaterials, are regularly utilized in everyday consumer products. The present study aimed to investigate the testicular toxicity and oxidative stress by AgNPs and the therapeutic role of the rocket seeds (Eruca sativa) in treatments. Forty male Wistar rats were divided into four equivalent groups (group 1, control; group 2, rocket seeds extract [RS]; group 3, AgNPs; group 4, AgNPs+RS). Our results showed that AgNPs induced a significant decrease in serum total testosterone, FSH (follicle-animating hormone), prolactin and LH (luteinizing hormone), testicular glutathione (GSH), superoxide dismutase (SOD), and glutathione S-transferase (GST). In contrast, a significant increase in testicular DNA, injury, testicular thiobarbituric acid, proliferating cell nuclear antigen, and tumor necrosis factor-α (TNFα) expressions after treatments with AgNPs when contrasted with the control group. Treatments of AgNPs with rocket seeds extract (AgNPs+RS) improved testicular functions and structure. Rocket seeds extract might offer benefits against the toxic nature of AgNPs.

Discovery of Novel 3-Cyanopyridines as Survivin Modulators and Apoptosis Inducers.

The overexpression of survivin is usually accompanied by an increased resistance of cancer cells to chemotherapeutic agents in addition to cancer aggressiveness. Consequently, survivin is considered as an attractive target to develop new promising anticancer candidates. A series of novel 3-cyanopyridine derivatives was synthesized and assessed for their cytotoxic activity against three human cancer cell lines: prostate carcinoma (PC-3), breast cancer (MDA-MB-231) and hepatocellular carcinoma (HepG2). In addition, their activities were evaluated in comparison with a standard anticancer drug 5-FU. Compounds 5c and 5e both exhibited promising cytotoxicity against all the tested cell lines; especially, 5e showed better cytotoxic effect than the reference drug 5-FU. In order to evaluate the safety of these compounds, they were tested on the normal cell line WI-38, revealing their toxic selectivity toward cancer cells over normal ones. Further studies were performed in order to understand their mechanism of action; we examined the ability of our promising compounds 5c and 5e to induce cell cycle arrest. Both resulted in a notable induction of cell cycle arrest at the G2/M phase, along with an increase in the DNA content in the pre-G1 phase, giving us an indication of the incidence of apoptosis. 5c and 5e were further subjected to additional study using Annexin V-FITC assay in order to evaluate their ability to induce apoptosis. The results showed a marked increase in the early and late apoptotic cells, as well as an increase in the percentage of necrosis. Furthermore, Western blotting assay was accomplished using different concentrations of 5c and 5e. The results revealed a striking reduction in survivin expression through proteasome-dependent survivin degradation in addition to a decrease in the expression of some other inhibitor of apoptosis proteins (IAP) family proteins: Livin, XIAP, and C-IAP1 in a concentration-dependent manner. A docking study of 5c and 5e compounds in the dimerization site of survivin was also performed, showing agreement with the in vitro anti-survivin activity.

From petals to healing: consolidated network pharmacology and molecular docking investigations of the mechanisms underpinning Rhododendron arboreum flower's anti-NAFLD effects.

Rhododendron arboreum: Sm., also known as Burans is traditionally used as an anti-inflammatory, anti-diabetic, hepatoprotective, adaptogenic, and anti-oxidative agent. It has been used since ancient times in Indian traditional medicine for various liver disorders. However, the exact mechanism behind its activity against NAFLD is not known. The aim of the present study is to investigate the molecular mechanism of Rhododendron arboreum flower (RAF) in the treatment of NAFLD using network pharmacology and molecular docking methods. Bioactives were also predicted for their drug-likeness score, probable side effects and ADMET profile. Protein-protein interaction (PPI) data was obtained using the STRING platform. For the visualisation of GO analysis, a bioinformatics server was employed. Through molecular docking, the binding affinity between potential targets and active compounds were assessed. A total of five active compounds of RAF and 30 target proteins were selected. The targets with higher degrees were identified through the PPI network. GO analysis indicated that the NAFLD treatment with RAF primarily entails a response to the fatty acid biosynthetic process, lipid metabolic process, regulation of cell death, regulation of stress response, and cellular response to a chemical stimulus. Molecular docking and molecular dynamic simulation exhibited that rutin has best binding affinity among active compounds and selected targets as indicated by the binding energy, RMSD, and RMSF data. The findings comprehensively elucidated toxicity data, potential targets of bioactives and molecular mechanisms of RAF against NAFLD, providing a promising novel strategy for future research on NAFLD treatment.

Rosuvastatin and diosmetin inhibited the HSP70/TLR4 /NF-κB p65/NLRP3 signaling pathways and switched macrophage to M2 phenotype in a rat model of acute kidney injury induced by cisplatin.

Numerous efforts to manage acute kidney injury (AKI) were unsuccessful because its pathophysiology is still poorly understood. Thus, our research hotspot was to explore the possible renoprotective effects of rosuvastatin (Ros) and diosmetin (D) on macrophage polarization and the role of HSP70/TLR4/MyD88/NF-κB p65/NLRP3/STAT3 signaling in cis-induced AKI and study the activity of D against uropathogenic bacteria. Fifty-four albino male rats were randomized into 9 groups equally: Control, Ros, D20, D40, untreated Cis, and Cis groups cotreated with Ros, D20, D40 and Ros+D40 for 10 days. Our results indicated that Ros and D, in a dose-dependent manner, markedly restored body weight, systolic blood pressure, and renal histological architecture besides significantly upregulated SOD levels, expression of anti-inflammatory CD163 macrophages, arginase1levels, IL-10 levels,STAT3 and PCNA immunoreactivity. Also, they significantly downregulated renal index, serum urea, serum creatinine, serum cystatin c, inflammatory biomarkers (C reactive protein, IL1ß & TNF-α), MDA levels, HSP70/TLR4/MyD88/NF-κB p65/NLRP3 expressions, proinflammatory CD68 macrophages and caspase-3 immunoreactivity, resulting in a reversal of cis-induced renal damage. These findings were further confirmed by molecular docking that showed the binding affinity of Ros and D towards TLR4 and NLRP3. Furthermore, D had antibacterial action with a minimum inhibitory concentration ranging from 128 to 256 µg/mL and caused a delay in the growth of the tested isolates, and negatively affected the membrane integrity. In conclusion, Ros and D had antioxidant, anti-inflammatory and antiapoptotic properties and switched macrophage from proinflammatory CD68 to anti-inflammatory CD163. Additionally, the targeting of HSP70/TLR4/MyD88/NF-κB p65/NLRP3/STAT3 signals are effective therapeutic strategy in AKI.

Design, synthesis, and anti-hepatocellular carcinoma of thiopyrimidine/chalcone hybrids as dual STAT3/STAT5 inhibitors.

Among the promising therapeutic targets for treating cancer are the continuously active STAT proteins, which are important in the progression of many malignancies. Here, we detail the STAT3/5 inhibitory action and thiopyrimidine/chalcone hybrid design, production, and anti-hepatocellular carcinoma activity. The prepared hybrids were assessed for their cytotoxic effect on HepG2 and Huh7 liver cancer cells. The most active compounds 5e and 5h (IC50 range from 0.55 to 2.58 µM) were further evaluated against normal THLE cells to examine their safety profiles. The hybrids 5e and 5h were additionally tested for their potential to inhibit STAT3 and STAT5a. They showed dual inhibitory action, with a decrease in the level of STAT3 by 65 and 87 times, respectively, and a decrease in the level of STAT5 by 60 and 79.5 times, respectively, compared to the control. Additionally, western blot analysis of compound 5h revealed inhibition of STAT3 and STAT5 phosphorylation at Tyr705 and Tyr694, respectively, with only a slight decrease in the total expression of STAT3 and STAT5 proteins. And lastly, molecular docking research provided additional insight on the 5h binding mechanism in the STAT3 and STAT5 SH2 domains.

New Imadazopyrazines with CDK9 Inhibitory Activity as Anticancer and Antiviral: Synthesis, In Silico, and In Vitro Evaluation Approaches.

This study describes the synthesis and biological activity of new imadazopyrazines as first-in-class CDK9 inhibitors. The inhibition of CDK9 is a well-established therapeutic target in cancer therapy. The new compounds were assessed using an in vitro kinase assay against CDK9. In this assay, compound 1d exhibited the highest CDK9 inhibition with an IC50 of 0.18 µM. The cytotoxicity effect of the novel compounds was evaluated in three cancer cell lines: HCT116, K652, and MCF7. The results of this assay showed a correlation between the antiproliferative effect of the inhibitors and their CDK9 inhibitory effect in the biochemical assay. This suggests CDK9 inhibition as a mechanistic pathway for their anticancer effect. Several compounds demonstrated potent cytotoxic effects with single-digit micromolar IC50 values yielded through an MTT assay. The compounds with the most promising data were further assessed for their antiviral activity against human Coronavirus 229E. The results showed that compound 4a showed the highest antiviral potency with an IC50 of 63.28 µM and a selectivity index of 4.8. In silico target prediction data showed that 4a displayed a good affinity to proteases. The result of the docking studies of 4a with COVID-19 main protease revealed a high binding affinity, which confirmed the results obtained from in vitro study. The physiochemical and in silico pharmacokinetic parameters indicated reasonable drug-likeness properties of the new compounds, including solubility, lipophilicity, absorption, oral bioavailability, and metabolic stability. Further lead optimization of this novel scaffold could lead to a revolution of a new class of preclinical CDK9 agents.

The complex role of MEG3: An emerging long non-coding RNA in breast cancer.

MEG3, a significant long non-coding RNA (lncRNA), substantially functions in diverse biological processes, particularly breast cancer (BC) development. Within the imprinting DLK-MEG3 region on human chromosomal region 14q32.3, MEG3 spans 35 kb and encompasses ten exons. It exerts regulatory effects through intricate interactions with miRNAs, proteins, and epigenetic modifications. MEG3's multifaceted function in BC is evident in gene expression modulation, osteogenic tissue differentiation, and involvement in bone-related conditions. Its role as a tumor suppressor is highlighted by its influence on miR-182 and miRNA-29 expression in BC. Additionally, MEG3 is implicated in acute myocardial infarction and endothelial cell function, emphasising cell-specific regulatory mechanisms. MEG3's impact on gene activity encompasses transcriptional and post-translational adjustments, including DNA methylation, histone modifications, and interactions with transcription factors. MEG3 dysregulation is linked to unfavourable outcomes and drug resistance. Notably, higher MEG3 expression is associated with enhanced survival in BC patients. Overcoming challenges such as unravelling context-specific interactions, understanding epigenetic control, and translating findings into clinical applications is imperative. Prospective endeavours involve elucidating underlying mechanisms, exploring epigenetic alterations, and advancing MEG3-based diagnostic and therapeutic approaches. A comprehensive investigation into broader signaling networks and rigorous clinical trials are pivotal. Rigorous validation through functional and molecular analyses will shed light on MEG3's intricate contribution to BC progression.

A review of Glycogen Synthase Kinase-3 (GSK3) inhibitors for cancers therapies.

The intricate molecular pathways governing cancer development and progression have spurred intensive investigations into novel therapeutic targets. Glycogen Synthase Kinase-3 (GSK3), a complex serine/threonine kinase, has emerged as a key player with intricate roles in various cellular processes, including cell proliferation, differentiation, apoptosis, and metabolism. Harnessing GSK3 inhibitors as potential candidates for cancer therapy has garnered significant interest due to their ability to modulate key signalling pathways that drive oncogenesis. The review encompasses a thorough examination of the molecular mechanisms underlying GSK3's involvement in cancer progression, shedding light on its interaction with critical pathways such as Wnt/ß-catenin, PI3K/AKT, and NF-κB. Through these interactions, GSK3 exerts influence over tumour growth, invasion, angiogenesis, and metastasis, rendering it an attractive target for therapeutic intervention. The discussion includes preclinical and clinical studies, showcasing the inhibitors efficacy across a spectrum of cancer types, including pancreatic, ovarian, lung, and other malignancies. Insights from recent studies highlight the potential synergistic effects of combining GSK3 inhibitors with conventional chemotherapeutic agents or targeted therapies, opening avenues for innovative combinatorial approaches. This review provides a comprehensive overview of the current state of research surrounding GSK3 inhibitors as promising agents for cancer treatment.

Novel 2-substituted-quinoxaline analogs with potential antiproliferative activity against breast cancer: insights into cell cycle arrest, topoisomerase II, and EGFR activity.

Breast cancer is a global health concern, with increasing disease burden and disparities in access to healthcare. Late diagnosis and limited treatment options in underserved areas contribute to poor outcomes. In response to this challenge, we developed a novel family of 2-substituted-quinoxaline analogues, combining coumarin and quinoxaline scaffolds known for their anticancer properties. Through a versatile synthetic approach, we designed, synthesized, and characterized a set of 2-substituted quinoxaline derivatives. The antiproliferative activity of the synthesized compounds was assessed toward the MCF-7 breast cancer cells. Our investigations showed that the synthesized compounds exhibit considerable antiproliferative activity toward MCF-7 cells. Notably, compound 3b, among examined compounds, displayed a superior inhibitory effect (IC50 = 1.85 ± 0.11 µM) toward the growth of MCF-7 cells compared to the conventional anticancer drug staurosporine (IC50 = 6.77 ± 0.41 µM) and showed minimal impact on normal cells (MCF-10A cell lines, IC50 = 33.7 ± 2.04 µM). Mechanistic studies revealed that compound 3b induced cell cycle arrest at the G1 transition and triggered apoptosis in MCF-7 cells, as evidenced by increasing the percentage of cells arrested in the G2/M and pre-G1 phases utilizing flow cytometric analysis and Annexin V-FITC/PI analysis. Moreover, compound 3b was found to substantially suppress topoisomerase enzyme activity in MCF-7 cells. Molecular modeling studies further supported the potential of compound 3b as a therapeutic candidate by demonstrating significant binding affinity to the active sites of both topoisomerase II and EGFR proteins. Taken together, the presented 2-substituted-quinoxaline analogues, especially compound 3b, show promise as potential candidates for the development of effective anti-breast cancer drugs.