Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice.

BACKGROUND: Mefenamic acid (MFA), a common analgesic, causes central nervous system (CNS) toxicity at high doses with a proposed activity on the Gamma-aminobutyric acid (GABA) system. However, it remains unknown whether flumazenil (FMZ), a GABA type A receptor (GABAAR) antagonist, can reverse MFA toxicity. METHODS: The behavioral and neurophysiological effects of MFA were investigated in mice with and without FMZ pre-treatment. The elevated zero maze (EZM) and marble burying tests were used to assess anxiety-like behaviors and burying activities, respectively. The standard bar test was used to evaluate catalepsy, while the actophotometer test was used to measure locomotor activity. Seizure intensity was scored, and fatalities were counted. RESULTS: Without FMZ pre-treatment, MFA induced behavioral and neurophysiological effects in a dose-dependent manner as follows: At a dose of 20 mg/kg, i.p, MFA-treated mice exhibited anxiety-like behaviors, which was determined by a significant increase in the time spent in the closed areas and a significant decrease in the number of entries to the open areas of the EZM apparatus. These mice also showed a significant decrease in the burying activity, manifested as a significant decrease in the number of buried marbles. At 40 mg/kg, i.p., MFA-treated mice showed catalepsy that was associated with a significant decrease in locomotor activity. At a dose of 80 mg/kg, i.p., mice developed fatal tonic-clonic seizures (seizure score = 4). Pre-treatment with FMZ (5 mg/kg, i.p.) significantly reversed the anxiety-like behaviors and restored marble-burying activity. Additionally, FMZ prevented catalepsy, significantly restored locomotor activity, reduced seizure intensity (seizure score = 0.3) and significantly reduced mortalities. CONCLUSIONS: The present study's findings indicate that activation of the GABAAR is involved in the CNS toxicity of MFA, and FMZ reverses MFA toxicity by interfering with this receptor.

The pro-inflammatory cytokine IL-Iß alteration by deer (Rusa unicolor) antler extract on osteoarthritis rat model.

Osteoarthritis is a disease associated with articular cartilage degradation, intra-articular area inflammation, and subchondral bone replacement. Cytokine IL-1ß has a prominent function in the inflammations process that passes in the joints. The 70% ethanol extracts of deer antler (250 and 500 mg/kg BW) and glucosamine sulfate (250 kg/BW) were evaluated for four weeks in reducing cytokine IL-1ß to rat model OA-induced Monosodium iodoacetate. Measurements of joint diameter in rat's knee and hyperalgesia were performed on weeks 0, 1, 2, 3, 4, 5, 6, and 7. The presence of a significant difference in the stimulation thermal latency (p = 0.00) and the resulting increase in swelling of joint diameter (p = 0.00) are evidence that MIA has successfully induced the rat modeling of OA. A significant decrease in cytokine IL-Iß levels was shown on week 3 after MIA injection (p = 0.00). Both concentrations of deer extracts significantly reduced knee joint diameter (p = 0.00), latency thermal stimulation (p = 0.00), and cytokine IL-1ß levels (p = 0.00). Based on the results, it can be concluded that the 70% ethanol extract of deer antler is a potential medicine for OA therapy.

Carrageenophyte Kappaphycus malesianus Inhibits Microglia-Mediated Neuroinflammation via Suppression of AKT/NF-κB and ERK Signaling Pathways.

Neuroinflammation is an inflammatory response in any part of the central nervous system triggered by the activation of microglia and astrocytes to produce proinflammatory cytokines in the brain. However, overproduction of proinflammatory cytokines further contributes to the development of neurodegenerative disorders. Red seaweed, Kappaphycus malesianus, is a predominant carrageenophyte commercially cultivated in Semporna, Sabah, Malaysia. It is an important source of raw material for kappa-carrageenan productions in the food, pharmaceutical and cosmetics industries. However, no studies have been conducted focusing on the antineuroinflammatory effects of K. malesianus. The aim of the present study was to investigate the effect of the antineuroinflammatory activity of K. malesianus extracts (ethyl acetate, ethanol and methanol) on lipopolysaccharide-stimulated BV2 microglia and the underlying mechanisms involved in the regulation of neuroinflammatory pathways. Extract with the most promising antineuroinflammatory activity was analyzed using liquid chromatography-mass spectrometry (LC-MS). Our results show that methanol extract has a convincing antineuroinflammatory effect by suppressing both AKT/NF-κB and ERK signaling pathways to inhibit the expression of all proinflammatory cytokines without causing a cytotoxicity effect. LC-MS analysis of methanol extract revealed two compounds: prosopinine and eplerenone. Our findings indicated that metabolites of K. malesianus are potent antineuroinflammatory agents with respect to prevention of neurological disorders.

Synthesis and In-Vivo Evaluation of Benzoxazole Derivatives as Promising Anti-Psoriatic Drugs for Clinical Use.

2-(4-Chlorophenyl)-5-benzoxazoleacetic acid (CBA) and its ester, methyl-2-(4-chloro-phenyl)-5-benzoxazoleacetate (MCBA), were synthesized, and their structures were confirmed by 1HNMR, IR, and mass spectrophotometry. The anti-psoriatic activities of CBA and MCBA were tested using an imiquimod (IMQ)-induced psoriatic mouse model, in which mice were treated both topically (1% w/w) and orally (125 mg/kg) for 14 days. The erythema intensity, thickness, and desquamation of psoriasis were scored by calculating the psoriasis area severity index (PASI). The study also included the determination of histopathological alterations in the skin tissues of treated mice. Topical and oral administration of CBA and MCBA led to a reduction in erythema intensity, thickness, and desquamation, which was demonstrated by a significant decrease in the PASI value. In addition, skin tissues of mice treated with CBA and MCBA showed less evidence of psoriatic alterations, such as hyperkeratosis, parakeratosis, scale crust, edema, psoriasiform, and hyperplasia. After administration of either topical or oral dosing, the anti-psoriatic effects were found to be stronger in MCBA-treated than in CBA-treated mice. These effects were comparable to those produced by Clobetasol propionate, the reference drug. This drug discovery could be translated into a potential new drug for future clinical use in psoriasis treatment.

Dopaminergic mechanisms in the lateral hypothalamus regulate feeding behavior in association with neuropeptides.

This study investigated dopaminergic function in the lateral hypothalamus (LH) in the regulation of feeding behavior. Refeeding increased dopamine levels in the LH. Glucose injection also increased dopamine levels in the LH. When the retrograde tracer Fluoro-Gold (FG) was injected into the LH, FG-positive cells were found in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNC), which were mostly tyrosine hydroxylase-positive. Injection of the dopamine D1 receptor agonist SKF 38393, but not the antagonist SCH 23390, into the LH increased food intake. Similarly, injection of the dopamine D2 receptor agonist quinpirole, but not the antagonist l-sulpiride, into the LH increased food intake. The effect of each agonist was blocked by its respective antagonist. Furthermore, injection of quinpirole, but not SKF 38393, decreased the mRNA level of preproorexin. In addition, injection of SKF 38393 decreased the mRNA levels of neuropeptide Y and agouti-related peptide, whereas the injection of quinpirole increased the mRNA level of proopiomelanocortin. These results indicate that food intake activates dopamine neurons projecting from the VTA/SNC to the LH through an increase in blood glucose levels, which terminates food intake by stimulation of dopamine D1 and D2 receptors. It is also possible that stimulation of dopamine D1 and D2 receptors in the LH inhibits feeding behavior through different neuropeptides.

Exploring the antidiabetic and anti-inflammatory potential of Lavandula officinalis essential oil: In vitro and in silico insights.

Medicinal plants have been utilized for centuries in traditional medicine systems worldwide, providing a rich source of bioactive compounds with diverse biological activities. Lavandula officinalis, a member of the Lamiaceae family, has been recognized for its multifaceted pharmacological activities. In this current investigation, our primary objective was to scrutinize the in vitro inhibitory potential of L. officinalis essential oil (LOEO) against alpha-amylase and alpha-glucosidase, with the aim of understanding its antidiabetic effects. Additionally, the assay encompassed tyrosinase and lipoxygenase (LOX) to assess its anti-inflammatory attributes. Unraveling the underlying molecular mechanisms of these activities prompted an in-silico study. The purpose was to establish correlations between in-vitro observations and computational insights derived from molecular docking, which forecasts the interaction of LOEO molecules with their respective targets, alongside ADMET prediction. The Gas Chromatography-Mass Spectrometry (GC-MS) analysis allow to identify eighteen compounds, with the dominance of L-camphor (43.12 %), 1,8-cineole (34.27 %) and borneol (8.60 %) in LOEO. The antidiabetic evaluation revealed that LOEO exhibited noteworthy inhibitory activity against both α-amylase and α-glucosidase, displaying IC50 values of 3.14 ± 0.05 mg/mL and 2.07 ± 0.03 mg/mL, respectively. The subsequent in-silico study highlighted the particularly strong binding affinity of (E)-Farnesene, with a binding score of -7.4 kcal/mol for alpha-glucosidase, while Germacrene D displayed the highest affinity among the ligands (-7.9 kcal/mol) for the alpha-amylase target. Furthermore, the investigation into in vitro anti-inflammatory activity unveiled LOEO efficacy against tyrosinase (IC50 = 42.74 µg/mL) and LOX (IC50 = 11.58 ± 0.07 µg/mL). The in-silico analysis echoed these findings, indicating α-Cadinene's notable binding affinity of 6 kcal/mol with tyrosinase and α-Cedrene's binding score of -6.5 kcal/mol for LOX. Impressively, for both COX-1 and COX-2, α-Cedrene exhibited significant binding affinities of -7.6 and -7.3 kcal/mol, respectively. The convergence between the in vitro and in silico outcomes underscores the potential of LOEO and its constituent compounds as potent inhibitors targeting both diabetes and the inflammatory processes.

Bioactive compounds from nature: Antioxidants targeting cellular transformation in response to epigenetic perturbations induced by oxidative stress.

Oxidative stress results from a persistent imbalance in oxidation levels that promotes oxidants, playing a crucial role in the early and sustained phases of DNA damage and genomic and epigenetic instability, both of which are intricately linked to the development of tumors. The molecular pathways contributing to carcinogenesis in this context, particularly those related to double-strand and single-strand breaks in DNA, serve as indicators of DNA damage due to oxidation in cancer cases, as well as factors contributing to epigenetic instability through ectopic expressions. Oxidative stress has been considered a therapeutic target for many years, and an increasing number of studies have highlighted the promising effectiveness of natural products in cancer treatment. In this regard, we present significant research on the therapeutic targeting of oxidative stress using natural molecules and underscore the essential role of oxidative stress in cancer. The consequences of stress, especially epigenetic instability, also offer significant therapeutic prospects. In this context, the use of natural epi-drugs capable of modulating and reorganizing the epigenetic network is beginning to emerge remarkably. In this review, we emphasize the close connections between oxidative stress, epigenetic instability, and tumor transformation, while highlighting the role of natural substances as antioxidants and epi-drugs in the anti-tumoral context.

Phytochemical characterization, antimicrobial properties and in silico modeling perspectives of Anacyclus pyrethrum essential oil.

Medicinal plants are used widely in the treatment of various infectious diseases. One of these medical plants is Moroccan plants such as Anacyclus pyrethrum. In this study, the essential oil isolated from the leaves of Anacyclus pyrethrum (APEO) by the hydrodistillation method was analyzed using (GC/MS) analysis. A total of forty-four compounds were identified form the oil and the oxygenated monoterpenes were the most abundant class of compounds. The major identified compound is santolina alcohol (40.7 %), followed by germacrene-D (8.9 %). The in-vitro assessment of the antimicrobial efficacy of APEO encompassed an investigation involving six microbial strains, including two Gram-positive bacteria, four Gram-negative bacteria, and three fungal strains. The findings revealed noteworthy antibacterial and antifungal properties against all examined microorganisms, with inhibitory zone diameters ranging from 25.67 ± 0.06 mm to 25.19 ± 0.03 mm for Gram-positive bacteria and from 22.34 ± 0.01 mm to 14.43 ± 0.02 mm for Gram-negative bacteria, as determined through the disc-diffusion assay. In the case of antifungal activity, inhibitory zones ranged from 24.57 ± 0.04 mm to 18.37 ± 0.06 mm. Further evaluation revealed that the MIC values of Gram-positive bacteria were at the concentration 0.25 % v/v, while MBC values ranged from 0.25 % to 1.0 % v/v. The Gram-negative bacteria exhibited MIC values spanning from 0.5 % to 2.0 % v/v, with MBC values in the range of 0.5 %-2.0 % v/v. For the fungal strains, MIC values ranged from 0.5 % to 1.0 % v/v, while the MFC consistently remained at 1.0 % for all tested fungal strains. The assessment of the MBC/MIC and MFC/MIC ratios collectively indicates that A. pyrethrum EO possesses bactericidal and fungicidal attributes. The in silico study of bioavailability predictions for compounds in APEO based on six physicochemical properties show optimal physiochemical properties including size, lipophilicity, solubility, flexibility, and saturation. α-Pinene, limonene, germacrene D, and (E)-ß-farnesene are non-polar due to their lack of polar groups, and the ADME profile indicates desirable properties for considering these compounds in drug development. Molecular docking investigation indicates that all the compounds of APEO reside well into the binding site of the DNA gyrase B enzyme of Staphylococcus aureus by mediating a number of significant interactions with the binding site residues. The ADME analysis suggested that the major compounds APEO possess desirable properties for further consideration in drug development. In light of these findings, APEO could serve as a natural source for the elaboration of new and active antimicrobial drugs.

Unlocking the combined action of Mentha pulegium L. essential oil and Thym honey: In vitro pharmacological activities, molecular docking, and in vivo anti-inflammatory effect.

Mentha pulegium L., a plant widely embraced for its therapeutic properties by populations worldwide, including Morocco, has long been recognized for its potential in treating various ailments. This study aims to comprehensively evaluate the antioxidant, anti-inflammatory, and dermatoprotective properties of essential oil derived from M. pulegium, and thyme honey as well as their combined effects. To unravel the chemical composition, a rigorous GC-MS analysis was conducted. Subsequently, we examined their antioxidant potential through three distinct assays: DPPH●, hydrogen peroxide assay, and xanthine oxidase assay. The anti-inflammatory properties were scrutinized through both in vitro and in vivo experiments. Simultaneously, the dermatoprotective efficacy was investigated in vitro by evaluating tyrosinase inhibition. Our findings revealed that pulegone constitutes the predominant compound in M. pulegium essential oil (MPEO), constituting a remarkable 74.82 % of the composition. Significantly, when the essential oil was combined with thym honey, it exhibited superior anti-inflammatory and dermatoprotective effects across all in vivo and in vitro tests. Moreover, our in silico molecular docking analysis hinted at the potential role of cyclohexanone, 3-methyl, an element found in the MPEO, in contributing to the observed outcomes. While this study has unveiled promising results regarding the combined in vitro, in vivo and in silico biological activities of the essential oil and honey, it is imperative to delve further into the underlying mechanisms through additional experimentation and alternative experimental methods. Understanding these mechanisms in greater detail will not only enhance our comprehension of the therapeutic potential but also pave the way for the development of innovative treatments and applications rooted in the synergy of these natural compounds. Furthermore, it would be advantageous to test different possible combinations using experimental design model. Moreover, it would be better to test the effect of single compounds of MPEO to clearly elucidate their efficiency. MPEO alone or combined with thyme honey may be a useful for the development of novel biopharmaceuticals.

Bovine hydroxyapatite-based scaffold accelerated the inflammatory phase and bone growth in rats with bone defect.

Hydroxyapatite (HA) is a biomaterial widely used to treat bone defect, such as due to traffic accident. The HA scaffold is obtained from synthetic HA or natural sources, such as bovine hydroxyapatite (BHA). This study aims to compare the characteristics and in vivo performance of BHA-based and HA-based scaffolds. For this purpose, the scaffold was formulated with gelatin (GEL) and characterised by SEM-EDX, FTIR and mini autograph. The defect model was carried out on the femur area of Wistar rats classified into three animal groups: defect, HA-GEL and BHA-GEL. Postoperatively (7, 14 and 28 days), the bone was radiologically evaluated, and stained with haematoxylin-eosin, anti-CD80 and anti-CD163. The BHA-GEL scaffold showed a regular surface and spherical particle shape, whereas the HA-GEL scaffold exhibited irregular surface. The BHA-GEL scaffold had higher pore size and compressive strength and lower calcium-to-phosphorus ratio than the HA-GEL scaffold. In vivo study showed that the expression of CD80 in the three experimental groups was not significantly different. However, the expression of CD163 differed significantly between the groups. The BHA-GEL group showed robust expression of CD163 on day 7, which rapidly decreased over time. It also showed increased osteoclasts, osteoblasts and osteocytes cell count that contributed to the integrity of the defect area. In conclusion, the BHA-based scaffold exhibited the desired physical and chemical characteristics that benefit in vivo performance versus the HA-based scaffold. Thus, the BHA-based scaffold may be used as a bone graft.

Hydroxychloroquine Toxicity in the Vital Organs of the Body: In Vivo Study.

BACKGROUND: Hydroxychloroquine (HCQ) toxicity can adversely affect vital organs, cause pathologic ocular damage, and can have direct cardiovascular effects. This study aims to identify the biochemical, hematological, and histological alterations of the vital organs associated with the effects of HCQ. METHODS: Male albino rats were exposed to the equivalent of HCQ therapeutic doses given to human patients being affected by malaria, lupus erythematosus, and COVID-19. The animal blood samples were subjected to hematological analysis, biochemical analysis, liver function tests, kidney function tests, and cardiac biomarkers. Liver, kidney, heart, spleen, and testis biopsies were subjected to histological examination. RESULTS: HCQ significantly lowered the values of erythrocytes, hemoglobin, hematocrit, platelets, leucocytes, and lymphocytes but significantly increased the values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase, alkaline phosphatase, lactate dehydrogenase, cholesterol, and chlorine ions. The renal tissues of HCQ-treated animals demonstrated glomerular fragmentation, partial atrophy degeneration, renal tubules hydropic degeneration, hyaline cast formation, and interstitial edema formation. Additionally, the heart exhibited myofiber necrosis, myolysis, wavy appearance, disorganization, and disarray. The testicular tissues also demonstrated spermatocyte degeneration, spermatogenic cell sloughing, testicular interstitial edema, and occasional spermatogenic arrest. Additionally, the spleen showed a decrease in the number and size of the white pulp follicles, a decrease in the number of apoptotic activity, and a decline in the number of T-rich cells. However, the red pulp demonstrated a diffuse decline in B rich-lymphocytes and macrophages. The liver was also the least affected but showed Kupffer cell hyperplasia and occasional hepatocyte dysplasia. CONCLUSIONS: The results indicate that chronic exposure to HCQ could alter the structures and functions of the vital organs.

Differentiation of osteoblasts: the links between essential transcription factors.

Osteoblasts, cells derived from mesenchymal stem cells (MSCs) in the bone marrow, are cells responsible for bone formation and remodeling. The differentiation of osteoblasts from MSCs is triggered by the expression of specific genes, which are subsequently controlled by pro-osteogenic pathways. Mature osteoblasts then differentiate into osteocytes and are embedded in the bone matrix. Dysregulation of osteoblast function can cause inadequate bone formation, which leads to the development of bone disease. Various key molecules are involved in the regulation of osteoblastogenesis, which are transcription factors. Previous studies have heavily examined the role of factors that control gene expression during osteoblastogenesis, both in vitro and in vivo. However, the systematic relationship of these transcription factors remains unknown. The involvement of ncRNAs in this mechanism, particularly miRNAs, lncRNAs, and circRNAs, has been shown to influence transcriptional factor activity in the regulation of osteoblast differentiation. Here, we discuss nine essential transcription factors involved in osteoblast differentiation, including Runx2, Osx, Dlx5, ß-catenin, ATF4, Ihh, Satb2, and Shn3. In addition, we summarize the role of ncRNAs and their relationship to these essential transcription factors in order to improve our understanding of the transcriptional regulation of osteoblast differentiation. Adequate exploration and understanding of the molecular mechanisms of osteoblastogenesis can be a critical strategy in the development of therapies for bone-related diseases.Communicated by Ramaswamy H. Sarma.

Pharmaceutical Development of Intraperitoneal Arachis hypogaea as a Renal Protective Agent.

BACKGROUND: Kidneys are among the vital organs of the human body; therefore, damage from any exogenous/endogenous agent may put human life at risk. Arachis hypogaea (AH) contains different free radical scavenging flavonoids, stilbenes, and tannins. This research aimed to elucidate the possible nephroprotective mechanism of AH methanolic crude extract (AHcr) and n-hexane oil fraction (AHO) against gentamycin-induced nephrotoxicity. METHODS: After the extraction of the crude oil of the plant, they were tested against a Gentamycin (GM)-treated group of Swiss Albino mice for their nephroprotective action. Animals were divided into six (6) equal groups with five (5) animals in each group. These groups were: control group (0.5 mL normal saline via intraperitoneal -i.p), gentamycin group (gentamycin 100 mg/kg i.p), Silymarin + gentamycin group (Silymarin 50 mg/kg and gentamycin 100 mg/kg i.p), plant extract (AHcr1) and gentamycin group (AHcr1 250 mg/kg and gentamycin 100 mg/kg i.p), AHcr2 + gentamycin group (AHcr2; 500 mg/kg and gentamycin 100 mg/kg i.p) and the hexane oil fraction (AHO) + gentamycin (AHO 1 mL/kg and GM 100 mg/kg i.p). After completion of doses, animals were sacrificed for the collection of blood to further investigate biochemical changes and histopathological changes in kidney tissues. RESULTS: Serum creatinine, urea, and blood urea nitrogen significantly increased (p < 0.001) in the gentamycin-treated group as compared to the control group. The elevated level of serum creatinine, urea, and blood urea nitrogen was decreased significantly (p < 0.001) in groups treated with AHcr and AHO compared to the gentamycin group. Similarly, the histopathological study of kidney tissues from the gentamycin group showed tubular necrosis, vacuolation, and fibrosis. CONCLUSIONS: The effect of crude extract and hexane soluble fraction of AH caused a significant reversal of gentamycin-induced nephrotoxicity.

Effect of L-Carnosine in Patients with Age-Related Diseases: A Systematic Review and Meta-Analysis.

INTRODUCTION: L-carnosine has been found to have multimodal activity. AIM: The aim of this review was to find out the efficacy of L-carnosine in patients with age-related diseases. METHODS: Clinical studies evaluated the effect of L-carnosine on cancer, cardiovascular disease, diabetes, and neurodegenerative disorders were searched in electronic bibliographic databases. The protocol has been registered with PROSPERO (CRD42022314033). The revised Cochrane risk of bias tool for randomized trials was used to assess all of the reports for risk of bias. RevMan 5.4 was used to conduct the meta-analysis. RESULTS: Following the screening process, 14 papers were selected for systematic review, with 9 of them being qualified for meta-analysis. Many of the included studies showed that L-carnosine has potential therapeutic activity in age related diseases. Results from the meta-analysis showed that in diabetes mellitus, HbA1c [mean difference (MD) 95% CI = -1.25 (-2.49, -0.022); p = 0.05; p = 0.001; I2 = 85%] and fasting blood sugar (FBS) [MD 95% CI = -12.44 (-22.44, -2.44); p = 0.01; p = 0.40; I2 = 0%] and in neurodegenerative disorder, Wechsler Memory Scale Logical Memory 2 (WMS-LM2) [MD 95% CI = 1.34 (0.83, 1.85); p < 0.00001; p = 0.43; I2 = 0%], showed statistically significant difference, favoring the L-carnosine group over the control group. While in neurodegenerative disorder, Alzheimer 's Disease Assessment Scale (ADAS) [MD 95% CI = 0.98 (-1.55, -0.42); p = 0.0007; p = 0.86; I2 = 0%] and Back Depression Inventory (BDI) [MD 95% CI = -1.12 (-1.87, -0.37); p = 0.003; p = 0.73; I2 = 0%] showed statistically significant difference, favoring the control group over L-carnosine group. CONCLUSIONS: Clinical studies were conducted to manage chemotherapy induced toxicities and there are no clinical studies available for its anti-cancer use, and the current evidence does not support its use in the treatment of cardiovascular disease.

Computational approach in searching for dual action multitarget inhibitors for osteosarcoma.

Osteosarcoma is a common primary malignant bone tumor that typically manifests in the second decade of life. This study aimed to identify osteogenic compounds that potentially serve as multitarget inhibitors for osteosarcoma. The study was a molecular docking study of nine Food and Drug Administration-approved compounds with osteogenic properties to the key membrane proteins of osteosarcoma. The ligands used were raloxifene, simvastatin, dexamethasone, risedronate, ibandronate, zoledronic acid, ascorbic acid, alendronate, and ß-glycerophosphate, whereas the target proteins used were RET, fibroblast growth factor receptor 1, KIT, PDGFRA, VEGFR1, and VEGFR2. Chem3D version 15.0.0.106 was used for ligand preparation, and AutoDockTools version 1.5.6 was used for protein preparation, whereas molecular docking was conducted using AutoDock Vina. Raloxifene, simvastatin, and dexamethasone had the lowest binding activity to the target proteins. The binding affinity of raloxifene was from -8.4 to -10.0 kcal mol-1, that of simvastatin was -8.3 to -9.2 kcal mol-1, whereas dexamethasone ranged from -6.9 to -9.1 kcal mol-1. Most types of interactions were hydrophobically followed by hydrogen bonding. The current study suggests that raloxifene, simvastatin, and dexamethasone have the potential to act as multitarget inhibitors for osteosarcoma with the ability to induce bone remodeling.

Molecular mechanisms underlying the clinical efficacy of panobinostat involve Stochasticity of epigenetic signaling, sensitization to anticancer drugs, and induction of cellular cell death related to cellular stresses.

Panobinostat, also known as Farydak®, LBH589, PNB, or panobinostat lactate, is a hydroxamic acid that has been approved by the Food and Drug Administration (FDA) for its anti-cancer properties. This orally bioavailable drug is classified as a non-selective histone deacetylase inhibitor (pan-HDACi) that inhibits class I, II, and IV HDACs at nanomolar levels due to its significant histone modifications and epigenetic mechanisms. A mismatch between histone acetyltransferases (HATs) and HDACs can negatively affect the regulation of the genes concerned, which in turn can contribute to tumorigenesis. Indeed, panobinostat inhibits HDACs, potentially leading to acetylated histone accumulation, re-establishing normal gene expression in cancer cells, and helping to drive multiple signaling pathways. These pathways include induction of histone acetylation and cytotoxicity for the majority of tested cancer cell lines, increased levels of p21 cell cycle proteins, enhanced amounts of pro-apoptotic factors (such as caspase-3/7 activity and cleaved poly (ADP-ribose) polymerase (PARP)) associated with decreased levels of anti-apoptotic factors [B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra-large (Bcl-XL)], as well as regulation of immune response [upregulated programmed death-ligand 1 (PD-L1) and interferon gamma receptor 1 (IFN-γR1) expression] and other events. The therapeutic outcome of panobinostat is therefore mediated by sub-pathways involving proteasome and/or aggresome degradation, endoplasmic reticulum, cell cycle arrest, promotion of extrinsic and intrinsic processes of apoptosis, tumor microenvironment remodeling, and angiogenesis inhibition. In this investigation, we aimed to pinpoint the precise molecular mechanism underlying panobinostat's HDAC inhibitory effect. A more thorough understanding of these mechanisms will greatly advance our knowledge of cancer cell aberrations and, as a result, provide an opportunity for the discovery of significant new therapeutic perspectives through cancer therapeutics.

Identification and optimization of TDP1 inhibitors from anthraquinone and chalcone derivatives: consensus scoring virtual screening and molecular simulations.

Virtual screening aims to identify and rank compounds with drug/lead-like properties based on their affinity for the protein target. We developed a methodology that integrates structure- and ligand-based screening approaches to enhance hit rates against the TDP1 protein within a database of anthraquinone and chalcone derivatives, followed by evaluation of prioritized compounds through molecular simulations. This technique is particularly useful for training set imbalances. Four screening methods were used: QSAR, pharmacophore, shape similarity, and docking. Each method was individually trained to score compounds, and the scores were fused to create parallel Z-score fusion. The QSAR models exhibited satisfactory R2 values (0.84 to 0.75), whereas the pharmacophoric and shape similarity models demonstrated excellent performance (ROC:0.82-0.88). Docking enrichment analysis identified 6N0D as the optimal TDP1 crystal structure (ROC = 0.73). Remarkably, the consensus scoring method surpassed other screening methods, achieving the highest ROC value of 0.98. Docking screening prioritized compounds with binding modes resembling the co-crystallized ligands, whereas MMGBSA, consensus, and docking produced dynamic simulations that were as stable as the co-crystallized ligands. Additionally, the QSAR-selected compounds exhibited binding modes similar to those of commercially available TDP1 inhibitors. In this study, a strong correlation was found between the inhibitory concentrations and binding energy values of commercialized TDP1 inhibitors, indicating that the top-ranked compounds are expected to have potent inhibitory effects in the nano-/micromolar range. The results of this study establish that consensus scoring can be used as an adaptable mainstay virtual screening methodology, pending subsequent experimental validation for affirmation.Communicated by Ramaswamy H. Sarma.

Natural sources, biological effects, and pharmacological properties of cynaroside.

Cynaroside is a flavonoid, isolated from several species belonging to the Apiaceae, Poaceae, Lamiaceae, Solanaceae, Zingiberaceae, Compositae and other families and it can be extracted from seeds, roots, stems, leaves, barks, flowers, fruits, aerial parts, and the whole plant of these species. This paper discloses the current state of knowledge on the biological/pharmacological effects and mode of action to better understand the numerous health benefits of cynaroside. Several research works revealed that cynaroside could have beneficial effects on various human pathologies. Indeed, this flavonoid exerts antibacterial, antifungal, antileishmanial, antioxidant, hepatoprotective, antidiabetic, anti-inflammatory, and anticancer effects. Additionally, cynaroside exhibits its anticancer effects by blocking MET/AKT/mTOR axis by decreasing the phosphorylation level of AKT, mTOR, and P70S6K. For antibacterial activity, cynaroside reduces biofilm development of Pseudomonas aeruginosa and Staphylococcus aureus. Moreover, the incidence of mutations leading to ciprofloxacin resistance in Salmonella typhimurium was reduced after the treatment with cynaroside. In addition, cynaroside inhibited the production of reactive oxygen species (ROS), which reduced the damage to mitochondrial membrane potential caused by hydrogen peroxide (H2O2). It also enhanced the expression of the anti-apoptotic protein Bcl-2 and lowered that of the pro-apoptotic protein Bax. Cynaroside abrogated the up-regulation of c-Jun N-terminal kinase (JNK) and p53 protein expression triggered by H2O2. All these findings suggest that cynaroside could be used to prevent certain human diseases.

Reviewing the Prospective Pharmacological Potential of Isothiocyanates in Fight against Female-Specific Cancers.

Gynecological cancers are the most commonly diagnosed malignancies in females worldwide. Despite the advancement of diagnostic tools as well as the availability of various therapeutic interventions, the incidence and mortality of female-specific cancers is still a life-threatening issue, prevailing as one of the major health problems worldwide. Lately, alternative medicines have garnered immense attention as a therapeutic intervention against various types of cancers, seemingly because of their safety profiles and enhanced effectiveness. Isothiocyanates (ITCs), specifically sulforaphane, benzyl isothiocyanate, and phenethyl isothiocyanate, have shown an intriguing potential to actively contribute to cancer cell growth inhibition, apoptosis induction, epigenetic alterations, and modulation of autophagy and cancer stem cells in female-specific cancers. Additionally, it has been shown that ITCs plausibly enhance the chemo-sensitization of many chemotherapeutic drugs. To this end, evidence has shown enhanced efficacy in combinatorial regimens with conventional chemotherapeutic drugs and/or other phytochemicals. Reckoning with these, herein, we discuss the advances in the knowledge regarding the aspects highlighting the molecular intricacies of ITCs in female-specific cancers. In addition, we have also argued regarding the potential of ITCs either as solitary treatment or in a combinatorial therapeutic regimen for the prevention and/or treatment of female-specific cancers. Hopefully, this review will open new horizons for consideration of ITCs in therapeutic interventions that would undoubtedly improve the prognosis of the female-specific cancer clientele. Considering all these, it is reasonable to state that a better understanding of these molecular intricacies will plausibly provide a facile opportunity for treating these female-specific cancers.

Phytochemical analysis and evaluation of antimicrobial, antioxidant, and antidiabetic activities of essential oils from Moroccan medicinal plants: Mentha suaveolens, Lavandula stoechas, and Ammi visnaga.

Mentha suaveolens, Lavandula stoechas, and Ammi visnaga are widely used in Moroccan folk medicine against several pathological disorders, including diabetes and infectious diseases. This work was designed to determine the chemical profile of M. suaveolens (MSEO), L. stoechas (LSEO), and A. visnaga (AVEO) essential oils and assess their antimicrobial, antioxidant, and antidiabetic effects. The volatile components of LSEO, AVEO, and MSEO were analyzed using Gas Chromatography-Mass Spectrometry (GC-MS). The in vitro antidiabetic activity was assessed using α-amylase and α-glucosidase enzymes, while DPPH, FRAP, and ß-carotene/linoleic acid methods were used to determine the antioxidant capacity. The antimicrobial activities were investigated using disc diffusion and broth-microdilution assays. GC-MS investigation revealed that the main components were fenchone (29.77 %) and camphor (24.9 %) for LSEO, and linalool (38.29 %) for AVEO, while MSEO was mainly represented by piperitenone oxide (74.55 %). The results of the antimicrobial evaluation showed that all examined essential oils (EOs) had noticeable antimicrobial activity against both bacteria and yeast, especially Micrococcus luteus and Bacillus subtilis. The MIC, MBC, and MFC values were ranged from 0.015 % to 0.5 %. The MBC/MIC and MFC/MIC ratios were less than or equal to 4.0 % (v/v), indicating their noticeable bactericidal and candidacidal efficacy. Moreover, the three EOs showed significant inhibitory effects on α-amylase and α-glucosidase (p < 0.05). It also exerted remarkable activity on FRAP, ß-carotene, and DPPH radicals. These findings demonstrated that the tested plants have promising biological activities, validating their ethnomedicinal value and providing potential applications as natural drugs.