Improving plant adaptation to soil antimony contamination: the synergistic contribution of arbuscular mycorrhizal fungus and olive mill waste.

BACKGROUND: This study aimed to investigate the alterations in biochemical and physiological responses of oat plants exposed to antimony (Sb) contamination in soil. Specifically, we evaluated the effectiveness of an arbuscular mycorrhizal fungus (AMF) and olive mill waste (OMW) in mitigating the effects of Sb contamination. The soil was treated with a commercial strain of AMF (Rhizophagus irregularis) and OMW (4% w/w) under two different levels of Sb (0 and 1500 mg kg-1 soil). RESULTS: The combined treatment (OMW + AMF) enhanced the photosynthetic rate (+ 40%) and chlorophyll a (+ 91%) and chlorophyll b (+ 50%) content under Sb condition, which in turn induced more biomass production (+ 67-78%) compared to the contaminated control plants. More photosynthesis in OMW + AMF-treated plants gives a route for phenylalanine amino acid synthesis (+ 69%), which is used as a precursor for the biosynthesis of secondary metabolites, including flavonoids (+ 110%), polyphenols (+ 26%), and anthocyanins (+ 63%) compared to control plants. More activation of phenylalanine ammonia-lyase (+ 38%) and chalcone synthase (+ 26%) enzymes in OMW + AMF-treated plants under Sb stress indicated the activation of phenylpropanoid pathways in antioxidant metabolites biosynthesis. There was also improved shifting of antioxidant enzyme activities in the ASC/GSH and catalytic pathways in plants in response to OMW + AMF and Sb contamination, remarkably reducing oxidative damage markers. CONCLUSIONS: While individual applications of OMW and AMF also demonstrated some degree of plant tolerance induction, the combined presence of AMF with OMW supplementation significantly enhanced plant biomass production and adaptability to oxidative stress induced by soil Sb contamination.

Urtica pilulifera leaves extract mitigates cadmium induced hepatotoxicity via modulation of antioxidants, inflammatory markers and Nrf-2 signaling in mice.

Introduction: Cadmium (Cd) is a harmful heavy metal that results in many toxic issues. Urtica pilulifera showed potential pharmaceutical applications. This study investigated the possible ameliorative mechanism of Urtica pilulifera leaves extract (UPLE) against hepatotoxicity induced by cadmium chloride (CdCl2) in mice. Methods: In vitro phytochemical screening and the metal-chelating activity of UPLE were ascertained. Four groups of forty male mice were used (n = 10) as follows; Group 1 (G1) was a negative control. G2 was injected i.p., with UPLE (100 mg/kg b. wt) daily. G3 was injected i.p., with Cd (5 mg/kg b. wt) daily. G4 was injected with Cd as in G3 and with UPLE as in G2. On day 11, the body weight changes were evaluated, blood, and serum samples were collected for hematological and biochemical assessments. Liver tissues were used for biochemical, molecular, and histopathological investigations. Results: The results showed that UPLE contains promising secondary metabolites that considerably lessen the negative effects of Cd on liver. Furthermore, UPLE inhibited oxidative stress and inflammation; restored antioxidant molecules; and promoted nuclear-related factor-2 (Nrf-2) expression. Also, UPLE improved the histopathological alterations induced by Cd. Discussion: This study explored the beneficial role of UPLE treatment in Cd-induced liver injury through enhancing Nrf-2 signaling and antioxidant enzyme gene expression in the liver of mice. Therefore, UPLE could have valuable implications against hepatotoxicity induced by environmental cadmium exposure. Which can be used as a chelating agent against Cd.

Introducing of novel class of pyrano[2,3-c]pyrazole-5-carbonitrile analogs with potent antimicrobial activity, DNA gyrase inhibition, and prominent pharmacokinetic and CNS toxicity profiles supported by molecular dynamic simulation.

Microbiological DNA gyrase is recognized as an exceptional microbial target for the innovative development of low-resistant and more effective antimicrobial drugs. Hence, we introduced a one-pot facile synthesis of a novel pyranopyrazole scaffold bearing different functionalities; substituted aryl ring, nitrile, and hydroxyl groups. All new analogs were characterized with full spectroscopic data. The antimicrobial screening for all analogs was assessed against standard strains of Gm + ve and Gm-ve through in vitro considers. The screened compounds displayed very promising MIC/MBC values against some of the bacterial strains with broad or selective antibacterial effects. Of these, 4j biphenyl analog showed 0.5-2/2-8 µg/mL MIC/MBC for suppression and killing of Gm + ve and Gm-ve strains. Moreover, the antimicrobial screening was assessed for the most potent analogs against certain highly resistant microbial strains. Consequently, DNA gyrase supercoiling assay was done for all analogs using ciprofloxacin as reference positive control. Obviously, the results showed a different activity profile with potent analog 4j with IC50 value 6.29 µg/mL better than reference drug 10.2 µg/mL. Additionally, CNS toxicity testing was done using the HiB5 cell line for attenuation of GABA/NMDA expression to both 4j and ciprofloxacin compounds that revealed better neurotransmitter modulation by novel scaffold. Importantly, docking and dynamic simulations were performed for the most active 4j analog to investigate its interaction with DNA binding sites, which supported the in vitro observations and compound stability with binding pocket. Finally, a novel scaffold pyranopyrazole was introduced as a DNA gyrase inhibitor with prominent antibacterial efficacy and low CNS side effect toxicity better than quinolones.Communicated by Ramaswamy H. Sarma.

Chromium(VI) Toxicity and Active Tolerance Mechanisms of Wheat Plant Treated with Plant Growth-Promoting Actinobacteria and Olive Solid Waste.

The present study aimed to assess the potential of plant growth-promoting Actinobacteria and olive solid waste (OSW) in ameliorating some biochemical and molecular parameters of wheat (Triticum aestivum) plants under the toxicity of high chromium levels in the soil. With this aim, a pot experiment was conducted, where the wheat plants were treated with a consortium of four Actinobacterium sp. (Bf treatment) and/or OSW (4% w/w) under two levels of nonstress and chromium stress [400 mg Cr(VI) per kg of soil] to estimate the photosynthetic traits, antioxidant protection machine, and detoxification activity. Both Bf and OSW treatments improved the levels of chlorophyll a (+47-98%), carotenoid (+324-566%), stomatal conductance (+17-18%), chlorophyll fluorescence (+12-28%), and photorespiratory metabolism (including +44-72% in glycolate oxidase activity, +6-72% in hydroxypyruvate reductase activity, and +5-44% in a glycine to serine ratio) in leaves of stressed plants as compared to those in the stressed control, which resulted in higher photosynthesis capacity (+18-40%) in chromium-stressed plants. These results were associated with an enhancement in the content of antioxidant metabolites (+10-117%), of direct reactive oxygen species-detoxifying enzymes (+49-94%), and of enzymatic (+40-261%) and nonenzymatic (+17-175%) components of the ascorbate-glutathione cycle in Bf- and OSW-treated plants under stress. Moreover, increments in the content of phytochelatins (+38-74%) and metallothioneins (+29-41%), as markers of detoxification activity, were recorded in the plants treated with Bf and OSW under chromium toxicity. In conclusion, this study revealed that the application of beneficial Actinobacteria and OSW as biofertilization/supplementation could represent a worthwhile consequence in improving dry matter production and enhancing plant tolerance and adaptability to chromium toxicity.

Pioglitazone ameliorates cisplatin-induced testicular toxicity by attenuating oxidative stress and inflammation via TLR4/MyD88/NF-κB signaling pathway.

BACKGROUND: Cisplatin (CIS) is a chemotherapeutic agent widely used to cure several cancers. It exerts detrimental cellular effects that restrain its clinical application as an antineoplastic agent, as testicular damage. Pioglitazone (PIO), a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, is used to treat type-2 diabetes mellitus. PIO has been reported to exert anti-inflammatory and antioxidant effects in different tissues. The present study aimed to investigate the effect of PIO in a rat model of cisplatin-induced testicular toxicity and address the possible role of the Toll-like receptors (TLR4) / myeloid differentiation factor 88 (MyD88) / nuclear factor-kappa B (NF-kB) signal pathway. METHODS: Rats received a single dose of cisplatin (7 mg/kg, IP) on the first day and PIO (10 mg/kg, P.O.) for 7 days. At the end of the treatment period, rats were killed. Testicular weights, histopathological alterations, and serum testosterone levels were determined. Moreover, tissue samples were collected for the estimation of oxidative stress parameters, inflammatory markers, and the determination of TLR4 /MyD88/NF-kB signaling. RESULTS: Concurrent PIO administration with CIS markedly improved testicular weights, histopathological alteration, and serum testosterone level changes. Moreover, Concurrent PIO administration abrogated oxidative stress status and inflammatory markers caused by CIS administration. Furthermore, PIO inhibited the expression levels of TLR4, MyD88, and NF-κBp65, proteins that are activated by CIS administration. CONCLUSION: These findings suggested that PIO can protect against cisplatin-induced testicular toxicity in rats through inhibition of the TLR4 /MyD88/NF-kB signal pathway.

Interactive Effect of Arbuscular Mycorrhizal Fungi (AMF) and Olive Solid Waste on Wheat under Arsenite Toxicity.

Heavy metal such as arsenite (AsIII) is a threat worldwide. Thus, to mitigate AsIII toxicity on plants, we investigated the interactive effect of olive solid waste (OSW) and arbuscular mycorrhizal fungi (AMF) on wheat plants under AsIII stress. To this end, wheat seeds were grown in soils treated with OSW (4% w/w), AMF-inoculation, and/or AsIII treated soil (100 mg/kg soil). AMF colonization is reduced by AsIII but to a lesser extent under AsIII + OSW. AMF and OSW interactive effects also improved soil fertility and increased wheat plants' growth, particularly under AsIII stress. The interactions between OSW and AMF treatments reduced AsIII-induced H2O2 accumulation. Less H2O2 production consequently reduced AsIII-related oxidative damages i.e., lipid peroxidation (malondialdehyde, MDA) (58%), compared to As stress. This can be explained by the increase in wheat's antioxidant defense system. OSW and AMF increased total antioxidant content, phenol, flavonoids, and α-tocopherol by approximately 34%, 63%, 118%, 232%, and 93%, respectively, compared to As stress. The combined effect also significantly induced anthocyanins accumulation. The combination of OSW+AMF improved antioxidants enzymes activity, where superoxide dismutase (SOD, catalase (CAT), peroxidase (POX), glutathione reductase (GR), and glutathione peroxidase (GPX) were increased by 98%, 121%, 105%, 129%, and 110.29%, respectively, compared to AsIII stress. This can be explained by induced anthocyanin percussors phenylalanine, cinamic acid and naringenin, and biosynthesic enzymes (phenylalanine aminolayse (PAL) and chalcone synthase (CHS)). Overall, this study suggested the effectiveness of OSW and AMF as a promising approach to mitigate AsIII toxicity on wheat growth, physiology, and biochemistry.

Valorizing the usage of olive leaves, bioactive compounds, biological activities, and food applications: A comprehensive review.

Olive oil production is a significant source of economic profit for Mediterranean nations, accounting for around 98 percent of global output. Olive oil usage has increased dramatically in recent years, owing to its organoleptic characteristics and rising knowledge of its health advantages. The culture of olive trees and the manufacture of industrial and table olive oil produces enormous volumes of solid waste and dark liquid effluents, involving olive leaves, pomace, and olive oil mill wastewaters. These by-products cause an economic issue for manufacturers and pose major environmental concerns. As a result, partial reuse, like other agronomical production wastes, is a goal to be achieved. Because these by-products are high in bioactive chemicals, which, if isolated, might denote components with significant added value for the food, cosmetic, and nutraceutical sectors, indeed, they include significant amounts of beneficial organic acids, carbohydrates, proteins, fibers, and phenolic materials, which are distributed differently between the various wastes depending on the olive oil production method and table olive agronomical techniques. However, the extraction and recovery of bioactive materials from chosen by-products is a significant problem of their reasonable value, and rigorous detection and quantification are required. The primary aims of this review in this context are to outline the vital bioactive chemicals in olive by-products, evaluate the main developments in extraction, purification, and identification, and study their uses in food packaging systems and safety problems.

The Wound-Healing Potential of Olea europaea L. Cv. Arbequina Leaves Extract: An Integrated In Vitro, In Silico, and In Vivo Investigation.

Olea europaea L. Cv. Arbequina (OEA) (Oleaceae) is an olive variety species that has received little attention. Besides our previous work for the chemical profiling of OEA leaves using LC−HRESIMS, an additional 23 compounds are identified. An excision wound model is used to measure wound healing action. Wounds are provided with OEA (2% w/v) or MEBO® cream (marketed treatment). The wound closure rate related to vehicle-treated wounds is significantly increased by OEA. Comparing to vehicle wound tissues, significant levels of TGF-ß in OEA and MEBO® (p < 0.05) are displayed by gene expression patterns, with the most significant levels in OEA-treated wounds. Proinflammatory TNF-α and IL-1ß levels are substantially reduced in OEA-treated wounds. The capability of several lignan-related compounds to interact with MMP-1 is revealed by extensive in silico investigation of the major OEA compounds (i.e., inverse docking, molecular dynamics simulation, and ΔG calculation), and their role in the wound-healing process is also characterized. The potential of OEA as a potent MMP-1 inhibitor is shown in subsequent in vitro testing (IC50 = 88.0 ± 0.1 nM). In conclusion, OEA is introduced as an interesting therapeutic candidate that can effectively manage wound healing because of its anti-inflammatory and antioxidant properties.

Diacerein ameliorates acetaminophen hepatotoxicity in rats via inhibiting HMGB1/TLR4/NF-κB and upregulating PPAR-γ signal.

BACKGROUND: Acetaminophen (APAP) is a worldwide antipyretic as well as an analgesic medication. It has been extensively utilized during the outbreak of coronavirus 2019 (COVID-19). APAP misuse would lead to liver injury. Diacerein (DIA), an anthraquinone derivative, has antioxidant and inflammatory properties. Hence, this study attempted to evaluate the impact of DIA treatment on liver injury induced by APAP and its influence on nuclear factor-κB (NF-κB) /toll-like receptor 4 (TLR4)/high mobility group box-1(HMGB-1) signaling as well as the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) expression. METHODS: Male albino rats received 25 as well as 50 mg/kg/day DIA orally for seven days. One hour after the last administration, rats received APAP (1gm/kg, orally). For histopathological analysis, liver tissues and blood were collected, immunohistochemical (IHC) assay, biochemical assay, as well as quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: DIA markedly reduced liver injury markers and ameliorated histopathological changes. Moreover, DIA dose-dependently alleviated oxidative stress status caused by APAP administration along with inflammatory markers, including the level of interleukin-1 beta (IL-1ß), myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6). Furthermore, DIA downregulated protein levels as well as mRNA of HMGB-1, TLR4, NF-κB p65 expression, and enhanced PPAR-γ expression. Moreover, DIA ameliorated apoptotic (Bax) and caspase-3 expressions and increased the anti-apoptotic (Bcl2) expression. CONCLUSIONS: This study demonstrated that DIA exerts anti-apoptotic, anti-inflammatory, and antioxidant properties against liver injury induced by APAP that is attributed to inhibition of the HMGB1/TLR4/NF-κB pathway, besides upregulation of the expression of PPAR-γ.

Musa sp. Leaves Extract Ameliorates the Hepato-Renal Toxicities Induced by Cadmium in Mice.

Heavy metals intoxication causes several health problems that necessitate finding new protective and therapeutic approaches. This study aimed to evaluate the impact of Musa sp. leaves extract (MLE) on hepato-renal toxicities induced by cadmium (Cd) in male mice. The phytochemical screening, metal chelating activity (MCA), and the median lethal dose (LD50) of MLE were determined. Fifty CD-1 male mice were used and intraperitoneally (i.p.) injected with MLE (1000 to 5000 mg/kg b.wt) for MLE LD50 determination. Another 50 mice were used for evaluating the effect of MLE on Cd toxicity. Blood samples were collected for hematological, liver, and kidney functions assessments. Liver tissue homogenates were used for determination of oxidant/antioxidant parameters. Liver and kidney tissues were harvested for histopathological and molecular investigations. MLE showed potent in vitro antioxidant activities. The MCA and LD50 of the MLE were 75 µg/mL and 3000 mg/kg b.wt, respectively. MLE showed beneficial therapeutic activity against hepato-renal toxicities in Cd-intoxicated mice, evidenced by improving the hematological, biochemical, histopathological, and molecular alterations.

CTCF Expression and Dynamic Motif Accessibility Modulates Epithelial-Mesenchymal Gene Expression.

Epithelial-mesenchymal transition (EMT) and its reversal, mesenchymal-epithelial transition (MET) drive tissue reorganization critical for early development. In carcinomas, processing through EMT, MET, or partial states promotes migration, invasion, dormancy, and metastatic colonization. As a reversible process, EMT is inherently regulated at epigenetic and epigenomic levels. To understand the epigenomic nature of reversible EMT and its partial states, we characterized chromatin accessibility dynamics, transcriptomic output, protein expression, and cellular phenotypes during stepwise reversible EMT. We find that the chromatin insulating protein machinery, including CTCF, is suppressed and re-expressed, coincident with broad alterations in chromatin accessibility, during EMT/MET, and is lower in triple-negative breast cancer cell lines with EMT features. Through an analysis of chromatin accessibility using ATAC-seq, we identify that early phases of EMT are characterized by enrichment for AP-1 family member binding motifs, but also by a diminished enrichment for CTCF binding motifs. Through a loss-of-function analysis, we demonstrate that the suppression of CTCF alters cellular plasticity, strengthening the epithelial phenotype via the upregulation of epithelial markers E-cadherin/CDH1 and downregulation of N-cadherin/CDH2. Conversely, the upregulation of CTCF leads to the upregulation of EMT gene expression and an increase in mesenchymal traits. These findings are indicative of a role of CTCF in regulating epithelial-mesenchymal plasticity and gene expression.

Cold-pressed raspberry seeds oil ameliorates high-fat diet triggered non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is considered one of the most serious public health problems affecting liver. The reported beneficial impact of raspberries on obesity and associated metabolic disorder makes it a suitable candidate against NAFLD. In the current study, the chemical profile of raspberry seed oil (RO) was characterized by analysis of fatty acid and tocopherol contents using high-performance liquid chromatography (HPLC) in addition to the determination of total phenolic and flavonoids. High levels of unsaturated fatty acids, linoleic acid (49.9%), α-linolenic acid (25.98%), and oleic acid (17.6%), along with high total tocopherol content (184 mg/100 gm) were detected in oil. The total phenolic and flavonoid contents in RO were estimated to be 22.40 ± 0.25 mg gallic acid equivalent (GAE)/100 mg oil and 1.34 ± 0.15 mg quercetin (QU)/100 mg, respectively. Anti-NAFLD efficacy of RO at different doses (0.4 and 0.8 mL) in a model of a high-fat diet (HFD) fed rats was assessed by estimating lipid profile, liver enzyme activity, glucose and insulin levels as well as adipokines and inflammatory marker. Peroxisome proliferator-activated receptor γ (PPARγ), which is a molecular target for NAFLD was also tested. Liver histopathology was carried out and its homogenate was used to estimate oxidative stress markers. Consumption of RO significantly improved lipid parameters and hepatic enzyme activities, reduced insulin resistance and glucose levels, significantly ameliorated inflammatory and oxidative stress markers. Furthermore, RO treatment significantly modulated adipokines activities and elevated PPARγ levels. Raspberry seed oil administration significantly improved these HFD induced histopathological alterations. Moreover, a molecular docking study was performed on the identified fatty acids and tocopherols. Among the identified compounds, oleic acid, α-linolenic acid and γ-tocopherol exhibited the highest docking score as PPARγ activator posing them as a potential anti-NAFLD drug leads. Study findings suggest RO as an effective therapeutic candidate for ameliorating NAFLD.

Nuclear Receptor-Mediated Metabolic Reprogramming and the Impact on HR+ Breast Cancer.

Metabolic reprogramming enables cancer cells to adapt to the changing microenvironment in order to maintain metabolic energy and to provide the necessary biological macromolecules required for cell growth and tumor progression. While changes in tumor metabolism have been long recognized as a hallmark of cancer, recent advances have begun to delineate the mechanisms that modulate metabolic pathways and the consequence of altered signaling on tumorigenesis. This is particularly evident in hormone receptor positive (HR+) breast cancers which account for approximately 70% of breast cancer cases. Emerging evidence indicates that HR+ breast tumors are dependent on multiple metabolic processes for tumor progression, metastasis, and therapeutic resistance and that changes in metabolic programs are driven, in part, by a number of key nuclear receptors including hormone-dependent signaling. In this review, we discuss the mechanisms and impact of hormone receptor mediated metabolic reprogramming on HR+ breast cancer genesis and progression as well as the therapeutic implications of these metabolic processes in this disease.

CPT1A and fatty acid ß-oxidation are essential for tumor cell growth and survival in hormone receptor-positive breast cancer.

Chromosome 11q13-14 amplification is a defining feature of high-risk hormone receptor-positive (HR+) breast cancer; however, the mechanism(s) by which this amplicon contributes to breast tumorigenesis remains unclear. In the current study, proteogenomic analyses of >3000 breast tumors from the TCGA, METABRIC and CPTAC studies demonstrated that carnitine palmitoyltransferase 1A (CPT1A), which is localized to this amplicon, is overexpressed at the mRNA and protein level in aggressive luminal tumors, strongly associated with indicators of tumor proliferation and a predictor of poor prognosis. In vitro genetic studies demonstrated that CPT1A is required for and can promote luminal breast cancer proliferation, survival, as well as colony and mammosphere formation. Since CPT1A is the rate-limiting enzyme during fatty acid oxidation (FAO), our data indicate that FAO may be essential for these tumors. Pharmacologic inhibition of FAO prevented in vitro and in vivo tumor growth and cell proliferation as well as promoted apoptosis in luminal breast cancer cells and orthotopic xenograft tumor models. Collectively, our data establish an oncogenic role for CPT1A and FAO in HR+ luminal tumors and provide preclinical evidence and rationale supporting further investigation of FAO as a potential therapeutic opportunity for the treatment of HR+ breast cancer.

Identification of non-classical hCA XII inhibitors using combination of computational approaches for drug design and discovery.

Human carbonic anhydrase XII (hCA XII) isozyme is of high therapeutic value as a pharmacological target and biomarker for different types of cancer. The hCA XII is one of the crucial effectors that regulates extracellular and intracellular pH and affects cancer cell proliferation, invasion, growth and metastasis. Despite the fact that interaction features of hCAs inhibitors with the catalytic site of the enzyme are well described, lack in the selectivity of the traditional hCA inhibitors based on the sulfonamide group or related motifs is an urgent issue. Moreover, drugs containing sulfanomides can cause sulfa allergies. Thus, identification of novel non-classical inhibitors of hCA XII is of high priority and is currently the subject of a vast field of study. This study was devoted to the identification of novel potential hCA XII inhibitors using comprehensive set of computational approaches for drug design discovery: generation and validation of structure- and ligand-based pharmacophore models, molecular docking, re-scoring of virtual screening results with MMGBSA, molecular dynamics simulations, etc. As the results of the study several compounds with alternative to classical inhibitors chemical scaffolds, in particular one of coumarins derivative, have been identified and are of high interest as potential non-classical hCA XII inhibitors.

Association of health literacy and other risk factors with glycemic control among patients with type 2 diabetes in Kuwait: A cross-sectional study.

BACKGROUND: Poor health literacy (HL) has received much attention recently as a risk factor for poor health outcomes especially among patients with chronic diseases. The degree to which HL affects health outcomes is unknown among patients with type 2 diabetes mellitus (T2DM) in Kuwait. This study aimed to investigate the association between HL and glycated hemoglobin (HbA1c) among patients with T2DM. METHODS: 356 patients with T2DM were selected from 27 primary care clinics covering the state of Kuwait. HL was measured by the Short Test of Functional Health Literacy in Adults (STOFHLA). Prevalence of uncontrolled HbA1c was estimated and its association with HL was modeled and tested using Poisson regression with log-link function and robust variance-covariance matrix, while adjusting for several confounders. RESULTS: The prevalence of uncontrolled HbA1c was 77.8%. Among those with inadequate or marginal HL, about 50.7% have uncontrolled HbA1c. The prevalence of uncontrolled HbA1c among those on diet alone was 36.3% lower compared to those on mixed treatment regimen (APR = 0.637, 95% CI: 0.455-0.891, PV = 0.008). The prevalence of uncontrolled HbA1c among patients on oral hypoglycemic (OH) drugs alone was 22.3% lower compared to those on mixed treatment (OH plus Insulin) regimen (APR = 0.777, 95% CI: 0.697-0.865, PV < 0.001). For every one-year increase in age, there is 1.4% reduction in the prevalence of uncontrolled HbA1c (APR = 0.986, 95% CI: 0.978-0.994, PV < 0.001). For one STOFHLA score increase, there is 0.3% reduction in the prevalence of uncontrolled HbA1c (APR = 0.997, 95% CI: 0.994-1.00, PV = 0.055). Finally, for every year increase since T2DM onset, there is 1.1% increase in the prevalence of uncontrolled HbA1c (APR = 1.011, 95% CI: 1.003-1.019, PV = 0.008). CONCLUSIONS: The prevalence of uncontrolled HbA1c among patients with T2DM in Kuwait is high. Half of T2DM with inadequate or marginal HL have uncontrolled HbA1c. Patients on diet alone or OH alone have lower prevalence of uncontrolled HbA1c compared to those on mixed treatment regimen. Older T2DM patients or those with higher STOFHLA score have lower prevalence of uncontrolled HbA1c, while those with longer T2DM onset have higher prevalence of uncontrolled HbA1c. Future interventions should focus on younger patients, improve HL, and establish better communications between physicians and patients with T2DM for better glycemic control.

Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts.

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is highly heterogeneous, fibrotic, and hypovascular, marked by extensive desmoplasia and maintained by the tumor cells, cancer-associated fibroblasts (CAFs) and other stromal cells. There is an urgent need to identify and develop treatment strategies that not only target the tumor cells but can also modulate the stromal cells. A growing number of studies implicate the role of regulatory DNA elements called super-enhancers (SE) in maintaining cell-type-specific gene expression networks in both normal and cancer cells. Using chromatin activation marks, we first mapped SE networks in pancreatic CAFs and epithelial tumor cells and found them to have distinct SE profiles. Next, we explored the role of triptolide (TPL), a natural compound with antitumor activity, in the context of modulating cell-type-specific SE signatures in PDAC. We found that TPL, cytotoxic to both pancreatic tumor cells and CAFs, disrupted SEs in a manner that resulted in the downregulation of SE-associated genes (e.g., BRD4, MYC, RNA Pol II, and Collagen 1) in both cell types at mRNA and protein levels. Our observations suggest that TPL acts as a SE interactive agent and may elicit its antitumor activity through SE disruption to re-program cellular cross talk and signaling in PDAC. Based on our findings, epigenetic reprogramming of transcriptional regulation using SE modulating compounds such as TPL may provide means for effective treatment options for pancreatic cancer patients.

Novel 1,2,4-triazole derivatives as apoptotic inducers targeting p53: Synthesis and antiproliferative activity.

A series of novel thiazolo[3,2-b][1,2,4]-triazoles 3a-n has been synthesized and evaluated in vitro as potential antiproliferative. Compounds 3b-d exhibited significant antiproliferative activity. Compound 3b was the most potent with Mean GI50 1.37 µM comparing to doxorubicin (GI50 1.13 µM). The transcription effects of 3b, 3c and 3d on the p53 were assessed and compared with the reference doxorubicin. The results revealed an increase of 15-27 in p53 level compared to the test cells and that p53 protein level of 3b, 3c and 3d was significantly inductive (1419, 571 and 787 pg/mL, respectively) in relation to doxorubicin (1263 pg/mL). The docking study of the new compounds 3a-n revealed high binding scores for the new compounds toward p53 binding domain in MDM2. The docking analyses revealed the highest affinities for compounds 3b-d which induced p53 activity in MCF-7 cancer cells. Compound 3b which exhibited the highest antiproliferative activity and induced the highest increase in p53 level in MCF-7 cells showed also the highest affinity to MDM2.

Psoriasis Among Adolescents in Kuwait and the Role of Siblings, Breastfeeding, and Household Cat and Secondhand Smoke Exposure: A Cross-Sectional Study.

INTRODUCTION: Globally, the epidemiology of psoriasis is poorly understood, and most countries lack essential epidemiologic data regarding disease burden and its determinants. This study sought to estimate the prevalence of psoriasis among adolescents in Kuwait and assess its association with different risk factors, including obesity, sibship size, breastfeeding, and exposure to household secondhand smoke (SHS) and pets. METHODS: Schoolchildren aged 11-14 years (n = 3864) were enrolled in a cross-sectional study. Lifetime and current (past 12 months) prevalence of psoriasis were ascertained according to ever having a history of doctor-diagnosis plus current active lesion(s) and/or current use of treatment of psoriasis. Associations were assessed using Poisson regression with robust variance estimation, and adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) were estimated. RESULTS: The lifetime and current prevalence of psoriasis were estimated to be 3.6% (136/3806) and 1.1% (42/3806), respectively. Commonly reported anatomical sites affected by psoriasis included scalp (47.6%) and the extensor surface of the knees (50%) and elbows (38.1%). Household SHS exposure was associated with increased lifetime psoriasis (aPR = 1.41, 95% CI 1.07-1.98), and showed a trend for association with current psoriasis (1.77, 0.89-3.53). Similarly, cat-keeping during infancy was associated with lifetime psoriasis (1.96, 1.14-3.37), and demonstrated a trend for association with current psoriasis (1.49, 0.52-1.98). In contrast, breastfeeding was associated with a decreased lifetime psoriasis (0.62, 0.44-0.89), but was not associated with current psoriasis. Trend analyses showed that the prevalence of lifetime and current psoriasis increased with increasing numbers of total, older, and younger siblings. CONCLUSIONS: Psoriasis affects a considerable proportion of schoolchildren in Kuwait. Interestingly, psoriasis prevalence was related to risk factors also found in allergic diseases, such as exposure to SHS, cat-keeping in infancy, breastfeeding, and sibship size, possibly suggesting a role of immune dysregulation.

Effect of gamma radiation on combination therapy of certain antiepileptic drugs in rats.

The current study was designed to estimate the effect of υ-radiation on male rats pretreated with Levetiracetam (LEV) and/or Oxcarbazepine (OXC). Poly-treatment of rats with LEV, OXC and υ-radiation showed a significant elevation in the activity of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and isoenzyme creatinine kinase-MB (CK-MB) along with, an increase in the level of creatinine, urea, cardiac troponin (cTnI) and glutamate. These increases were associated with a decrease in acetylcholine (Ach) and υ-aminobutyric acid (GABA) levels. The data further revealed a significant increase of the apoptotic mediators tumor necrosis factor alpha (TNF-α) and brain caspase3 as well as, alterations in the oxidative stress parameters. The Results of the histopathological examination of liver, kidney, heart and brain tissues indicated coincidence with those recorded by the biochemical analysis. It seems promising to conclude that the exposure to υ-radiation intensified the deleterious and detrimental effect of dual treatment of LEV and OXC in rats.