Fragment-based drug design of novel inhibitors targeting lipoprotein (a) kringle domain KIV-10-mediated cardiovascular disease.

Cardiovascular diseases (CVDs) are the leading cause of death globally, attributed to a complex etiology involving metabolic, genetic, and protein-related factors. Lipoprotein(a) (Lp(a)), identified as a genetic risk factor, exhibits elevated levels linked to an increased risk of cardiovascular diseases. The lipoprotein(a) kringle domains have recently been identified as a potential target for the treatment of CVDs, in this study we utilized a fragment-based drug design approach to design a novel, potent, and safe inhibitor for lipoprotein(a) kringle domain. With the use of fragment library (61,600 fragments) screening, combined with analyses such as MM/GBSA, molecular dynamics simulation (MD), and principal component analysis, we successfully identified molecules effective against the kringle domains of Lipoprotein(a). The hybridization process (Breed) of the best fragments generated a novel 249 hybrid molecules, among them 77 exhibiting superior binding affinity (≤ -7 kcal/mol) compared to control AZ-02 (-6.9 kcal/mol), Importantly, the top ten molecules displayed high similarity to the control AZ-02. Among the top ten molecules, BR1 exhibited the best docking energy (-11.85 kcal/mol ), and higher stability within the protein LBS site, demonstrating the capability to counteract the pathophysiological effects of lipoprotein(a) [Lp(a)]. Additionally, principal component analysis (PCA) highlighted a similar trend of motion during the binding of BR1 and the control compound (AZ-02), limiting protein mobility and reducing conformational space. Moreover, ADMET analysis indicated favorable drug-like properties, with BR1 showing minimal violations of Lipinski's rules. Overall, the identified compounds hold promise as potential therapeutics, addressing a critical need in cardiovascular medicine. Further preclinical and clinical evaluations are needed to validate their efficacy and safety, potentially ushering in a new era of targeted therapies for CVDs.

Flaxseed oil fraction reverses cardiac remodeling at a molecular level: improves cardiac function, decreases apoptosis, and suppresses miRNA-29b and miRNA 1 gene expression.

Flaxseed is an ancient commercial oil that historically has been used as a functional food to lower cholesterol levels. However, despite its longstanding treatment, there is currently a lack of scientific evidence to support its role in the management of cardiac remodeling. This study aimed to address this gap in knowledge by examining the molecular mechanism of standardized flaxseed oil in restoring cardiac remodeling in the heart toxicity vivo model. The oil fraction was purified, and the major components were standardized by qualitative and quantitative analysis. In vivo experimental design was conducted using isoproterenol ISO (85 mg/kg) twice subcutaneously within 24 h between each dose. The rats were treated with flaxseed oil fraction (100 mg/kg orally) and the same dose was used for omega 3 supplement as a positive control group. The GC-MS analysis revealed that α-linolenic acid (24.6%), oleic acid (10.5%), glycerol oleate (9.0%) and 2,3-dihydroxypropyl elaidate (7%) are the major components of oil fraction. Physicochemical analysis indicated that the acidity percentage, saponification, peroxide, and iodine values were 0.43, 188.57, 1.22, and 122.34 respectively. As compared with healthy control, ISO group-induced changes in functional cardiac parameters. After 28-day pretreatment with flaxseed oil, the results indicated an improvement in cardiac function, a decrease in apoptosis, and simultaneous prevention of myocardial fibrosis. The plasma levels of BNP, NT-pro-BNP, endothelin-1, Lp-PLA2, and MMP2, and cTnI and cTn were significantly diminished, while a higher plasma level of Topo 2B was observed. Additionally, miRNA - 1 and 29b were significantly downregulated. These findings provide novel insight into the mechanism of flaxseed oil in restoring cardiac remodeling and support its future application as a cardioprotective against heart diseases.

LC-MS based metabolic profiling and wound healing activity of a chitosan nanoparticle-loaded formula of Teucrium polium in diabetic rats.

Healing of wounds is the most deteriorating diabetic experience. Felty germander (Teucrium polium) possesses antioxidant, anti-inflammatory and antimicrobial activities that could accelerate wound healing. Further, nanohydrogels help quicken healing and are ideal biomaterials for drug delivery. In the current study, the chemical profiling, and standardization of T. polium methanolic extract by LC-ESI/TOF/MS/MS and quantitative HPLC-DAD analyses were achieved. The wound healing enhancement in diabetic rats by T. polium nanopreparation (TP-NP) as chitosan nanogel (CS-NG) and investigating the potential mechanisms were investigated. The prepared hydrogel-based TP-NP were characterized with respect to particle size, zeta potential, pH, viscosity, and release of major components. LC-ESI/TOF/MS/MS metabolomic profiling of T. polium revealed the richness of the plant with phenolic compounds, particularly flavonoids. In addition, several terpenoids were detected. Kaempferol content of T. polium was estimated to be 7.85 ± 0.022 mg/ g of dry extract. The wound healing activity of TP-NP was explored in streptozotocin-induced diabetic rats. Diabetic animals were subjected to surgical wounding (1 cm diameter). Then they were divided in 5 groups (10 each). These included Group 1 (untreated control rats), Group 2 received the vehicle of CS-NG; Group 3 (0.5 g of TP prepared in hydrogel), Group 4 (0.5 g of TP-NP), Group 5 represented a positive control treated with 0.5 g of a commercial product. All treatments were applied topically for 21 days. Application of TP-NP on skin wounds of diabetic animals accelerated the healing process as evidenced by epithelium regeneration, formation of granulation tissue followed by epidermal proliferation, along with keratinization as verified by H&E. This was confirmed through enhanced collagen synthesis, as shown by raised hydroxyproline content and Col1A1 gene expression. Moreover, TP-NP significantly alleviated wound oxidative burst and diminished the expressions of inflammatory biomarkers. Meanwhile, TP-NP could enhance the expressions of transforming growth factor beta1 (TGF-ß1), in addition to the angiogenic markers; vascular endothelia growth factor A (VEGFA) and platelet-derived growth factor receptor alpha (PDGFRα). Collectively, chitosan nanogel of T. polium accelerates wound healing in diabetic rats, which could be explained - at least partly - through alleviating oxidative stress and inflammation coupled with pro-angiogenic capabilities.

Anti-Fibrotic Efficacy of Apigenin in a Mice Model of Carbon Tetrachloride-Induced Hepatic Fibrosis by Modulation of Oxidative Stress, Inflammation, and Fibrogenesis: A Preclinical Study.

BACKGROUND: Hepatic fibrosis is a major health problem all over the world, and there is no effective treatment to cure it. Hence, the current study sought to assess the anti-fibrotic efficacy of apigenin against CCl4-induced hepatic fibrosis in mice. METHODS: Forty-eight mice were put into six groups. G1: Normal Control, G2: CCl4 Control, G3: Silymarin (100 mg/kg), G4 and G5: Apigenin (2 &20 mg/Kg), G6: Apigenin alone (20 mg/Kg). Groups 2, 3, 4, and 5 were given CCl4 (0.5 mL/kg. i.p.) twice/week for six weeks. The level of AST, ALT, TC, TG, and TB in serum and IL-1ß, IL-6, and TNF-α in tissue homogenates were assessed. Histological studies by H&E staining and Immunostaining of liver tissues were also performed. RESULTS: The CCl4-challenged group showed increased serum AST (4-fold), ALT (6-fold), and TB (5-fold). Both silymarin and apigenin treatments significantly improved these hepatic biomarkers. The CCl4-challenged group showed reduced levels of CAT (89%), GSH (53%), and increased MDA (3-fold). Both silymarin and apigenin treatments significantly altered these oxidative markers in tissue homogenates. The CCl4-treated group showed a two-fold increase in IL-1ß, IL-6, and TNF-α levels. Silymarin and apigenin treatment considerably decreased the IL-1ß, IL-6, and TNF-α levels. Apigenin treatment inhibited angiogenic activity, as evidenced by a decrease in VEGF (vascular endothelial growth factor) expression in liver tissues, and a decline in vascular endothelial cell antigen expression (CD34). CONCLUSIONS: Finally, these data collectively imply that apigenin may have antifibrotic properties, which may be explained by its anti-inflammatory, antioxidant, and antiangiogenic activities.

The use of therapeutic drug monitoring for early identification of vedolizumab response in Saudi Arabian patients with inflammatory bowel disease.

Vedolizumab is a humanized monoclonal antibody used to treat moderate-to-severe inflammatory bowel disease (IBD). The aim of the study was to assess the effectiveness of the induction of vedolizumab trough level in predicting short-term (week 14) clinical outcomes, and covariates that affect the response in Saudi Arabian patients. This prospective, real-life study included a total of 16 patients (4 Crohn's disease (CD) and 12 ulcerative colitis (UC)) with a confirmed diagnosis of IBD and generally naïve to receiving vedolizumab therapy. Using ELISA assay, vedolizumab induction trough and peak levels were measured at weeks 0, 2, and 6. The follow-up assessment was at week 14, where clinical outcomes were measured using the partial Mayo score for UC, and the CD activity score (CDAI), and Harvey Bradshaw index (HBI) for CD. At week 14, 9 patients (52.9%) out of 16 patients demonstrated response to therapy; clinical remission was reported in 5 patients (29.4%), and in 4 cases a clinical response was noted (23.5%). Clinical remission at week 14 was linked significantly with week 6 median vedolizumab levels in responders (25.1 µg/ml 95% CI: 16.5-42.9) compared to non-responders (7.7 µg/ml, 95% CI: 4.6-10.6) (P = 0.002). Receiver operator curve analysis at week 6 identified a cut-off > 8.00 µg/mL for short-term clinical remission. Also, at week 14, BMI significantly correlated with week 6 vedolizumab trough levels (P = 0.02). No other covariates correlated with drug levels at any time point examined. Week 6 early vedolizumab trough level measurements in IBD patients predicted short-term week 14 clinical remission.

Acute Kidney Injury: Definition, Management, and Promising Therapeutic Target.

Acute kidney injury (AKI) is caused by a sudden loss of renal function, resulting in the build-up of waste products and a significant increase in mortality and morbidity. It is commonly diagnosed in critically ill patients, with its occurrence estimated at up to 50% in patients hospitalized in the intensive critical unit. Despite ongoing efforts, the death rate associated with AKI has remained high over the past half-century. Thus, it is critical to investigate novel therapy options for preventing the epidemic. Many studies have found that inflammation and Toll-like receptor-4 (TLR-4) activation have a significant role in the pathogenesis of AKI. Noteworthy, challenges in the search for efficient pharmacological therapy for AKI have arisen due to the multifaceted origin and complexity of the clinical history of people with the disease. This article focuses on kidney injury's epidemiology, risk factors, and pathophysiological processes. Specifically, it focuses on the role of TLRs especially type 4 in disease development.

Novel Nanoconjugate of Apamin and Ceftriaxone for Management of Diabetic Wounds.

Diabetic hyperglycemia delays wound healing, leading to serious consequences. Topical antibiotics can reduce the risk of a wound infection during healing; nevertheless, the microbial fight against antibiotics brings about public health challenges. Anti-microbial peptides (AMPs) belong to a novel class of drug that is used to prevent and treat systemic and topical infections. The aim of the current work was to achieve better wound healing in diabetic rats by conjugating the anti-microbial peptide "apamin" (APA) with the broad-spectrum antibiotic "ceftriaxone" (CTX) to form a nanocomplex. The CTX-APA nanoconjugate formulation was optimized using a Box-Behnken design. The optimized CTX-APA nanoconjugate formulation was evaluated for its size and zeta potential, and was then examined using transmission electron microscopy (TEM). The CTX-APA nanoconjugate was loaded onto a hydroxypropyl methylcellulose (2% w/v)-based hydrogel. It was observed that the application of the CTX-APA nanocomplex on the wounded skin of diabetic rats accelerated the regeneration of the epithelium, granulation tissue formation, epidermal proliferation, and keratinization. The nanocomplex was capable of significantly reducing the expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), while increasing the expression of transforming growth factor beta-1 (TGF-ß1) as well as the angiogenic markers: hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF). Conclusively, the application of an ion-paired CTX-APA nanocomplex enhances wound healing in diabetic rats.

Lycorine Ameliorates Thioacetamide-Induced Hepatic Fibrosis in Rats: Emphasis on Antioxidant, Anti-Inflammatory, and STAT3 Inhibition Effects.

Liver fibrosis is a foremost medical concern worldwide. In Saudi Arabia, numerous risk factors contribute to its high rates. Lycorine-a natural alkaloid-has antioxidant, anti-inflammatory, and antitumor activates. It has been reported to inhibit STAT3 in cancer. Therefore, this study aimed at investigating the possible antifibrotic effect of lycorine against thioacetamide (TAA)-induced liver fibrosis in rats and at elucidating the possible mechanisms. Liver fibrosis was induced by TAA (200 mg/kg i.p.), three per week for four weeks. Treatment with lycorine (0.5 and 1 mg/kg/d) amended TAA-induced rise of serum transaminases that was confirmed histopathologically. Moreover, it ameliorated liver fibrosis in a dose-dependent manner, as indicated by hindering the TAA-induced increase of hepatic hydroxyproline content, α-smooth muscle actin (α-SMA) and transforming growth factor (TGF-ß1) expressions. TAA-induced oxidative stress was amended by lycorine treatment via restoring reduced glutathione and diminishing lipid peroxidation. Moreover, lycorine ameliorated hepatic inflammation by preventing the rise of inflammatory cytokines. Notably, lycorine inhibited STAT3 activity, as evidenced by the decreased phospho-STAT3 expression, accompanied by the elevation of the hepatic Bax/Bcl-2 ratio. In conclusion, lycorine hinders TAA-induced liver fibrosis in rats, due to-at least partly-its antioxidative and anti-inflammatory properties, along with its ability to inhibit STAT3 signaling.

Evaluation of lyophilized royal jelly and garlic extract emulgels using a murine model infected with methicillin-resistant Staphylococcus aureus.

The limited therapeutic options associated with methicillin-resistant Staphylococcus aureus (MRSA) necessitate search for innovative strategies particularly, use of natural extracts such as lyophilized royal jelly (LRJ) and garlic extract (GE). Therefore, out study aimed to formulate emulgels containing different concentrations of both LRJ and GE and to evaluate their activities using a murine model infected with MRSA clinical isolate. Four plain emulgel formulas were prepared by mixing stearic acid/yellow soft paraffin-based O/W emulsion formulae based on Carbopol 940, Na alginate, Na carboxymethylcellulose or Hydroxypropyl methyl cellulose E4. Sodium alginate-based emulgel was selected for preparation of four medicated emulgel formulations combining LRJ and GE at four different concentrations. The selected medicated emulgels were used for the in vivo studies. The emulgel formulated with Na alginate and HPMC (MF3) exhibited optimum smooth homogeneous consistency, neutral pH, acceptable viscosity, spreadability, extrudability values and best storage stability properties. In vivo results revealed that, the wounds infected with MRSA isolate in rates were wet (oozing) and showed pus formation when compared to injured uninfected wounds. MF3 formula containing 4% LRJ and 50% GE showed the maximum wound healing properties, both in the apparent physical wound healing measurements and in the histopathological examination. In conclusion, the medicated emulgel formulation (MF3) prepared with Na alginate was found optimum for topical application. MF3 formula containing 4% LRJ and 50% GE has shown the highest in vivo wound healing capacities. Further clinical studies should be conducted to prove both its safety and efficacy and the potential use in human.

Median Nerve Affection in Hypertensive Patients with and without Diabetes High-Resolution Ultrasound Assessment.

PURPOSE: Diabetes is a documented risk factor for peripheral neuropathy. It was reported that associated hypertension could increase this risk. The present study aimed to assess the effect of hypertension and diabetes on median nerve using high-resolution ultrasound. METHODS: The study includes 50 hypertensive patients (HTN group), 50 diabetic patients (DM group), 50 patients with coexisting diabetes and hypertension (HTN + DM group) and 50 healthy controls. Median nerve affection in the studied groups was studied by vibration perception thresholds (VPT). The median nerve cross-sectional area was determined at the nerve cross-sectional area of the median nerve at the carpal tunnel by high-resolution ultrasound. Clinical symptoms were assessed using Toronto Clinical Severity Score (TCSS). RESULTS: There was significantly higher median nerve CSA in all patient groups in comparison to controls. HTN + DM group had significantly higher median nerve CSA when compared with DM group. Patients with peripheral neuropathy in HTN + DM and DM groups had significantly higher median nerve CSA than patients without. Using ROC curve analysis, it was shown that median CSA could successfully distinguish patients with peripheral neuropathy from patients without in HTN + DM group [AUC (95% CI): 0.71 (0.54-0.89)] and in DM group [AUC (95% CI): 0.86 (0.72-0.99)]. CONCLUSION: Hypertensive patients with and without diabetes have significantly higher median nerve CSA when compared with controls.

Efficacy of Ultrasound-Guided Injection of Botulinum Toxin, Ozone, and Lidocaine in Piriformis Syndrome.

Background: Piriformis syndrome (PS) is a painful musculoskeletal condition characterized by a deep gluteal pain that may radiate to the posterior thigh and leg. This study was designed to compare the effectiveness of ozone and BTX to lidocaine injection in treating piriformis syndrome that was resistant to medication and/or physical therapy. Study design: Between November 2018 and August 2019, we involved eighty-four subjects diagnosed with piriformis syndrome in a double-blinded, prospective, randomized comparative study to receive an ultrasound-guided injection of lidocaine (control group), botulinum toxin A, or local ozone (28 patients each group) in the belly of the piriformis muscle. Pain condition evaluated by the visual analog score (VAS) was used as a primary outcome, and the Oswestry Disability Index (ODI) as a secondary outcome, before, at one month, two months, three months, and six months following the injection. Results: The majority (58.3%) of patients were male, while (41.7%) were female. At one month, a highly significant decrease occurred in VAS and ODI in the lidocaine and ozone groups compared to the botulinum toxin group (p < 0.001). At six months, there was a highly significant decrease in VAS and ODI in the botulinum toxin group compared to the lidocaine and ozone groups (p < 0.001). Conclusion: Botulinum toxin may assist in the medium- and long-term management of piriformis syndrome, while lidocaine injection and ozone therapy may help short-term treatment in patients not responding to conservative treatment and physiotherapy.

Auraptene nanoparticles ameliorate testosterone-induced benign prostatic hyperplasia in rats: Emphasis on antioxidant, anti-inflammatory, proapoptotic and PPARs activation effects.

Benign prostatic hyperplasia (BPH) is a disease that commonly strikes the majority of aged men. Developing new therapies to manage BPH with improved efficacy and safety is strongly needed. In this regard, auraptene is a natural compound with multiple pharmacological effects, but with poor oral bioavailability. This investigation aimed to assess the possible protection offered by auraptene-nanostructured lipid carrier (auraptene-NLC) in a BPH model induced by testosterone in rats. Auraptene-NLC had optimum particle size and drug release profile compared to raw auraptene. At doses (5 and 10 mg/kg), it hampered the rise in prostatic weights & indices relative to rats challenged with testosterone. Moreover, auraptene-NLC alleviated histopathological abnormalities in prostate architecture and decreased the glandular epithelial height. Additionally, testosterone-induced oxidative stress was alleviated by auraptene-NLC and inhibited raised lipid peroxidation, catalase and superoxide dismutase exhaustion as well as enhanced glutathione content. Moreover, it significantly reduced the prostate content of nuclear factor κB, Interleukins1ß & 6, as well as transforming growth factor ß, compared to testosterone group. The proapoptotic activity of auraptene-NLC (10 mg/kg) was confirmed by a significant increase of prostate cleaved caspase-3, boosted Bax/Bcl2 mRNA ratio that was further confirmed by assessing their protein expressions. Furthermore, the beneficial effects of auraptene-NLC against BPH were substantiated by ameliorating testosterone-induced decline of nuclear PPARα & PPARγ and inhibiting the increased expression of cyclin D1 protein. In conclusion, auraptene-NLC offers a protective effect in rats whereby BPH was induced by testosterone, via its anti-inflammatory, antioxidant and proapoptotic activities, and PPAR family activation.

Wound Healing Activity of Opuntia ficus-indica Fixed Oil Formulated in a Self-Nanoemulsifying Formulation.

INTRODUCTION: Delayed wound healing represents a common health hazard. Traditional herbal products have been often utilized to promote wound contraction. The current study aimed at assessing the wound healing activity of Opuntia ficus-indica seed oil (OFI) and its self-nanoemulsifying drug delivery system (OFI-SNEDDS) formula in a rat model of full-thickness skin excision. METHODS: Based on droplet size, an optimized OFI-SNEDDS formula was prepared and used for subsequent evaluation. Wound healing activity of OFI and OFI-SNEDDS was studied in vivo. RESULTS: The optimized OFI-SNEDDS formula droplet size was 50.02 nm. The formula exhibited superior healing activities as compared to regular OFI seed oil-treated rats at day 14 of wounding. This effect was further confirmed by histopathological examinations of H&E and Masson's Trichrome-stained skin sections. Moreover, OFI-SNEDDS showed the highest antioxidant and anti-inflammatory activities as compared to OFI seed oil-treated animals. Both OFI and OFI-SNEDDS significantly enhanced hydroxyproline skin content and upregulated Col1A1 mRNA expression, accompanied by enhanced expression of transforming factor-beta (TGF-ß). Further, OFI-SNEDDS improved angiogenesis as evidenced by increased expression of vascular endothelial growth factor (VEGF). CONCLUSION: OFI possesses wound healing properties that are enhanced by self-emulsification of the oil into nano-droplets. The observed activity can be attributed, at least partly, to its anti-inflammatory, pro-collagen and angiogenic properties.

Carvedilol Exerts Neuroprotective Effect on Rat Model of Diabetic Neuropathy.

Diabetic neuropathy (DN) commonly occurs in diabetics, affecting approximately 50% of both type 1 and 2 diabetic patients. It is a leading cause of non-traumatic amputations. Oxidative stress could play a key role in the pathophysiology of DN. This study aimed to investigate the potential neuroprotective effect of carvedilol on STZ-induced DN in rats. Thirty male Sprague Dawley rats (weighing 200-250 g) were randomly divided into five groups (six/group), where group 1 (negative control) received only the vehicle (0.5% of carboxymethyl cellulose orally 1 ml/kg). DN was induced by a single injection of remaining rats with streptozotocin (STZ; 50 mg/kg, i.p.). After diabetes induction, group 2 served as the diabetic untreated animals; while groups 3 and 4 were treated with carvedilol (1 and 10 mg/kg/d, orally, respectively). Group 5 received a-lipoic acid as a reference neuroprotective (100 mg/kg/d, orally). All treatments were continued for 45 days after diabetes induction, followed by behavioural tests. After sacrificing the animals, dorsal root ganglia, and sciatic nerves were collected for histopathological examination and biochemical assessments. Briefly, STZ administration caused cold allodynia, induced oxidative stress, and increased nerve growth factor (NGF) concentration. Nevertheless, carvedilol improved the behavioural tests, ameliorated the oxidative imbalance as manifested by reducing malondialdehyde, restoring glutathione content, and superoxide dismutase activity. Carvedilol also decreased NGF concentration in DRG homogenate. In conclusion, this study demonstrates the neuroprotective effect of carvedilol in an experimentally induced DN rat model through-at least partly-its antioxidant effect and reduced NGF concentration in DRG.

Protective and therapeutic effects of the flavonoid "pinocembrin" in indomethacin-induced acute gastric ulcer in rats: impact of anti-oxidant, anti-inflammatory, and anti-apoptotic mechanisms.

Peptic ulcer including gastric and duodenal ulcers is a common gastro-intestinal disorder worldwide, associated with a significant mortality due to bleeding and perforation. Numerous efforts are being exerted to look for natural drugs that lack the potential side effects but still keep beneficial effects for treatment and/or prevention of gastric ulcer. Pinocembrin (PINO) is a natural flavonoid retaining anti-microbial, anti-oxidant, and anti-inflammatory activities. The present study was conducted to investigate the protective and therapeutic effects of PINO against indomethacin (INDO)-induced gastric ulcer in rats and the possible underlying mechanisms. PINO (25 and 50 mg/kg) promoted mucus secretion, decreased ulcer index, and inhibited histopathological changes induced by INDO. Further investigation of possible mechanisms showed that PINO significantly attenuated INDO-induced oxidative and inflammatory responses in both doses when administrated before or after ulcer induction. PINO downregulated mRNA expression level of p38-mitogen-activated protein kinase (p38-MAPK) which subsequently inhibited NF-κB activation and inflammatory cytokine release including tumor necrosis factor-α (TNF-α) and interleukin-1beta (IL-1ß). Additionally, PINO inhibited apoptotic activity which was confirmed by downregulation of caspase-3 transcription. The current results demonstrated the promising therapeutic activity of PINO against INDO-induced gastric ulcer due to-at least partly-its anti-oxidant, anti-inflammatory, and anti-apoptotic effects.

The Neuroprotective Effect of Carvedilol on Diabetic Neuropathy: An In Vitro Study.

Diabetic neuropathy serves as a major complication for diabetic patients across the world. The use of effective treatment is integral for reducing the health complications for diabetic patients. This study has evaluated the carvedilol potential neuroprotective effect on diabetic neuropathy. An in vitro model of diabetic neuropathy was used, including dorsal root ganglia (DRG) that were cultured from male adult mice C57BL. These were incubated for about twenty-four hours in high glucose (HG) media (45 mM). Some cells were incubated with carvedilol (10 µM). Neuronal viability, neuronal morphology, and activating transcription factor 3 (AFT3) were measured. The cell viability was decreased, along with neuronal length, soma area, and soma perimeter with HG media. Also, there was an overexpression of ATF3, which is a neuronal stress response marker. The pretreatment with carvedilol increased the viability of DRG as compared to HG-treated cells. Also, it significantly protected the DRG from HG-induced morphology changes. Though it shows a decrease in AFT3 expression, the statistical results were insignificant. The current study demonstrates the neuroprotective effect of carvedilol against HG-induced DN using an in vitro model. This could be through carvedilol antioxidant effects.

Naringin treatment improved main clozapine-induced adverse effects in rats; emphasis on weight gain, metabolic abnormalities, and agranulocytosis.

Schizophrenia is one of the major neuropsychiatric disorders affecting people worldwide. Unfortunately, currently available antipsychotic medications possess several side effects. Among them, clozapine is one of the atypical antipsychotics prescribed in schizophrenia wing to its blocking effect on dopamine (D2) and serotonin (5-HT1c ) receptors. However, it has been recently reserved for resistant schizophrenia due to its several side effects. The current research aimed at investigating potential naringin add-on benefit to cease the main side effects of clozapine in ketamine-induced psychosis in rats. In this study, schizophrenia was induced in rats via ketamine administration that could promote neuropathological patterns of schizophrenia. Afterwards, clozapine and naringin were administered to rats in order to improve such effects induced by ketamine. Clozapine administration promoted weight gain, hyperglycemia, dyslipidemia, and agranulocytosis. However, naringin was able to reduce such adverse effects when added to clozapine treatment. Naringin increased total leukocyte count preventing agranulocytosis either when administered alone or in combination with clozapine. In addition, via its metabolic activities, naringin treatment lowered serum total cholesterol and triglycerides levels. Moreover, naringin prevented weight gain when administered. Finally, naringin reduced serum glucose level preventing hyperglycemia associated with clozapine treatment. Collectively, these findings may suggest that naringin possesses a potential add-on benefit to clozapine in treatment of schizophrenia.

Bisoprolol responses (PK/PD) in hypertensive patients: A cytochrome P450 (CYP) 2D6 targeted polymorphism study.

BACKGROUND: Bisoprolol is an effective ß1-adrenergic blocker, an inter-individual genetic variability was recorded in its response. This study aimed at investigating the association of CYP2D6*2A (rs1080985) and CYP2D6*10 (rs1065852) single-nucleotide polymorphism (SNP) with Bisoprolol response in cardiac patients attending King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia. PATIENTS AND METHODS: In the study, 107 patients were enrolled. Five mL of venous blood was collected from each patient and genotyping for CYP2D6*2A and CYP2D6*10 using Vivid® CYP2D6 Green Screening Kit (Life Technologies, USA). Response to Bisoprolol was evaluated through assessment of diastolic and systolic blood pressure and by measuring Bisoprolol plasma level using triple quad mass spectrometer (TQ-MS). RESULTS: All patients were found to carry homozygous wild type CYP2D6*10 (GG) and none were carrying heterozygous (GA) or mutant homozygous (AA) genotype. CYP2D6*2A allele was detected in the homozygous wild type (GG) in 70 out of 107 patients, the heterozygous (GC) in 19 patients, and the homozygous mutant (CC) in 18 patients with minor allele frequency (MAF) of 25.7%. The plasma concentrations of Bisoprolol in CC carriers were significantly lower than those in GG & CC carriers by 25%, and 51%; respectively. Higher systolic and diastolic blood pressures were also observed in CC carriers than GG and CC carriers. CONCLUSION: There is a possible association of CYP2D6*2A genotype with plasma concentration of bisoprolol. This could provide a helpful tool to choose the optimum dose for bisoprolol, depending on the patient's genotyping, in order to increase effectiveness and ameliorate its toxicity.