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.

α-Glucosidase, butyrylcholinesterase and acetylcholinesterase inhibitory activities of phenolic compounds from Carthamus tinctorius L. flowers: In silico and in vitro studies.

Chemical investigation of Carthamus tinctorius L. flowers resulted in isolation of seven metabolites that were identified as; p-Hydroxybenzoic acid (1), trans hydroxy cinnamic acid (2), kaempferol-6-C-glucoside (3), astragalin (4), cartormin (5), kaempferol-3-O-rutinoside (6), and kaempferol-3-O-sophoroside (7). Virtual screening of the isolated compounds against human intestinal α-glucosidase, acetylcholinesterase, and butyrylcholinesterase was carried out. Additionally, the antioxidant activity of the bioactive compounds was assessed. Compounds 1 and 5 exhibited moderate binding affinities to acetylcholinesterase (binding energy -5.33 and -4.18 kcal/mol, respectively), compared to donepezil (-83.33kcal/mol). Compounds 1-7 demonstrated weak affinity to butyrylcholinesterase. Compounds 2 and 4 displayed moderate binding affinity to human intestinal α-glucosidase,compared to Acarbose (reference compound), meanwhile compound 2 exhibited lower affinity. Molecular dynamic studies revealed that compound 4 formed a stable complex with the binding site throughout a 100 ns simulation period. The in-vitro results were consistent with the virtual experimental results, as compounds 1 and 5 showed mild inhibitory effects on acetylcholinesterase (IC50s 150.6 and 168.7 µM, respectively). Compound 4 exhibited moderate α-glucosidase inhibition with an IC50 of 93.71 µM. The bioactive compounds also demonstrated notable antioxidant activity in ABTS [2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)], ORAC (oxygen radical-absorbance capacity), and metal chelation assays, suggesting their potential in improving dementia in Alzheimer's disease (AD) and mitigating hyperglycemia.

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.

Tetramethylpyrazine ameliorates indomethacin-induced gastric ulcer in rats: Impact on oxidative, inflammatory, and angiogenic machineries.

Available antiulcer medications reveal partial efficacy and numerous adverse reactions. Tetramethylpyrazine (TMP) was known for its potential antioxidant, anti-inflammatory and angiogenic properties. The aim of current study was to investigate the potential gastroprotective effect of TMP against indomethacin-induced gastric ulcer in rats with possible underlying mechanisms. TMP was tested at 3 doses (15, 30 & 60 mg/kg/d po) three days before indomethacin challenge (25 mg/kg ip). Gastric tissue was evaluated morphologically and histopathologically. Oxidative statuses were assessed via glutathione content (GSH), malondialdhyde (MDA) and catalase (CAT) activity, while TNFα and IL-6 were measured as inflammatory mediators. Gastric PGE2 was investigated in addition to vascular endothelial growth factor (VEGF). TMP was effective (at 30 and 60 mg/kg/d) in promoting mucus secretion and preventing histopathologic changes induced by indomethacin. Mechanistically, TMP significantly enhanced GSH content and CAT activity while reducing lipid peroxidation as expressed by MDA concentration. Moreover, TMP effectively reduced TNFα, IL-6 and intracellular adhesion molecule (ICAM-1) concentrations. On the other hand, TMP enhanced both COX-1 and PGE2 and encouraged angiogenesis via increasing VEGF expression. In conclusion, TMP possesses a protective effect against indomethacin-induced gastric ulcer. This could be explained - at least partly - by its antioxidant, anti-inflammatory and angiogenic effects.

Polyphenols from Tamarix nilotica: LC⁻ESI-MSn Profiling and In Vivo Antifibrotic Activity.

Tamarix nilotica (Ehrenb.) Bunge (Tamaricaceae), an indigenous plant to the Middle East region, is well-known as a medicinal plant for treating many human ailments. The current study aimed at exploring the polyphenol profile of the alcohol soluble fraction of aqueous T. nilotica extract, assessing its in vivo antifibrotic activity and the possible underlying mechanism, to unravel the impact of quantitative difference of sulphated polyphenols content on the antifibrotic activity of T. nilotca grown in two different habitats. Polyphenol profiling of T. nilotica extracts was performed using HPLC-HRESI-QTOF-MS-MS. The major polyphenol components included sulphated flavonoids, phenolic acids and free aglycones. The antifibrotic activity was evaluated through carbon tetrachloride-induced liver fibrosis in rats. Biochemical evaluations revealed that both fractions ameliorated the increased levels of hepatic aminotransferases, lipid peroxidation, hydroxyproline, α-smooth muscle actin (α-SMA), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and nuclear factor kappa B (NF-κB). Moreover, both fractions reduced catalase activity (CAT) and enhanced hepatic glutathione (GSH) content. Histopathological imaging undoubtedly confirmed such results. In conclusion, the T. nilotica polyphenol-rich fraction exhibited potential antifibrotic activity in rats. Significant alterations in GSH levels were recorded based on the sulphated polyphenol metabolite content.

Report- Role of prostaglandin H synthase in activation of acrylonitrile to cyanide.

The present study aimed at investigating the in-vitro oxidation of acrylonitrile (ACN) to cyanide (CN-) by prostaglandin H synthase (PHS). Detection of CN- is considered a marker for free radical intermediates involved in ACN-induced toxicity. First, most favorable circumstances for ACN oxidation were characterized: pH (4.5), temperature (37ºC) and time of incubation (60 min.). In addition, the concentrations of ACN, PHS and H2O2 in incubation mixtures were assessed for further reaction characterization. The reaction maximum velocity (Vmax) was calculated to be 582.75 pmol CN-/mL/min and the Michaelis-Menten constant (Km) was 149.25 µmol ACN. Adding PHS inhibitors; resveratrol, quercetin, indomethacin or troloc-C to the reaction mixtures significantly reduced the rate of ACN oxidation. In conclusion, the present study demonstrates the ability of PHS to oxidize ACN to CN- and provides a clue for the explanation of ACN target toxicity.

Novel quinoline-3-carboxamides (Part 2): Design, optimization and synthesis of quinoline based scaffold as EGFR inhibitors with potent anticancer activity.

EGFR has a key role in cell growth. Its mutation and overexpression share in epithelial malignancies and tumor growth. Quinazoline and quinoline derivatives are common anticancer intracellular inhibitors of EGFR kinase, and their optimization is an important issue for development of potent targeted anticancer agents. Based on these facts, different strategies were used for optimizing our reported quinoline-3-carboxamide compound III (EGFR IC50 = 5.283 µM and MCF-7 IC50 = 3.46 µM) through different molecular modeling techniques. The optimized compounds were synthesized and subjected to EGFR binding assay and accordingly some more potent inhibitors were obtained. The most potent quinoline-3-carboxamides were the furan derivative 5o; thiophene derivative 6b; and benzyloxy derivative 10 showing EGFR IC50 values 2.61, 0.49 and 1.73 µM, respectively. Furthermore, the anticancer activity of compounds eliciting potent EGFR inhibition (5o, 5p, 6b, 8a, 8b, and 10) was evaluated against MCF-7 cell line where they exhibited IC50 values 3.355, 3.647, 5.069, 3.617, 0.839 and 10.85 µM, respectively. Compound 6b was selected as lead structure for further optimization hoping to produce more potent EGFR inhibitors.

Telmisartan ameliorates carbon tetrachloride-induced acute hepatotoxicity in rats.

This study assessed the potential hepatoprotective effect of telmisartan (TLM), a selective angiotensin II type 1 (AT1 ) receptor blocker, on carbon tetrachloride (CCl4 )-induced acute hepatotoxity in rats. Intraperitoneal injection of male Wistar rats with CCl4 1 mL kg-1 , 1:1 mixture with corn oil for 3 days increased serum alanine transaminase, aspartate transaminase, and alkaline phosphatase activities as well as total bilirubin, triglycerides and total cholesterol levels. This is in addition to the disrupted histological architecture in the CCl4 group. Rats receiving CCl4 and co-treated with TLM (3 and 10 mg kg-1 , orally) showed ameliorated serum biochemical and histological changes almost to the control level. Nevertheless, rats treated with TLM (1 mg kg-1 ) didn't show any significant changes compared to CCl4 intoxicated group. In addition, TLM rectified oxidative status disrupted by CCl4 intoxication. Interestingly, TLM protected against CCl4 -induced expressions of nuclear factor-κB, inducible nitric oxide synthase and cyclooxygenase-II, in a dose related manner. Moreover, TLM (3 and 10 mg kg-1 ) significantly modified CCl4 -induced elevation in tumor necrosis factor-α and nitric oxide levels. Furthermore, TLM showed a marked decline in CD68+ cells stained areas and reduced activity of myeloperoxidase enzyme compared to CCl4 -intoxicated group. In conclusion, both doses of TLM (3 and 10 mg kg-1 ) showed significant hepato-protective effects. However, TLM at a dose of 10 mg kg-1 didn't show significant efficacy above 3 mg kg-1 which is nearly equivalent to the human anti-hypertensive dose of 40 mg. Thus, may be effective in guarding against several hepatic complications due to its antioxidant and anti-inflammatory activities. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 359-370, 2017.

Hepatoprotective and antioxidant effect of ellagitannins and galloyl esters isolated from Melaleuca styphelioides on carbon tetrachloride-induced hepatotoxicity in HepG2 cells.

Context In a previous study, the total extract of Melaleuca styphelioides Sm. (Myrtaceae) showed a significant hepatoprotective effect in a CCl4-induced toxicity model in mice. However, the active components responsible for the activity of the extract were not identified. Objective To determine the in vitro hepatoprotective activity of the isolated pure compounds from M. styphelioides leaves using the CCl4-challenged HepG2 cell model. Materials and methods The hepatoprotective activity of the compounds (at concentrations of 100, 50 and 25 µm), the total extract and silymarin (Sil) (100, 50 and 25 µg/ml) was determined by measuring the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) after pretreatment with the tested samples for one hour. Glutathione (GSH) and superoxide dismutase activity (SOD) were estimated to determine the mechanisms of the hepatoprotective activity. Results Some compounds showed marked hepatoprotection, including tellimagrandin I, which produced 42, 36 and 31% decrease in ALT and 47, 43 and 37% decrease in AST, at the tested concentrations, respectively, pedunculagin (32, 32 and 30% decrease for ALT and 48, 48 and 45% for AST), tellimagrandin II (38, 32 and 26% decrease for ALT and 45, 40 and 34% for AST) and pentagalloyl glucose (30, 28 and 26% decrease for ALT and 45, 38 and 36% for AST). Tellimagrandin I and II showed the highest increase in GSH (113, 105 and 81% and 110, 103 and 79%, respectively), which was comparable to Sil. Pedunculagin produced the highest increase in SOD (497, 350 and 258%). Conclusion This study highlights promising natural hepatoprotective candidates derived from M. styphelioides.

The effect of pomegranate fruit extract on testosterone-induced BPH in rats.

BACKGROUND: Benign prostatic hyperplasia (BPH) affects many men after the age of 50 years. Inflammation and oxidative stress along with apoptotic changes are thought to play an important role in the pathology of BPH. Pomegranate contains a variety of polyphenolic compounds that have been studied in a medley of diseases for their anti-oxidant, anti-inflammatory and pro-apoptotic properties. Therefore, this study examined the effect of Pomegranate Fruit Extract (PFE) on the development of BPH using a testosterone-induced BPH model in rats. METHODS: A total of 48 rats were randomly divided into six groups of eight, one group served as the control, BPH was induced by testosterone 3 mg/kg S.C. daily in four groups, three of them received PFE by oral gavage daily at doses of 25, 50, and 100 mg/kg respectively, while one group received PFE at a dose of 50 mg/kg without induction of BPH. RESULTS: PFE at a dose of 100 mg/kg was the most effective in decreasing testosterone-induced increase in prostate weight, prostate weight/body weight ratio, and PAP levels by 30.8%, 55%, and 68% respectively and in preventing the accompanying histological changes. In the BPH model, testosterone significantly decreased GSH, SOD, and CAT to 0.45, 0.64, and 0.88 of the control group values respectively, and significantly increased MDA by >6-fold. In combination with testosterone, PFE dosed at 100 mg/kg significantly increased GSH, SOD, and CAT to 0.83, 0.92, and 0.93 of the control group values respectively, whereas MDA was significantly decreased by 72% compared with the testosterone treated group. In addition to this, at the range of doses studied, PFE lowered COX-II, iNOS, Ki-67 expression, and increased apoptotic index. CONCLUSION: The current findings elucidate the effectiveness of PFE in preventing testosterone-induced BPH in rats. This could be attributed, at least partly, to its anti-oxidant, anti-inflammatory, and pro-apoptotic properties.

A Systemic Review on Aloe arborescens Pharmacological Profile: Biological Activities and Pilot Clinical Trials.

Since ancient times, plants and herbal preparations have been used as medicine. Research carried out in the last few decades has verified several such claims. Aloe arborescens Miller, belonging to the Aloe genus (Family Asphodelaceae), is one of the main varieties of Aloe used worldwide. The popularity of the plant in traditional medicine for several ailments (antitumor, immunomodulatory, antiinflammatory, antiulcer, antimicrobial and antifungal activity) focused the investigator's interest on this plant. Most importantly, the reported studies have shown the plant effectiveness on various cancer types such as liver, colon, duodenal, skin, pancreatic, intestinal, lung and kidney types. These multiple biological actions make Aloe an important resource for developing new natural therapies. However, the biological activities of isolated compounds such as glycoprotein, polysaccharides, enzyme and phenolics were insufficient. Considering all these, this contribution provides a systematic review outlining the evidence on the biological efficacy of the plant including the pharmacology and the related mechanisms of action, with specific attention to the various safety precautions, and preclinical and clinical studies, indicating the future research prospects of this plant.

Design, synthesis and biological evaluation of novel quinazoline-based anti-inflammatory agents acting as PDE4B inhibitors.

A novel series of quinzoline based compounds (IIIa-d, VIa-f, IXa-f) were designed, synthesized and screened for their inhibitory activity towards the PDE4B isoform. The in vivo anti-inflammatory effect of the titled compounds (IIIa-d, VIa-f, IXa-f) as well as their effect on the level of tumor necrosis factor (TNF-α) were evaluated. Among all of the synthesized compounds, IXb, IXd and IXf, exhibited good inhibitory activity against PDE4B enzyme with inhibition percentages of 42, 62 and 68%, respectively. Most of the tested compounds showed potent anti-inflammatory activity compared to indomethacin with a marked decrease in TNF-α level. The ulcerogenic effect of the tested compounds was also examined. The gastric mucosa of the tested animals remained intact after oral administration of the hit compounds. Additionally, docking study was used to explore the possible binding mode of the active compounds on the PDE4B enzyme as well as to illustrate the selectivity of the active hits on the PDE4B isoform.

Live/real time three-dimensional transesophageal echocardiographic assessment of the spinal cord.

We present an adult patient in whom live/real time three-dimensional transesophageal echocardiography (3DTEE) provided incremental value in the assessment of the spinal cord as compared to two-dimensional transesophageal echocardiographic (2DTEE) findings published in the literature. It improved accurate identification and assessment of the anterior radiculomedullary spinal arteries which may have an important clinical application in monitoring for spinal cord ischemia during thoracic aortic surgery. Because the spinal cord and spinal canal could be examined using not only transverse but also coronal (frontal), sagittal, and oblique planes, 3DTEE further allowed for three-dimensional measurements of the dimensions and volumetric analysis of the visualized spinal cord and spinal canal. These may have implications in the assessment of spinal cord edema due to trauma and other conditions which result in increase in the size and volume of the spinal cord.

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.

Caffeic acid phenethyl ester synergistically enhances docetaxel and paclitaxel cytotoxicity in prostate cancer cells.

Evidence is growing for the beneficial role of selective estrogen receptor modulators (SERM) in prostate diseases. Caffeic acid phenethyl ester (CAPE) is a promising component of propolis that possesses SERM activity. This study aimed at investigating the modulatory impact of CAPE on docetaxel (DOC) and paclitaxel (PTX) cytotoxicity in prostate cancer cells and exploring the possible underlying mechanisms for this chemomodulation. CAPE significantly increased DOC and PTX potency in PC-3, DU-145 and LNCaP prostate cancer cells. Combination index calculations showed synergistic interaction of CAPE/DOC and CAPE/PTX cotreatments in all the tested cell lines. Subsequent mechanistic studies in PC-3 cells indicated that cyclin D1 and c-myc were significantly reduced in the combined treatment groups with concurrent increase in p27kip. DNA-ploidy analysis indicated a significant increase in the percentage of cells in pre-G1 in CAPE/DOC and CAPE/PTX cotreatments. Decreased Bcl-2/Bax ratio together with increased caspase-3 activity and protein abundance were observed in the same groups. Estrogen receptor-ß (ER-ß) and its downstream tumor suppressor forkhead box O1 levels were significantly elevated in CAPE and combination groups compared to DOC or PTX-alone. ER-α and insulin-like growth factor-1 receptor protein abundance were reduced in the same groups. CAPE significantly reduced AKT, ERK and ER-α (Ser-167) phosphorylation in PC-3 cells. CAPE-induced inhibition of AKT phosphorylation was more prominent (1.7-folds higher) in cells expressing ER-α such as PC-3 compared to LNCaP. In conclusion, CAPE enhances the antiproliferative and cytotoxic effects of DOC and PTX in prostate cancer cells. This can be, at least partly, attributed to CAPE augmentation of DOC and PTX proapoptotic effects in addition to CAPE-induced alterations in ER-α and ER-ß abundance.

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.

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.

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.

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.