Cardioprotective effect of 2-methoxy phenol derivatives against oxidative stress-induced vascular complications: An integrated in vitro, in silico, and in vivo investigation.

BACKGROUND: Oxidative stress and inflammation play crucial roles in macro/microvascular complications. Phenolic compounds and their derivatives show promise as therapeutic agents for diseases like cancer, metabolic disorders, and cardiovascular diseases. With their antioxidant and anti-inflammatory properties, these compounds hold potential for mitigating vascular complications and improving overall health. METHODOLOGY: This study aimed to assess the therapeutic potential of five 2-methoxy phenol derivatives (T2, T5, T6, T7, and T8) as antioxidants, anti-inflammatory agents, and vasorelaxants using in vitro, in silico, and in vivo approaches. RESULTS: Among all, T2 exhibited substantial antioxidant potential against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radicals with IC50 (27.97 µg/mL), nitric oxide (NO) radicals (IC50 = 34.36 µg/mL), hydroxyl (OH) radicals (IC50 = 34.83 µg/mL) and Iron chelation (IC50 = 24.32 µg/mL). Molecular docking analysis confirms that all derivatives, particularly T2, exhibit favorable binding energies with the target proteins, ACE (-7.7 Kcal/mol), ECE-1 (-7.9 Kcal/mol), and COX-1 (-7.8 Kcal/mol). All of the compounds demonstrated satisfactory physicochemical and pharmacokinetic characteristics, and showed minimal to no toxicity during in silico, in vitro, and in vivo assessments. In isolated aortic rings from Sprague Dawley rats, pre-contracted with high K+ (80 mM), T2 induced vasorelaxation in dose dependent manner and shifted calcium response curves to the right as compared to verapamil. T2 also showed substantial platelet aggregation inhibition in a dose dependent manner with IC50 21.29 µM. All derivatives except T7 exhibited significant conservation of endogenous antioxidants i.e. catalase (CAT), peroxidase (POD), superoxide dismutase (SOD) and reduced glutathione (GSH) and significantly suppressed serum levels of inflammatory markers i.e. nitric oxide (NO), peroxides (TBARS), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2). CONCLUSION: The study concludes that T2 has significant antioxidant potential and vasorelaxant effects with adequate pharmacokinetics, making it a promising lead compound for further molecular investigation in cardiovascular disorders.

Effects of Drying Temperature and Solvents on In Vitro Diabetic Wound Healing Potential of Moringa oleifera Leaf Extracts.

The delayed healing of wounds among people with diabetes is a severe problem worldwide. Hyperglycemia and increased levels of free radicals are the major inhibiting factors of wound healing in diabetic patients. Plant extracts are a rich source of polyphenols, allowing them to be an effective agent for wound healing. Drying temperature and extraction solvent highly affect the stability of polyphenols in plant materials. However, there is a need to optimize the extraction protocol to ensure the efficacy of the final product. For this purpose, the effects of drying temperature and solvents on the polyphenolic composition and diabetic wound healing activity of Moringa oleifera leaves were examined in the present research. Fresh leaves were oven dried at different temperatures (10 °C, 30 °C, 50 °C, and 100 °C) and extracted in three solvents (acetone, ethanol, and methanol) to obtain twelve extracts in total. The extracts were assessed for free radical scavenging and antihyperglycemic effects using DPPH (2,2-diphenylpicrylhydrazyl) and α- glucosidase inhibition assays. Alongside this, a scratch assay was performed to evaluate the cell migration activity of M. oleifera on the human retinal pigment epithelial cell line. The cytotoxicity of the plant extracts was assessed on human retinal pigment epithelial (RPE) and hepatocellular carcinoma (Huh-7) cell lines. Using high-performance liquid chromatography, phenolic compounds in extracts of M. oleifera were identified. We found that an ethanol-based extract prepared by drying the leaves at 10 °C contained the highest amounts of identified polyphenols. Moringa oleifera extracts showed remarkable antioxidant, antidiabetic, and cell migration properties. The best results were obtained with leaves dried at 10 °C and 30 °C. Decreased activities were observed with drying temperatures of 50 °C and above. Moreover, M. oleifera extracts exhibited no toxicity on RPE cells, and the same extracts were cytotoxic for Huh-7 cells. This study revealed that M. oleifera leaves extracts can enhance wound healing in diabetic conditions due to their antihyperglycemic, antioxidant, and cell migration effects. The leaves of this plant can be an excellent therapeutic option when extracted at optimum conditions.

Anti-diabetic Activity of Brucine in Streptozotocin-Induced Rats: In Silico, In Vitro, and In Vivo Studies.

Diabetes mellitus (DM) is a complex and multiple group of disorders, and understanding the molecular mechanisms is a key role in identifying various markers involved in the diagnosis of the disease. Brucine is derived from the seeds of Strychnos nux-vomica L. (Loganiaceae), which has been used in traditional medicine to cure a variety of ailments, such as chronic rheumatism, nervous system diseases, dyspepsia, gonorrhea, anemia, and bronchitis, and has analgesic, anti-inflammatory, anti-oxidant, anti-snake venom, and anti-diabetic properties. The anti-diabetic potential of brucine was studied utilizing in vitro, in silico, in vivo, and molecular methods, including streptozotocin-induced diabetic rat models, α-glucosidase and α-amylase inhibitory assays, and via Auto-DocVina software. Brucine exhibits binding affinities of -5.0 to -10.1 Kcal/mol against chosen protein targets, according to an in silico investigation. In vitro studies revealed that brucine inhibited the enzymes α-amylase and α-glucosidase, and brucine (20 mg/kg) reduced blood glucose levels, oral glucose tolerance overload, body weight, glycosylated hemoglobin levels, total cholesterol, triglycerides, low-density lipoprotein, alanine transaminase, aspartate aminotransferase, total bilirubin, and alkaline phosphatase and elevated high-density lipoprotein levels in in vivo studies. The brucine binding energy against certain protein targets ranges from -5.0 to -10.1 Kcal/mol. It has anti-diabetic, anti-hyperlipidemic, hepatoprotective, anti-oxidant, and anti-inflammatory properties, which are mediated via inhibition of α-glucosidase and α-amylase.

Complete chloroplast genome sequencing and comparative analysis of threatened dragon trees Dracaena serrulata and Dracaena cinnabari.

Dracaena (Asparagaceae family) tree is famous for producing "dragon blood"-a bioactive red-colored resin. Despite its long history of use in traditional medicine, little knowledge exists on the genomic architecture, phylogenetic position, or evolution. Hence, in this study, we sequenced the whole chloroplast (cp) genomes of D. serrulata and D. cinnabari and performed comparative genomics of nine genomes of the genus Dracaena. The results showed that the genome sizes range from 155,055 (D. elliptica) to 155,449 (D. cochinchinensis). The cp genomes of D. serrulata and D. cinnabari encode 131 genes, each including 85 and 84 protein-coding genes, respectively. However, the D. hokouensis had the highest number of genes (133), with 85 protein coding genes. Similarly, about 80 and 82 repeats were identified in the cp genomes of D. serrulata and D. cinnabari, respectively, while the highest repeats (103) were detected in the cp genome of D. terniflora. The number of simple sequence repeats (SSRs) was 176 and 159 in D. serrulata and D. cinnabari cp genomes, respectively. Furthermore, the comparative analysis of complete cp genomes revealed high sequence similarity. However, some sequence divergences were observed in accD, matK, rpl16, rpoC2, and ycf1 genes and some intergenic spacers. The phylogenomic analysis revealed that D. serrulata and D. cinnabari form a monophyletic clade, sister to the remaining Dracaena species sampled in this study, with high bootstrap values. In conclusion, this study provides valuable genetic information for studying the evolutionary relationships and population genetics of Dracaena, which is threatened in its conservation status.

Pharmacological Basis of Rumex hastatus D. Don in Gastrointestinal Diseases with Focusing Effects on H+/K+-ATPase, Calcium Channels Inhibition and PDE Mediated Signaling: Toxicological Evaluation on Vital Organs.

This present study aimed to delineate Rumex hastatus D. Don crude extract (Rh.Cr), n-Hexane, ethyl acetate, aqueous fractions (Rh.n-Hex, Rh.ETAC, Rh.Aq) and rutin for antidiarrheal, antisecretory effects, anti-spasmodic, gastrointestinal transient time, anti H. pylori, antiulcer effects, and toxicology. The preliminary phytochemical analysis of Rumex hastatus showed different phytoconstituents and shows different peaks in GC-MC chromatogram. Rumex hastatus crude extract (Rh.Cr), fractions, and rutin attributed dose-dependent (50-300 mg/kg) protection (0-100%) against castor oil-induced diarrhea and dose-dependently inhibited intestinal fluid secretions in mice. They decreased the distance traversed by charcoal in the gastrointestinal transit model in rats. In rabbit jejunum preparations, Rh.Cr and Rh.ETAC caused a concentration-dependent relaxation of both spontaneous and K+ (80 mM)-induced contractions at a similar concentration range, whereas Rh.n-Hex, rutin, and verapamil were relatively potent against K+-induced contractions and shifted the Ca2+ concentration-response curves (CRCs) to the right, Rh.Cr (0.3-1 mg/mL) and Rh.ETAC (0.1-0.3 mg/mL) shifted the isoprenaline-induced inhibitory CRCs to the left. Rh.n-Hex, Rh.ETAC and rutin showed anti-H. pylori effect, also shows an inhibitory effect against H+/K+-ATPase. Rumex hastatus showed gastroprotective and antioxidant effects. Histopathological evaluation showed improvement in cellular architecture and a decrease in the expression of inflammatory markers such as, cyclooxygenase (COX-2), tumor necrosis factor (TN,F-α) and phosphorylated nuclear factor kappa B (p-NFƙB), validated through immunohistochemistry and ELISA techniques. In RT-PCR it decreases H+/K+-ATPase mRNA levels. Rumex hastatus was found to be safe to consume up to a dose of 2000 mg/kg in a comprehensive toxicity profile. Docking studies revealed that rutin against H+/K+-ATPase pump and voltage-gated L-type calcium channel showed E-values of -8.7 and -9.4 Kcal/mol, respectively. MD simulations Molecular Mechanics Poisson Boltzmann surface area and molecular mechanics Generalized Born surface area (MMPBSA/GBSA) findings are consistent with the in-vitro, in-vivo and docking results.

Effect of Rumex dentatus on Gastrointestinal Protection and Toxicology in Rodents via Investigating H+/K+-ATPase, Calcium Channels, and PDE Mediated Signaling.

This present study aims to delineate Rumex dentatus crude extract (Rd.Cr), n-Hexane, ethyl acetate, aqueous fractions (Rd.n-Hex, Rd.ETAC, and Rd.Aq), and emodin for antidiarrheal, antisecretory effects, anti-spasmodic, gastrointestinal transient time, anti-H. pylori, antiulcer effects, and toxicology. Plant extracts attributed dose-dependent protection against castor oil-induced diarrhea and dose-dependently inhibited intestinal fluid secretions in mice. They decreased the distance transverse by charcoal in the gastrointestinal transit model in rats. In rabbit jejunum preparations, it causes a concentration-dependent relaxation of both spontaneous and K+ (80 mM)-induced contraction, Rd.n-Hex and verapamil were relatively potent against K+-induced contractions and shifted the Ca2+ concentration-response curves (CRCs) to the right, Rd.Cr and Rd.ETAC shifted the isoprenaline-induced inhibitory CRCs to the left, showing potentiating effect similar to papaverine. Rd.n-Hex showed anti-H. pylori effect. Extracts and emodin also show an inhibitory effect against H+/K+-ATPase. Rumex dentatus showed a gastroprotective and antioxidant effect. Histopathological evaluation showed improvement in cellular architecture and decrease in the expression of inflammatory markers such as cyclooxygenase (COX2), tumor necrosis factor (TNF-α), and phosphorylated nuclear factor kappa B (p-NFƙB), validated through immunohistochemistry, ELISA, and western blot techniques. In RT-PCR, it decreases H+/K+-ATPase mRNA levels. Rumex dentatus was analyzed for certain safety aspects and exhibited a relative safety profile as no impairment was observed in kidneys, heart, liver, and brain further assisted by biochemical and hematological analysis. Docking studies revealed that emodin against H+/K+-ATPase pump and voltage gated L-type calcium channel showed E-value of -7.9 and -7.4 kcal/mol, respectively. MD simulations and molecular mechanics Poisson Boltzmann surface area and molecular mechanics Generalized Born surface area MMPBSA/GBSA findings are consistent with the in-vitro, in-vivo, and docking results. In conclusion, Rumex dentatus extracts and its phytoconstituent could be considered a potent antioxidant and anti-inflammatory drug candidates that possess anti-diarrheal, anti-secretary, antispasmodic, anti-H. pylori, and anti-ulcer potential. Toxicity studies were done according to OECD standards 425. It belongs to group 5 (LD50 > 2000 mg/kg), which suggests that it is in the lower toxicity class.

Novel Isoxazole Derivative Attenuates Ethanol-Induced Gastric Mucosal Injury through Inhibition of H+/K+-ATPase Pump, Oxidative Stress and Inflammatory Pathways.

Isoxazole derivatives are significant enough due to their wide range of pharmacological and therapeutic activities. The purpose of the current study is to use computational, in vitro, in vivo, and extensive molecular approaches to examine the possible anti-ulcer activity of 4-benzylidene-3 methyl-1,2-isoxazol-5(4H)-one (MBO). Biovia Discovery Studio visualizer (DSV) was utilized for virtual screening. A tissue antioxidant investigation, H+/K+-ATPase test, and anti-H. pylori activities were carried out. ELISA, immunohistochemistry, and PCR methods were employed for the proteome analysis. An ethanol-induced stomach ulcer model was used to examine the anti-ulcer potential in rats. The binding affinities for MBO ranged from -5.4 to -8.2 Kcal/mol. In vitro findings revealed inhibitory activity against H. pylori and the H+/K+-ATPase pump. It also enhanced levels of glutathione, catalase, and glutathione-S-transferase and reduced lipid peroxidation levels in gastric tissues of rats. In vivo results showed the gastro-protective effect of MBO (30 mg/kg) in ulcerative rat stomachs. The proteomic study revealed decreased expression of inflammatory markers (cyclooxygenase-2, p-NFkB, and TNF-α). In RT-PCR analysis, the expression levels of H+/K+-ATPase were reduced. Furthermore, ADMET (absorption, distribution, metabolism, excretion and toxicity) studies revealed that MBO has high GIT solubility and has a safer profile for cardiac toxicity. This study suggests that MBO displayed anti-ulcer potential, which may have been mediated through the inhibition of the H+/K+-ATPase pump, as well as antioxidant and anti-inflammatory pathways. It has the potential to be a lead molecule in the treatment of peptic ulcers with fewer adverse effects.

Cytoprotective Antioxidant, Anti-Inflammatory, and Antifibrotic Impact of Celery Seed Oil and Manuka Honey Against Cyclophosphamide-Induced Cystitis in Rabbits.

Patients treated with cyclophosphamide (CP) usually suffer from severe hemorrhagic cystitis (HC). Our previous study exhibited that mesna + celery cotherapy partially ameliorated HC. Therefore, there is a substantial need to seek alternative regimens to get complete protection against CP-induced HC. The current study investigated the effects of mesna + celery seed oil (MCSO) or mesna + manuka honey (MMH) cotherapy against CP-induced HC in adult male rabbits. The forty rabbits were divided into four equal groups and treated for three weeks. The control group (G1) received distilled water and the second group (G2) received CP (50 mg/kg/week). The third group (G3) received CP + MCSO (CPMCSO regimen), and the fourth group (G4) received CP + MMH (CPMMH regimen). The urinary bladder (UB) specimens were processed to evaluate UB changes through histopathological, immunohistochemical, ultrastructural, and biochemical investigations. In G2, CP provoked HC features (urothelial necrosis, ulceration, and sloughing), UB fibrosis, and TNF-α immunoexpression. Besides, CP reduced the activity of antioxidant enzymes (GPx1, SOD3, and CAT) and elevated the serum levels of NF-κB, TNF-α, IL-1B, and IL-6 cytokines in G2 rabbits. In contrast, the CPMMH regimen caused significant increments of UB protection against HC in G4 rabbits compared to the partial protection by the CPMCSO regimen in G3. Therefore, our study indicated for the first time that the novel CPMMH regimen resulted in complete UB protection against CP-induced HC via combined antioxidant, anti-inflammatory, and antifibrotic properties.

Biofabrication of ZnO nanoparticles using Acacia arabica leaf extract and their antibiofilm and antioxidant potential against foodborne pathogens.

Emergence of multidrug resistant pathogens is increasing globally at an alarming rate with a need to discover novel and effective methods to cope infections due to these pathogens. Green nanoparticles have gained attention to be used as efficient therapeutic agents because of their safety and reliability. In the present study, we prepared zinc oxide nanoparticles (ZnO NPs) from aqueous leaf extract of Acacia arabica. The nanoparticles produced were characterized through UV-Visible spectroscopy, scanning electron microscopy, and X-ray diffraction. In vitro antibacterial susceptibility testing against foodborne pathogens was done by agar well diffusion, growth kinetics and broth microdilution assays. Effect of ZnO NPs on biofilm formation (both qualitatively and quantitatively) and exopolysaccharide (EPS) production was also determined. Antioxidant potential of green synthesized nanoparticles was detected by DPPH radical scavenging assay. The cytotoxicity studies of nanoparticles were also performed against HeLa cell lines. The results revealed that diameter of zones of inhibition against foodborne pathogens was found to be 16-30 nm, whereas the values of MIC and MBC ranged between 31.25-62.5 µg/ml. Growth kinetics revealed nanoparticles bactericidal potential after 3 hours incubation at 2 × MIC for E. coli while for S. aureus and S. enterica reached after 2 hours of incubation at 2 × MIC, 4 × MIC, and 8 × MIC. 32.5-71.0% inhibition was observed for biofilm formation. Almost 50.6-65.1% (wet weight) and 44.6-57.8% (dry weight) of EPS production was decreased after treatment with sub-inhibitory concentrations of nanoparticles. Radical scavenging potential of nanoparticles increased in a dose dependent manner and value ranged from 19.25 to 73.15%. Whereas cytotoxicity studies revealed non-toxic nature of nanoparticles at the concentrations tested. The present study suggests that green synthesized ZnO NPs can substitute chemical drugs against antibiotic resistant foodborne pathogens.

Proteomic Analysis and In Vivo Studies Reveal the Potential Gastroprotective Effects of CHCl3 and Aqueous Extracts of Ficus palmata.

Ficus palmata is rich in several phytochemicals such as chromone, isoflavones, terpenes, lignans, coumarins, glycosides, and furanocoumarins and have been traditionally used for the management of different gastrointestinal disorders. This research reveals the effects of Ficus palmata fruit extracts-Ficus palmata chloroform (Fp.CHCl3) and Ficus palmata aqueous (Fp.Aq)-on gut activity through in vivo and in vitro analyses. Antidiarrheal and enteropooling assays were analyzed with castor oil-induced diarrhea and intestinal fluid accumulation. Jejunum tissues of rabbits were isolated (antispasmodic) for in vitro experiments. Antimotility was carried out by charcoal meal for determining transient time, and ethanol-induced ulcer assay was used to measure the ulceration of stomach; molecular pathways were assessed through proteomic approach. Fp.CHCl3 and Fp.Aq extracts attributed dose-dependently protection against diarrhea, and intestinal fluid secretions were inhibited dose dependently. Extracts of Fp.CHCl3 and Fp.Aq produced reduction in spontaneous and K+ (at 80 Mm)-induced contractions in isolated jejunum tissues, along with the decreased length covered by charcoal in charcoal meal transient time activity. The extract exhibited gastroprotective outcome in rats and reduced tumor necrotic factor (TNF-α) levels and IL-18, measured by proteomic approach. Morphological studies' results showed that ethanol induced significant gastritis, apoptosis, swelling of mucosa, and hydropic degeneration leading to cellular degeneration and necrosis, observed through staining techniques. Furthermore, ethanol activated the inflammation pathway in all gastric zones by elevating the levels of cyclooxygenase-2, TNF-α, and nuclear factor kappa light-chain enhancer of activated B-cells. Overall results expressed the antidiarrheal, antispasmodic, enteropooling, antimotility, and antiulcer activities of Ficus palmata fruit extract.

Thyme oil alleviates Ova-induced bronchial asthma through modulating Th2 cytokines, IgE, TSLP and ROS.

Bronchial asthma (BA) is a heterogeneous allergic respiratory disease with diverse inflammatory symptoms, pathology, and responses to treatment. Thyme is a natural product which is consisted of multiple phenolic compounds of therapeutic significance for treatment of cough and bronchitis. This study evaluated the efficacy of thyme oil against ovalbumin (OVA)-induced BA in an experimental rabbit model. Forty male rabbits were divided into four equal groups [control group (G1), OVA (G2), thyme oil (G3), and OVA plus thyme oil (G4)]. Animals were treated for 30 days, and clinical, histopathological (HP), histochemical (HC), immunohistochemical (IHC), morphometric, biochemical and flow cytometry methods were performed, followed by statistical analysis. All used methods revealed normal structure of the lung tissues in rabbits of G1 and G3. In contrast, the clinical examination of G2 rabbits revealed an obvious increase in the respiratory rate, sneezing and wheezing, whereas the HP, HC and IHC techniques exhibited substantial inflammatory changes in the peribronchio-vascular lung tissues with thinning, degeneration, apoptosis (using the TUNEL assay), necrosis, and shedding of the airway epithelium. Furthermore, the morphometric results confirmed significant increases in the numbers of inflammatory cells, goblet cells, eosinophils and apoptotic cells from (12, 0, 2, 2 cells) to (34,10, 16, 18 cells) respectively, as well as the area percentage of collagen fiber deposition and immunoexpression of eotaxin-1/10 high power fields. Additionally, the biochemical results revealed significant increases in the serum levels of TSLP, IL-4, IL-5, IL-9, IL-13, IgE and eotaxin-1 cytokines from (140, 40, 15, 38, 120, 100, 48) pg./ml to (360, 270, 130, 85, 365, 398, 110) pg./ml respectively, while analysis of ROS by flow cytometry revealed remarkable oxidative stress effects in G2 rabbits. On the other hand, treatment of rabbits with thyme oil in G4 substantially alleviated all OVA-induced alterations. Overall, our findings indicate for the first time that thyme oil can ameliorate OVA-induced BA via its immunomodulatory, anti-inflammatory, antiapoptotic, and antioxidant effects on the lung tissues of rabbits.

Juvenile progressive optic atrophy as the presenting feature of biotinidase deficiency, a treatable metabolic disorder.

A 10-year-old girl initially diagnosed with functional visual loss was later diagnosed with progressive optic atrophy. Directed questioning at 13 years of age revealed difficulty hearing that had not been noted by the parents. Whole exome sequencing and subsequent metabolic testing confirmed biotinidase deficiency. Although biotinidase deficiency classically manifests in early childhood with multiple manifestations, such as seizures and failure to thrive, a delayed-onset form can present primarily as juvenile progressive optic atrophy. Early diagnosis is critical because biotin supplementation prevents disease and deterioration.

Natural Dietary Supplement, Carvacrol, Alleviates LPS-Induced Oxidative Stress, Neurodegeneration, and Depressive-Like Behaviors via the Nrf2/HO-1 Pathway.

PURPOSE: Major depressive disorder (MDD) is a debilitating human health condition characterized by mood swings and is associated with a high probability of suicide attempts. Several studies have reported a role of neuroinflammation in MMD, yet the efficacy of natural drug substances on neuroinflammation-associated depression has not been well-investigated. The present study examined the neuroprotective effects of carvacrol on lipopolysaccharide (LPS)-induced neuroinflammation, depression, and anxiety-like behavior. METHODS: Male Sprague Dawley rats were divided into two experimental cohorts to determine the effects and the effective dose of carvacrol (whether 20 mg/kg or 50 mg/kg), and further demonstrate the mechanism of action of nuclear factor E2-related factor (Nrf2) in depression. RESULTS: We found marked neuronal alterations in the cortex and hippocampus of LPS-intoxicated animals that were associated with higher inflammatory cytokine expression such as cyclooxygenase (COX2), tumor necrosis factor-alpha (TNF-α), and c-Jun N-terminal kinase (p-JNK). These detrimental effects exacerbated oxidative stress, as documented by a compromised antioxidant system due to high lipid peroxidase (LPO). Carvacrol (20 mg/kg) significantly reverted these changes by positively modulating the antioxidant gene Nrf2, a master regulator of the downstream antioxidant pathway. To further investigate the role of Nrf2, an inhibitor of Nrf2 called all-trans retinoic acid (ATRA) was used, which further exacerbated LPS toxicity with a higher oxidative and inflammatory cytokine level. To further support our notion, we performed virtual docking of carvacrol with the Nrf2-Keap1 target and the resultant drug-protein interactions validated the in vivo findings. CONCLUSION: Collectively, our findings suggest that carvacrol (20 mg/kg) could activate the endogenous master antioxidant Nrf2, which further regulates the expression of downstream antioxidants, eventually ameliorating LPS-induced neuroinflammation and neurodegeneration.

Potential therapeutic natural products against Alzheimer's disease with Reference of Acetylcholinesterase.

Alzheimer's disease (AD), is the most common type of dementia primarily affecting the later years of life. Its prevalence is likely to increase in any aging population and will be a major burden on healthcare system by the mid of the century. Despite scientific and technological breakthroughs in the last 50 years, that have expanded our understanding of the disease on a system, cellular and molecular level, therapies that could stop or slow the progression of the disease are still unavailable. The Food and Drug Administration (FDA), has approved acetylcholinesterase (AChE) inhibitors (donepezil, galantamine, tacrine and rivastigmine) and glutamate receptor antagonist (memantine) for the treatment of AD. In this review we summarize the studies reporting phytocompounds and extracts from medicinal plants that show AChE inhibitory activities and could be of potential benefit in AD. Future research directions are suggested and recommendations made to expand the use of medicinal plants and their formulations to prevent, mitigate and treat AD.

Coadministration of Ginger Extract and Fluconazole Shows a Synergistic Effect in the Treatment of Drug-Resistant Vulvovaginal Candidiasis.

BACKGROUND: Azoles are the most common antifungal drugs used in the treatment of vulvovaginal candidiasis (VVC). The frequency of azole-resistant Candida isolates has increased dramatically in the last two decades. Here, we assessed the antifungal activity of a combination of fluconazole (FLZ) and methanolic extract of ginger (Meth-Gin) against drug-resistant vulvovaginal candidiasis (VVC) in a murine model. METHODS: The in vitro activity of FLZ or a combination of FLZ and Meth-Gin was determined against Candida albicans by the agar well diffusion, macrodilution, time-kill and the biofilm eradication methods. The therapeutic efficacy of the formulations was assessed by analyzing the fungal load, pro-inflammatory cytokines, percent apoptotic cells and the histological changes in the vaginal tissues of the mice. Moreover, the renal toxicity the drug formulation was evaluated by analyzing the levels of the blood urea nitrogen (BUN) and creatinine. RESULTS: The results of in vitro study demonstrated that FLZ did not show any activity against C. albicans, whereas a combination of FLZ and Meth-Gin demonstrated greater activity as shown by the data of the zone of growth inhibition, MIC and time-kill assay. FLZ or Meth-Gin treatment could not completely cure VVC, whereas a combination of FLZ and Meth-Gin was greatly effective in the treatment of VVC. The vaginal tissue from mice of the infected control group had the highest fungal load of 155370 ± 20617 CFUs. Treatment with FLZ at a dose of 40 mg/kg reduced the fungal load to 120863 ± 10723 CFUs. Interestingly, the mice treated with a combination of FLZ (40 mg/kg) and Meth-Gin (200 mg/kg) had a fungal load of 256 ± 152 CFUs. Besides, FLZ and Meth-Gin combination effectively reduced the pro-inflammatory cytokines (IL-1ß, TNF-α and IL-17) and the percentage of apoptotic cells in the vaginal tissues. Likewise, the histological analysis revealed the epithelial necrosis, shedding and ulceration in the vaginal tissue, whereas treatment with FLZ and Meth-Gin combination reversed the histopathological changes in the vaginal epithelium and lamina propria. CONCLUSION: The findings of the current study suggest that the co-administration of Meth-Gin and FLZ may have a potential therapeutic effect in the treatment of azole-resistant candidiasis.

Pharmacological evaluation of continentalic acid for antidiabetic potential.

BACKGROUND: Diabetes is a complex endocrine and metabolic disorder. Continentalic acid is a natural drug product found in roots of Aralia continentalis (family Araliaceae), which used in traditional medicine for treatment of rheumatic arthritis, lumbag, lameness, inflammation, gastritis, nephritis and diabetes mellitus. PURPOSE: This study is aim to investigate the continentalic acid anti-diabetic potential. METHODS: In-silico, in-vitro, in-vivo and molecular techniques were used to investigate various effects of continentalic acid by Auto Doc Vina, α-amylase and α-glucosidase inhibitory assay and alloxan-induced diabetes rats model. RESULTS: In-silico results revealed that continentalic acid exhibits binding energy values of - 5 to - 9.3Kcal/mol against selected targets. In-vitro assay showed that continentalic acid caused α-amylase and α-glucosidase enzymes inhibition. In-vivo finding exhibits that continentalic acid (50 mg/kg) decreased blood glucose level, body weight, oral glucose tolerance overload, glycosylated hemoglobin, triglycerides, total cholesterol, low density lipoprotein, aspartate transaminase, aspartate aminotransferase, alkaline phosphate, total bilirubin and increased high density lipoprotein (P < 0.05, P < 0.01, P < 0.001 vs. diabetic control group). In animals pancreas and liver tissues, continentalic acid enhanced glutathione-s-transferase, reduced glutathione, catalase and decreased lipid hydroperoxide level, improved cellular architecture in histopathological examination and decrease expression of inflammatory markers: cyclooxygenase 2, tumor necrosis factor alpha, phosphorylated-nuclear factor kappa B, prostaglandins E2, interleukin-18 and increased heme oxygenase-1, as evidenced in immunohistochemistry and enzyme-linked immunosorbent assay molecular investigations. CONCLUSIONS: This study shows that continentalic acid exhibited binding affinities against the different targets and anti-diabetic action, mediated possibly through α-amylase and α-glucosidase inhibition, anti-hyperlipidemic, hepatoprotection, antioxidant and anti-inflammatory pathways.

Biosynthesis of silver capped magnesium oxide nanocomposite using Olea cuspidata leaf extract and their photocatalytic, antioxidant and antibacterial activity.

Green chemistry is a modern area of research which covers synthesis of nanomaterials through useful, environmentally, economically friendly techniques and their use in different fields. The synthesis involves the formation of bimetallic nanomaterials to enhance their synergistic relationship and achieve special modulated properties. That's why bimetallic nanomaterials are extremely important and gaining interest among researchers in the field of medicinal chemistry for the treatment of various diseases. In this particular study, bimetallic nanoparticles synthesis was done by reduction procedure using leaf extract of Olea cuspidata. The phytochemicals in leaf extract act as stabilizing and capping agent in reduction of precursor's salts. The characterization of green synthesized Ag@MgO nanocomposite was done through several analytical techniques such as ultraviolet-visible (UV-vis) spectroscopy, X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), Scanning electron microscope (SEM), High resolution transmission electron microscope (HRTEM) and Zeta potential. To explore the biological potential of synthesized nanocomposite, antibacterial activities against gram negative (Escherichia coli) bacteria and gram positive (Staphylococcus aureus) has been evaluated. The photocatalytic activity in contrary to methylene blue (MB) decomposition was seen efficiently. Moreover, the antioxidant nature of green synthesized Ag@MgO nanocomposite was analyzed by destabilizing and scavenging maximum percentage (93 %) of dangerous and harmful 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical. The best and surprising results provided the information for the presence of essential and vital components in Olea Cuspidata in the form of organic acids (Citrus Acid) aids in stabilizing the entire structure with enhanced properties. Up to the best of our knowledge, the facts and results obtained regarding the structure of Ag@MgO nanocomposite clearly illustrates the uniqueness of green chemistry and also its role in future developing multifunctional nanoparticles in the field of nanobiotechnology.

Facile and eco-benign fabrication of Ag/Fe2O3 nanocomposite using Algaia Monozyga leaves extract and its' efficient biocidal and photocatalytic applications.

Noble metal/metal oxide nanocomposites are pet and spellbound candidates in biomedical and catalytic fields because of their awestruck properties. This report put forward the facile and environmentally friendly fabrication of Ag/Fe2O3 nanocomposite using the eqeous extract of Algaia Monozyga leaves. The Ag/ Fe2O3 bimetallic nanocomposite was prepared using AgNO3, FeCl3 (anhydrous) and plant leaves extract as a natural source for reduction and stabilization of this nanocomposite. We prepared a separate solution of Silver and Iron salts and upon addition of this solution to the plant extract, the conversion of colour to brown appears within 10 min at constant stirring at 350 rpm. To confirm the synthesis of nanocomposite, UV-vis spectroscopy, Scanning electron microscopy (SEM), EDX and X-ray diffraction spectroscopy were used. The as prepared nanocomposite was used for photocatalytic activity in degradation of Methylene Blue (MB) in the presence of light which shows effective photocatalytic activity. The antimicrobial activities were also determined for nanocomposite which were found to be efficient against human pathogenic multidrug resistant bacteria. The Ag/Fe2O3 nanocomposite significantly preventing the growth of Staphylococcus aureus, E.coli QH4 and Pseudomonas putida with zones of inhibition 23 (±0.5), 21 (±0.4) and 19 (±0.4) mm, respectively.The eco-benignly synthesized Ag/Fe2O3 nanocomposite could be a desired material for efficient remediation of toxic organic pollutants and microbes.

Therapeutic Effect of Bilsaan, Sambucus nigra Stem Exudate, on the OVA-Induced Allergic Asthma in Mice.

Asthma is characterized by the elevated level of Th2 immune responses, oxidative stress, and airway inflammation. Bilsaan, an exudate from the stem of Sambucus nigra, has been traditionally used in the treatment of various ailments in Saudi Arabia. Here, we investigated the therapeutic potential of Bilsaan against ovalbumin- (OVA-) induced allergic asthma in a mouse model. In order to induce allergic asthma, mice were intraperitoneally injected with alum-emulsified-OVA (20 µg/mouse) on days 0, 14, and 21 that is followed by an intranasal OVA exposure from days 22 to 30. During this time, mice were orally administered with Bilsaan at the doses of 5, 10, and 25 mg/kg. The numbers of total and differential inflammatory cells and the levels of Th2 cytokines (IL-4, IL-5, and IL-13) and IgE were determined in bronchoalveolar lavage fluid (BALF). Moreover, the therapeutic effect of Bilsaan was also assessed to analyze the oxidative stress and inflammatory changes in the lung tissues. The results demonstrated that Bilsaan treatment significantly reduced the total and differential inflammatory cell count in the BALF. The BALF from the mice treated with Bilsaan showed significantly lower levels of IL-4, IL-5, IL-13, and IgE. Interestingly, a similar pattern was observed in IL-4, IL-5, and IL-13 secreted by OVA-sensitized splenocytes from the mice of various groups. Bilsaan treatment alleviated the status of oxidative stress by modulating malondialdehyde (MDA), superoxide dismutase (SOD), and catalase levels in the lung. Moreover, Bilsaan treatment reduced the infiltration of inflammatory cells, thickening of alveolar wall, and congestion in the lung tissues. The findings of the present study demonstrated an antiasthmatic effect of Bilsaan through the modulation of Th2 immune responses, inflammation, and the oxidative stress.