Hexaconazole exposure may lead to Parkinson via disrupting glucocerebrosidase and parkin: molecular interaction, dynamics, MMPBSA and DFT based in-silico predictive toxicology.

Hexaconazole is a known fungicide for agricultural purposes. It has bioaccumulation ability which makes it important for its toxicological characterization. There are various neurological impacts of pollutants on human health. Therefore, in this study, we have done predictive analyses of the interaction mechanism of hexaconazole by molecular interaction analysis, molecular dynamics simulation, and Poisson-Boltzmann surface area (MM-PBSA) to assess hexaconazole's potency to disrupt the homeostasis of glucocerebrosidase (-7.9 kcal/mol) and parkin (-5.67 kcal/mol) proteins which have significant roles in the manifestation of Parkinson disease. The findings reveal that hexaconazole has the potency to form stable interactions with glucocerebrosidase and parkin. This research provides a molecular and atomic-level understanding of how hexaconazole exposure may disrupt the homeostasis of glucocerebrosidase and parkin. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration, and hydrogen bonding exhibited the potent molecular interactions of hexaconazole, which may lead to neurological manifestations such as Parkinson disease.

Preparation of novel S-allyl cysteine chitosan based nanoparticles for use in ischemic brain treatment.

Objective: To enhance the brain bioavailability of S-allyl-l-cysteine (SC) by developing novel S-allyl-l-cysteine chitosan nanoparticles (SC CS NPs) and examining the quantity of SC by developing a novel method of ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) in ischemic rat brain treatment. Methods: The ionotropic gelation method was used to develop S-allyl cysteine-loaded CS NPs. The 4-factor, 5-level central composite design was optimized to determine the effect of independent variables, i.e., particle size, polydispersity index (PDI), zeta potential, EE, and loading capacity, together with their characterization, followed by drug release and intranasal permeation to enhance the brain bioavailability and examination of their neurobehavioral and biochemical parameters with their histopathological examination. Results: SC CS NPs were optimized at the particle size of 93.21 ± 3.31 nm (PDI: 0.317 ± 0.003), zeta potential of 44.4 ± 2.93, and drug loading of 41.23 ± 1.97% with an entrapment efficiency of 82.61 ± 4.93% having sustain and controlled release (79.92 ± 3.86%) with great permeation (>80.0%) of SC. SC showed the retention time of 1.021 min and 162.50/73.05 m/z. SC showed good linearity in the range of 5.0-1300.0 ng mL-1, % inter-and-intraday accuracy of 96.00-99.06% and CV of 4.38-4.38%. We observed significant results, i.e., p < 0.001 for improved (AUC)0-24 and Cmax delivered via i.v. and i.n. dose. We also observed the highly significantly observations of SC CS NPs (i.n.) based on their treatment results for the biochemical, neurobehavioral, and histopathological examination in the developed ischemic MCAO brain rat model. Conclusion: The excellent significant role of mucoadhesive CS NPs of SC was proven based on the enhancement in the brain bioavailability of SC via i.n. delivery in rats and easy targeting of the brain for ischemic brain treatment followed by an improvement in neuroprotection based on a very small dose of SC.

Effects of Tiliroside and Lisuride Co-Treatment on the PI3K/Akt Signal Pathway: Modulating Neuroinflammation and Apoptosis in Parkinson's Disease.

Researchers are actively exploring potential bioactive compounds to enhance the effectiveness of Lisuride (Lis) in treating Parkinson's disease (PD) over the long term, aiming to mitigate the serious side effects associated with its extended use. A recent study found that combining the dietary flavonoid Tiliroside (Til) with Lis has potential anti-Parkinson's benefits. The study showed significant improvements in PD symptoms induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) when Til and Lis were given together, based on various behavioral tests. This combined treatment significantly improved motor function and protected dopaminergic neurons in rats with PD induced by MPTP. It also activated important molecular pathways related to cell survival and apoptosis control, as indicated by the increased pAkt/Akt ratio. Til and Lis together increased B-cell lymphoma 2 (Bcl-2), decreased caspase 3 activity, and prevented brain cell decay. Co-administration also reduced tumor necrosis factor alpha (TNF-α) and Interleukin-1 (IL-1). Antioxidant markers such as superoxide dismutase (SOD), catalase, and reduced glutathione significantly improved compared to the MPTP-induced control group. This study shows that using Til and Lis together effectively treats MPTP-induced PD in rats, yielding results comparable to an 8 mg/kg dose of levodopa, highlighting their potential as promising Parkinson's treatments.

Gallic-Acid-Loaded PLGA Nanoparticles: A Promising Transdermal Drug Delivery System with Antioxidant and Antimicrobial Agents.

The objective of this study was to develop an innovative gallic-acid (GA) drug delivery system that could be administered transdermally, resulting in enhanced therapeutic benefits and minimal negative consequences. The method employed involved the preparation of poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with GA through nanoprecipitation-denoted GA@PLGANPs. The results reveal that this strategy led to perfectly spherical, homogeneous, and negatively charged particles, which are suitable for administration via skin patches or ointments. A further analysis indicates that these GA@PLGANPs exhibit remarkable antioxidant activity as well as potent antibacterial effects against a diverse range of microorganisms, making them ideal candidates for numerous applications. Additionally, it has been observed that these nanoparticles can effectively mitigate oxidative stress while also significantly inhibiting microbial growth by exerting detrimental effects on bacterial cell walls or membranes. In conclusion, on the basis of the findings presented in this study, there is strong evidence supporting the potential use of GA@PLGANPs as an effective therapy option with reduced side effects compared to conventional drug delivery methods.

Exploring the Therapeutic Potential of Berberine and Tocopherol in Managing Diabetic Neuropathy: A Comprehensive Approach towards Alleviating Chronic Neuropathic Pain.

Diabetic neuropathy (DN) causes sensory dysfunction, such as numbness, tingling, or burning sensations. Traditional medication may not ease pain and discomfort, but natural remedies such as Berberine (BR) and vitamin E or Tocopherol (TOC) have therapeutic potential to reduce inflammation while improving nerve function. Novel substances offer a more potent alternative method for managing severe chronic neuropathic pain that does not react to standard drug therapy by targeting various pathways that regulate it. Rats with diabetic control received oral doses of BR + TOC that showed significant changes in serum insulin levels compared to DN controls after 90 days, suggesting a decrease in sensitivity to painful stimuli partly by modulating the oxidative stress of the inflammatory pathway such as TNF-α suppression or stimulation of TNF-α depending on the amount of dose consumed by them. NF-kB also played its role here. Administering doses of BR and TOC reduced heightened levels of NF-kB and AGEs, effectively counteracting inflammation-targeted key factors in diabetes, promising possibilities for the benefits of these molecules revealed through in vivo investigation. In summary, treating neuropathy pain with a more comprehensive and organic approach can involve harnessing the powerful capabilities of BR and TOC. These compounds have been found to not only considerably decrease inflammation but also provide effective nerve protection while enhancing overall nerve function. With their multifunctional impacts on various neuropathic pain pathways in the body, these naturally occurring substances offer an exciting possibility for those who encounter high levels of neuropathic distress that do not respond well to conventional medication-centred therapies.

Comparing oxygen demand in critical covid-19 patients using single versus double doses of tocilizumab.

OBJECTIVES: To compare the outcomes of single versus double doses of tocilizumab in patients with severe COVID-19, especially on different types of oxygenation requirements. METHODS: This cross-sectional study was carried out from January 2020 to March 2020. Patients diagnosed with COVID-19, who received at least one dose of tocilizumab, were included. The dependent variable was tocilizumab dose (single versus double). The primary outcome variable was oxygen demand on the first and last day of hospitalization. A series of comparisons between patients administered one dose of tocilizumab versus 2 doses were conducted. RESULTS: Herein, 80 patients with severe COVID-19 infection were included, of whom 68.8% received one dose of tocilizumab, while 31.3% received a double dose. Two-thirds of the patients were male, with an overall average age of 58 years. In patients receiving 2 doses, oxygen demand tended to worsen by the seventh day, while in those who received one dose. The group that received 2 doses had a longer length of hospital stay. CONCLUSION: This study could not capture the additional value of the second dose for different health outcomes. However, the results can inform clinician from experience when facing uncertainty due to new virus or variant.

Effects of Taraxerol on Oxidative and Inflammatory Mediators in Isoproterenol-Induced Cardiotoxicity in an Animal Model.

Myocardial infarction (MI) continues to be an important issue in healthcare systems worldwide, leading to high rates of morbidity and mortality. Despite ongoing efforts towards the development of preventive measures and treatments, addressing the challenges posed by MI remains difficult both in developed and developing countries. However, researchers recently investigated the potential cardioprotective effects of taraxerol utilizing an isoproterenol (ISO)-induced cardiotoxicity model among Sprague Dawley rats. Specifically, subcutaneous tissue injections consisting of 5.25 mg/kg or 8.5 mg/kg ISO were administered over two consecutive days as stimuli to induce cardiac injury. To investigate the possibility of preventing damage caused by ISO-induced cardiotoxicity by taraxerol treatment, five groups were formed: a normal control group (1% Tween 80), an ISO control group, an amlodipine group administered 5 mg/kg/day, and various doses of taraxerol. The study results showed that treatment significantly reduced cardiac marker enzymes. Additionally, pretreatment with taraxerol increased myocardial activity in SOD and GPx, leading to significant reductions in serum CK-MB levels along with MDA, TNF-α, and IL-6. Further histopathological analysis supported these observations, as treated animals had less cellular infiltration compared to untreated ones. These multifaceted findings suggest that oral administration of taraxerol could potentially protect hearts from ISO-caused damage by increasing endogenous antioxidant concentrations while decreasing pro-inflammatory cytokines.

Chlorogenic Acid Restores Ovarian Functions in Mice with Letrozole-Induced Polycystic Ovarian Syndrome Via Modulation of Adiponectin Receptor.

Around the world, polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic condition that typically affects 6-20% of females. Our study's major goal was to examine how chlorogenic acid (CGA) affected mice with endocrine and metabolic problems brought on by letrozole-induced PCOS. Group I served as the control for 81 days; Group II was given Letrozole (LETZ) orally at a dose of 6 mg/kg bw for 21 days to induce PCOS; Group III was given LETZ (6 mg/kg) for 21 days, followed by treatment with CGA (50 mg/kg bw daily) for 60 days. The study indicated that LETZ-treated mice displayed symptoms of PCOS, such as dyslipidemia, hyperinsulinemia, elevated testosterone, increases in inflammatory markers and malonaldehyde, and a decline in antioxidants (Ar, lhr, fshr, and esr2) in the ovaries. These alterations were affected when the mice were given CGA and were associated with reduced levels of adiponectin. Adiponectin showed interactions with hub genes, namely MLX interacting protein like (MLXIPL), peroxisome proliferator-activated receptor gamma Coactivator 1- alpha (PPARGC1), peroxisome proliferator-activated receptor gamma (Pparg), and adiponectin receptor 1 (Adipor1). Lastly, the gene ontology of adiponectin revealed that adiponectin was highly involved in biological processes. The findings from our research suggest that adiponectin has direct impacts on metabolic and endocrine facets of PCOS.

Phospholipid-Based Topical Nano-Hydrogel of Mangiferin: Enhanced Topical Delivery and Improved Dermatokinetics.

Mangiferin is a herbal drug that has proven anticancer potential. Owing to its lower aqueous solubility and poor oral bioavailability, the full pharmacological potential of this bioactive drug has not fully been explored. In the present study, phospholipid-based microemulsion systems were developed to bypass oral delivery. The globule size of the developed nanocarriers was less than 150 nm and the drug entrapment was >75% with a drug loading ~25%. The developed system offered a controlled release pattern following the Fickian drug release. This enhanced mangiferin's in vitro anticancer activity by four-fold, the cellular uptake was observed to be improved by three-fold on the MCF-7 cells. Ex vivo dermatokinetic studies showed substantial topical bioavailability with a prolonged residence time. The findings provide a simple technique to administer mangiferin via a topical route promising a safer, topically bioavailable and effective treatment option for breast cancer. Such scalable carriers with immense topical delivery potential may provide a better option for present-day topical products of a conventional nature.

Caraway Nanoemulsion Gel: A Potential Antibacterial Treatment against Escherichia coli and Staphylococcus aureus.

Novel antibiotics are needed due to the rise of antibiotic-resistant pathogens. Traditional antibiotics are ineffective due to antibiotic-resistant microorganisms, and finding alternative therapies is expensive. Hence, plant-derived caraway (Carum carvi) essential oils and antibacterial compounds have been selected as alternatives. In this, caraway essential oil as an antibacterial treatment was investigated using a nanoemulsion gel. Using the emulsification technique, a nanoemulsion gel was developed and characterized in terms of particle size, polydispersity index, pH, and viscosity. The results showed that the nanoemulsion had a mean particle size of 137 nm and an encapsulation efficiency of 92%. Afterward, the nanoemulsion gel was incorporated into the carbopol gel and was found to be transparent and uniform. The gel had in vitro cell viability and antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The gel safely delivered a transdermal drug with a cell survival rate of over 90%. With a minimal inhibitor concentration (MIC) of 0.78 mg/mL and 0.78 mg/mL, respectively, the gel demonstrated substantial inhibition for E. coli and S. aureus. Lastly, the study demonstrated that caraway essential oil nanoemulsion gels can be efficient in treating E. coli and S. aureus, laying the groundwork for the use of caraway essential oil as an alternative to synthetic antibiotics in the treatment of bacterial infections.

The Cardioprotective Effect of Corosolic Acid in the Diabetic Rats: A Possible Mechanism of the PPAR-γ Pathway.

The study was conducted to determine whether corosolic acid could protect the myocardium of diabetic rats from damage caused by isoproterenol (ISO) and, if so, how peroxisome proliferator-activated receptor gamma (PPAR-γ) activation might contribute into this protection. Diabetes in the rats was induced by streptozotocin (STZ), and it was divided into four groups: the diabetic control group, diabetic rats treated with corosolic acid, diabetic rats treated with GW9662, and diabetic rats treated with corosolic acid plus GW9662. The study was carried out for 28 days. The diabetic control and ISO control groups showed a decrease in mean arterial pressure (MAP) and diastolic arterial pressure (DAP) and an increase in systolic arterial pressure (SAP). The rat myocardium was activated by corosolic acid treatment, which elevated PPAR-γ expression. A histopathological analysis showed a significant reduction in myocardial damage by reducing myonecrosis and edema. It was found that myocardial levels of CK-MB and LDH levels were significantly increased after treatment with corosolic acid. By decreasing lipid peroxidation and increasing endogenous antioxidant levels, corosolic acid therapy showed a significant improvement over the ISO diabetic group. In conclusion, our results prove that corosolic acid can ameliorate ISO-induced acute myocardial injury in rats. Based on these results, corosolic acid seems to be a viable new target for the treatment of cardiovascular diseases and other diseases of a similar nature.

Zerumbone Protects Rats from Collagen-Induced Arthritis by Inhibiting Oxidative Outbursts and Inflammatory Cytokine Levels.

Rheumatoid arthritis (RA) is an immunocompromised disorder characterized by a marked increase in the synthesis of inflammatory molecules that stimulates the destruction of bones and cartilage. The conventional treatment modalities for RA are associated with adverse side effects and lack sensitivity, suggesting an immediate demand for alternate beneficial therapeutic remedies. The current study sought to understand more about zerumbone's anti-inflammatory properties in diagnosing collagen-induced arthritis (CIA) in experimental animals. The current study observed that zerumbone reduced clinical severity in CIA-induced animals compared to healthy animals. Zerumbone administration significantly decreased (p < 0.001) the concentration of SOD, CAT, GR, and GSH in treatment groups. Zerumbone administration drove down significantly (p < 0.001) the concentration of inflammatory cytokine molecules. Zerumbone was effective in bringing significant changes in levels of MPO, NO, LDH, MMP-8, and ELA. The therapeutic potential of zerumbone was found to be associated with reduced joint destruction and restored normal histology in the cartilage and tissue. Adsorption, distribution, metabolism, excretion, and toxicity studies were used to determine the druglike properties of zerumbone. ProTox-II studies revealed that zerumbone did not possess toxic properties like hepatotoxicity, immunotoxicity, carcinogenicity, mutagenicity, and cytotoxicity. Therefore, the present study evaluated the therapeutic properties of zerumbone in CIA animal models.

Protective Effect of Beta-Carotene against Myeloperoxidase- Mediated Oxidative Stress and Inflammation in Rat Ischemic Brain Injury.

Oxidative stress and inflammatory reaction play critical roles in ischemia/reperfusion (I/R) injury in the brain. ß-carotene (ßCAR) is a naturally occurring pigment present in fruits and vegetables that expresses antioxidant and anti-inflammatory activities. This study was conducted to investigate the involvement of Bcl2/Bax and NF-κB signaling pathways in the potential protective role of ßCAR against brain injury in a middle cerebral artery occlusion (MCAO) rat model. A focal brain ischemia model was created for 2 h, followed by reperfusion. Rats were given 10 and 20 mg/kg of ßCAR for 7 days orally before induction of ischemia, at the start of reperfusion, and 3 days after ischemia. Scores of neurological deficit were rated 24 h after induction of ischemia. Motor coordination and spontaneous coordinate activities were assessed using rotarod and activity cage, respectively. After 2 h of the last dose, the animals were killed and their brains were extracted for further examinations. The results of the study show that ßCAR diminished the score of neurological deficits and ameliorated motor coordination, balance, and locomotor activity in the I/R control group. Further, ßCAR resulted in diminution of malondialdehyde (MDA) and augmentation of reduced glutathione (GSH) contents, as well as the elevation of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) enzyme activities in the brain homogenates of I/R rats. ßCAR treatment significantly reduced nuclear factor kappa B (NF-κB) brain content and myeloperoxidase (MPO) activity and ameliorated the histological alterations in the brain tissues. ßCAR significantly suppressed Bcl-2-associated X protein (Bax) and caspase-3 expression, as well as upregulated B-cell lymphoma-2 (Bcl-2) expression, suggesting a neuroprotective potential via downregulating NF-kB and protecting the rat brain against the I/R-associated apoptotic injury.

Global Prevalence and Associated Clinical Markers of Thrombocytopenia in People Living with HIV: Evidence from Meta-Analysis.

Thrombocytopenia is one of the complications in human immunodeficiency virus (HIV) patients. To improve the health outcomes of patients living with HIV, it is important to understand the prevalence and pattern of associated key clinical markers globally. This meta-analysis, therefore, aimed to estimate the pooled prevalence of and associated clinical marker of thrombocytopenia globally. Methodology: The meta-analysis was conducted as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All statistical analyses were conducted using Stata. Twelve full-text papers out of 454 were eligible for meta-analysis. Results: Among 6686 participants, overall pooled prevalence of thrombocytopenia was 10.90% (95% CI: 7.91, 13.88) I2 = 93.62%. In addition, thrombocytopenia was more prevalent by 25.11% (95% CI: 13.33, 36.88) in patients with CD + T < 200 cells/µL, and less prevalent in patients with CD + T < 200 cells/µL 10.10% (95% CI: 7.37, 12.83), respectively. Conclusions and recommendations: This meta-analysis established the prevalence of thrombocytopenia among patients living with HIV, and that it may be more prevalent in patients with CD + T < 200 cells/µL indicating the necessity of routine screening for various haematological markers and a careful treatment plan for HIV patients.

Dostarlimab an Inhibitor of PD-1/PD-L1: A New Paradigm for the Treatment of Cancer.

Immunomodulation checkpoints usually adopted by healthy cells by tumors might cause an imbalance between host surveillance and tumor progression. Several tumors are incredibly resistant to standard treatment. The dynamic and long-lasting tumor regressions caused by antibodies targeting the PD-1/PD-L1 checkpoint have suggested a rebalancing of the host-tumor relationship. Checkpoint antibody inhibitors, like anti-PD-1/PD-L1, are unique inhibitors that reduce tumor growth by modulating the interaction between immune cells and tumor cells. These checkpoint inhibitors are swiftly emerging as a highly promising strategy for treating cancer because they produce impressive antitumor responses while having a limited number of adverse effects. Over the past several years, numerous checkpoint antibody inhibitors pointing to PD-1, PDL-1, and CTLA-4 have been available on the market. Despite its enormous success and usefulness, the anti-PD treatment response is restricted to certain kinds of cancer. This restriction can be attributed to the inadequate and diverse PD-1 expression in the tumor (MET) micro-environment. Dostarlimab (TSR-042), a drug that interferes with the PD-1/PD-L1 pathway, eliminates a crucial inhibitory response of an immune system and, as a result, has the potential to cause severe or deadly immune-mediated adverse effects. As cancer immunotherapy, dostarlimab enhances the antitumor immune response of the body.

Exploring the efficacy and contribution of Dupilumab in asthma management.

IgG4 monoclonal antibody Dupilumab binds to the alpha chain (IL4R) of both types of the ligand-binding domains (IL4R/ IL13R1; equally IL4 and IL13 specific) of the IL-4 receptor. The current focus on precision medicine techniques to blocking pathways implicated in allergy disorders is crucial to the development of Dupilumab and broadening its therapeutic uses. Our review describes how the IL-4R complexes signaling pathway works, explores the probable mechanisms of Dupilumab activity and addresses its clinical usefulness and safety in asthma. The FDA (Food and Drug Administration) already licences it to treat Alzheimer's disease and moderate-to-severe asthma, and it has shown highly significant results in the management of chronic rhinosinusitis and Eosinophilic esophagitis (EoE). Previous investigations and clinical trials undertaken by various pharmaceutical firms are examined in this review article to assess the existing literature fully. The discovery of Dupilumab and the expanding range of therapeutic uses are pertinent to the current focus on precision medicine methods to blocking asthma-related pathways.

Simultaneous Determination of Caffeine and Paracetamol in Commercial Formulations Using Greener Normal-Phase and Reversed-Phase HPTLC Methods: A Contrast of Validation Parameters.

There has been no assessment of the greenness of the described analytical techniques for the simultaneous determination (SMD) of caffeine and paracetamol. As a result, in comparison to the greener normal-phase high-performance thin-layer chromatography (HPTLC) technique, this research was conducted to develop a rapid, sensitive, and greener reversed-phase HPTLC approach for the SMD of caffeine and paracetamol in commercial formulations. The greenness of both techniques was calculated using the AGREE method. For the SMD of caffeine and paracetamol, the greener normal-phase and reversed-phase HPTLC methods were linear in the 50-500 ng/band and 25-800 ng/band ranges, respectively. For the SMD of caffeine and paracetamol, the greener reversed-phase HPTLC approach was more sensitive, accurate, precise, and robust than the greener normal-phase HPTLC technique. For the SMD of caffeine paracetamol in commercial PANEXT and SAFEXT tablets, the greener reversed-phase HPTLC technique was superior to the greener normal-phase HPTLC approach. The AGREE scores for the greener normal-phase and reversed-phase HPTLC approaches were estimated as 0.81 and 0.83, respectively, indicated excellent greenness profiles for both analytical approaches. The greener reversed-phase HPTLC approach is judged superior to the greener normal-phase HPTLC approach based on numerous validation parameters and pharmaceutical assays.

Determination of Chemical Composition, In Vitro and In Silico Evaluation of Essential Oil from Leaves of Apium graveolens Grown in Saudi Arabia.

The aim of this study was to explore the composition and evaluate the in silico and in vitro antioxidants and antimicrobial and anti-inflammatory effects of Apium graveolens var. dulce leaves essential oil (AGO) collected from Al-Kharj (Saudi Arabia). AGO was isolated using the hydro-distillation method, and its composition was studied using gas-chromatography-mass Spectrometry (GC-MS), antimicrobial activities using well diffusion assay, and antioxidant and anti-inflammatory activities using spectrophotometric methods. The pharmacological activities of their major compounds were predicted using PASS (prediction of activity spectra for substances) and drug-likening properties by ADME (absorption, distribution, metabolism, and excretion) through web-based online tools. Isocnidilide (40.1%) was identified as the major constituent of AGO along with ß-Selinene, Senkyunolide A, Phytyl acetate, and 3-Butylphthalide. AGO exhibited a superior antibacterial activity, and the strongest activity was detected against Gram-positive bacteria and Candida albicans. Additionally, it exhibited a weaker antioxidant potential and stronger anti-inflammatory effects. PASS prediction supported the pharmacological finding, whereas ADMET revealed the safety of AGO. The molecular docking of isocnidilide was carried out for antibacterial (DNA gyrase), antioxidant (tyrosinase), and anti-inflammatory (cyclooxygenase-2) activities. The docking simulation results were involved hydrophilic interactions and demonstrated high binding affinity of isocnidilide for anti-inflammatory protein (cycloxygenase-2). The presence of isocnidilide makes AGO a potential anti-inflammatory and antimicrobial agent. AGO, and its major metabolite isocnidilide, may be a suitable candidate for the future drug development.

Formulation of Genistein-HP ß Cyclodextrin-Poloxamer 188 Ternary Inclusion Complex: Solubility to Cytotoxicity Assessment.

The current study was designed to prepare the inclusion complex Genistein (GS) using Hydroxypropyl ß cyclodextrin (HP ß CD) and poloxamer 188 (PL 188). The binary inclusion complex (GS BC) and ternary inclusion complex (GS TC) were developed by microwave irradiation technique and evaluated for a comparative dissolution study. Further, the samples were assessed for FTIR, DSC, XRD, and NMR for the confirmation of complex formation. Finally, antioxidant and antimicrobial studies and cytotoxicity studies on a breast cancer (MCF-7) cell line were conducted. The dissolution study result showed a marked increment in GS dissolution/release after incorporation in binary (GS: HP ß CD, 1:1) and ternary (GS: HP ß CD: PL 188; 1:1:0.5) inclusion complexes. Moreover, the ternary complex exhibited a significant enhancement (p < 0.05) in dissolution than did the binary complexes. This might be due to the presence of PL 188, which helps in solubility enhancement of GS. DSC, XRD and SEM evaluation confirmed the modification in the structure of GS. FTIR and NMR results indicated the formation of an inclusion complex. The antioxidant and antimicrobial activity results revealed that GS TC has shown significant (p < 0.05) higher activity than pure GS. The cytotoxicity study results also depicted concentration-dependent cytotoxicity. GS TC exhibited significantly (p < 0.05) high cytotoxicity to cancer cells (IC50 = 225 µg/mL) than pure GS (IC50 = 480 µg/mL). Finally, it was concluded that a remarkable enhancement in the dissolution was observed after the inclusion of GS in the ternary complex and it therefore has significant potential for the treatment of breast cancer.

Attenuation of rotenone toxicity in SY5Y cells by taurine and N-acetyl cysteine alone or in combination.

There is accumulating evidence that supports the involvement of reactive oxygen species (ROS), mitochondrial dysfunction and inflammation in the pathogenesis of neurodegenerative diseases. Thus, it is plausible that a multi-targeted therapeutic approach may be a more effective strategy to retard or even potentially halt the progression of the disease. Taurine is an organic acid that has a role in the regulation of oxidative stress and promoting mitochondrial normal functions, and N-Acetyl cysteine (NAC) is a well-known anti-oxidant and glutathione precursor. The main purpose of this study was to examine the cytoprotective effects of taurine alone or in combination with NAC against rotenone-induced toxicity in the SH-SY5Y neuroblastoma cell line. Taurine treatment produced a concentration-dependent reduction in rotenone-induced cell death. From this, we tested sub-effective concentrations of taurine in combination with low, sub-effective concentrations of NAC against rotenone toxicity, and found the combined treatment afforded greater cytoprotection than either treatment alone. The combined taurine/NAC treatment also attenuated rotenone-induced reductions in aconitase activity suggesting the cytoprotection afforded by the combined treatment may be associated with anti-oxidative mechanisms. Together, our data suggest that a multi-targeted approach may yield new avenues of research exploring the utility of combining therapeutic agents with different mechanisms of actions at concentrations lower than previously tested and shown to be cytoprotective.