Lack of Syndecan-1 promotes the pathogenesis of experimental rheumatoid arthritis.

Syndecan-1 (Sdc-1), a transmembrane heparan sulfate protein, is implicated in several pathophysiological processes including rheumatoid arthritis (RA). The exact role of Syndican-1 in this autoimmune disease is still undetermined. This study explores the involvement level of Sdc-1 in the development of RA in a collagen II-induced arthritis mice model. RA was induced in two mice strains (wild-type BALB/c group and Sdc-1 knockout) by collagen II. Mice underwent regular clinical observations and scoring. After sacrifice, leg biopsies were taken from mice for histological examination, using a variety of stains. In addition, proteins were extracted, and molecular assessment of TNF-α was performed using the western blot technique. In the Sdc-1 knockout group, clinical scoring results showed a significantly more severe experimental RA; histology showed a significant increase in bone erosion, cartilage destruction, inflammation, and less granulated mast cells than the wild-type. In addition, molecular assessment of TNF-α showed more increase in expression in the Sdc-1 knockout models compared to the wild-type. Data suggest that lack of Sdc-1 enhances the inflammatory characteristics in RA. However, more molecular studies and investigations are needed to determine its exact role and possible mechanisms involved.

Barriers toward xenotransplantation in Arab World.

Organ transplant is a crucial therapeutic strategy offering a life-saving and transformative medical intervention. It provides an opportunity to improve their quality of life and increase their lifespan. The shortage of organs remains a critical global challenge, leading to a prolonged waiting times for organ receivers, which contributes to an increase in morbidity and mortality rates. Hence, xenotransplantation offered a promising solution to the global shortage of organs through the use of animal organs, leading to an increase in donor availability, reducing waiting times, minimizing organ trafficking, improving genetic engineering advancements, and driving scientific innovation. Even though xenotransplantation has many benefits in the clinical setting, it has many barriers that are hindering its achievements and constraining its occurrence. Some barriers to xenotransplant are general, such as the immunological barrier, while others are specific to certain regions due to local causes. The Arab region exhibits disparities in clinical settings compared to the global context, marked by the huge economic crisis and a shortage of trained healthcare professionals. Considering the huge resources and advancements needed in the field of xenotransplantation, this review aims to explore the specific barriers toward xenotransplantation in the Arab countries, highlighting the challenges to overcome these barriers.

Sexual dimorphism in acute myocardial infarction-induced acute kidney injury: cardiorenal deteriorating effects of ovariectomy in premenopausal female mice.

Acute kidney injury (AKI) is a common complication of cardiovascular diseases (CVDs) in both males and females, increasing mortality rate substantially. Premenopausal females appear to be more protected, suggesting a potential protective role of female sex hormones. Here, we tested the hypothesis that ovariectomy (OVX) eliminates the beneficial effect of female sex on renal protection following acute myocardial infarction (MI). Seven days post-MI, both sexes exhibited worsened kidney function and a substantial decrease in total kidney NAD levels. Unlike MI female mice, MI males showed exacerbated morphological alterations with increased proinflammatory, proapoptotic, and profibrotic biomarkers. The expression of NAD+ biosynthetic enzymes NAMPT and NMRK-1 was increased in MI females only, while males showed a substantial increase in NAD+ consuming enzyme PARP-1. OVX did not eliminate the female-sex protection of glomerular morphology but was associated with swelling of proximal convoluted tubules with MI as in males. With OVX, MI females had enhanced proinflammatory cytokine release, and a further decrease in creatinine clearance and urine output was observed. Our findings suggest that MI induced AKI in both sexes with pre-menopausal female mice being more protected. Ovariectomy worsens aspects of AKI in females after MI, which may portend increased risk for development of chronic kidney disease.

IL-33 induces type-2-cytokine phenotype but exacerbates cardiac remodeling post-myocardial infarction with eosinophil recruitment, worsened systolic dysfunction, and ventricular wall rupture.

Myocardial infarction (MI) is the leading cause of mortality worldwide. Interleukin (IL)-33 (IL-33) is a cytokine present in most cardiac cells and is secreted on necrosis where it acts as a functional ligand for the ST2 receptor. Although IL-33/ST2 axis is protective against various forms of cardiovascular diseases, some studies suggest potential detrimental roles for IL-33 signaling. The aim of the present study was to examine the effect of IL-33 administration on cardiac function post-MI in mice. MI was induced by coronary artery ligation. Mice were treated with IL-33 (1 µg/day) or vehicle for 4 and 7 days. Functional and molecular changes of the left ventricle (LV) were assessed. Single cell suspensions were obtained from bone marrow, heart, spleen, and peripheral blood to assess the immune cells using flow cytometry at 1, 3, and 7 days post-MI in IL-33 or vehicle-treated animals. The results of the present study suggest that IL-33 is effective in activating a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response. However, IL-33 administration was associated with worsened cardiac function and adverse cardiac remodeling in the MI mouse model. IL-33 administration increased infarct size, LV hypertrophy, cardiomyocyte death, and overall mortality rate due to cardiac rupture. Moreover, IL-33-treated MI mice displayed a significant myocardial eosinophil infiltration at 7 days post-MI when compared with vehicle-treated MI mice. The present study reveals that although IL-33 administration is associated with a reparative phenotype following MI, it worsens cardiac remodeling and promotes heart failure.

A rare case of pelvic bone duplication.

Iliac bone malformations are rare and result from early disturbance of the genetic and epigenetic processes that come together to form the pelvic girdle. We report the case of a 5-month-old boy found to have a duplication of the ilium and describe the likely causes of this very rare malformation.

Hyperuricemia, Hypertension, and Chronic Kidney Disease: an Emerging Association.

Uric acid is a product of purine metabolism and has been linked to gout and kidney calculi. Chronic kidney disease (CKD) and hypertension (HTN) are two major public health problems, and both are associated with increased risk of cardiovascular events. Emerging evidence suggests a pathogenic role of hyperuricemia in the development of HTN and CKD, in addition to progression of CKD, by inducing renal inflammation, endothelial dysfunction, and activation of the renin-angiotensin system. In addition, several epidemiological studies have linked hyperuricemia with an increased risk of HTN and CKD. A few clinical trials have assessed the use of uric acid-lowering therapies such as allopurinol and febuxostat in the management of HTN and delaying progression of CKD. To date, most of these trials are short-term with a small sample size; however, their results are encouraging and provide a rationale for larger randomized controlled trials to establish the role of uric acid-lowering therapies in the management of HTN, in addition to prevention of CKD progression and cardiovascular events.

Pruritus ani: more than a decade of personal experience in Lebanon.

INTRODUCTION: Pruritus ani is a common medical condition that is difficult to treat in the absence of obvious predisposing factors. Hereby, we report more than a ten-year experience in the management of pruritus ani stressing the importance of early detection, identification of the etiology, and management. METHODOLOGY: A total of 124 patients were managed in the surgical clinic. The follow-up was between 11 to 17 months. All patients had the symptoms for a period of time ranging between 6 and 40 months. Patients were treated according to their respective etiology. Medical cases like contact dermatitis and psoriasis were treated by applying proper topical ointments, while other cases like anal fissure and fistula were treated surgically. Idiopathic patients were treated by tattooing (injection to perianal skin with methylene blue). RESULTS & DISCUSSION: The majority of patients with known medical etiology responded favorably to conservative treatment (≈ 92%). In addition, surgical management for anorectal disorders like hemorrhoids and fistula showed a consistent improvement (94%). However, patients who had their symptoms neglected for longtime or had used over the counter medication without a proper medical follow-up, experienced a lower success rate of cure (76%). CONCLUSION: Patients who were diagnosed and treated at first hand, showed better results than those who sought late medical advice and management (i.e. > 18 months). In light of the above, a multidisciplinary team approach consisting of a proctologist, a gastroenterologist and a dermatologist is recommended.

Establishing an OCD Model in BALB/c Mice Using RU24969: A Molecular and Behavioural Study of Optimal Dose Selection.

Obsessive-compulsive disorder (OCD) is a disabling disease characterized by distressing obsessions and repetitive compulsions. The etiology of OCD is poorly known, and mouse modeling allows to clarify the genetic and neurochemical basis of this disorder and to investigate potential treatments. This study evaluates the impact of the 5-HT1B agonist RU24969 on the induction of OCD-like behaviours in female BALB/c mice (n = 30), distributed across five groups receiving varying doses of RU24969. Behavioural assessments, including marble test, tail suspension test, sucrose preference test, forced swim test, and nestlet shredding test, were conducted. Gene expression and protein quantitation of Gabra1 and serotonin transporter in mouse brain were also performed. Marble-burying behaviour increased significantly at high doses of RU24969 (15-20 mg/kg). The forced swimming test consistently showed elevated values at the same high concentrations, compared to the control. Altered reward-seeking behaviour was indicated by the sucrose preference test, notably at 15 and 20 mg/kg doses of RU24969. Nestlet shredding results did not show statistical significance among the tested animal groups. Gene expression analysis revealed reduced Gabra1 expression with increasing doses of RU, while serotonin transporter was not related to varying doses of RU24969. Western blotting corroborated these trends. The results underscore complex interactions between the serotonin system, GABAergic signaling, and OCD-relevant behaviours and suggest the use of intraperitoneal injection of 15 mg/kg of RU24969 to induce OCD-like behaviour in BALB/c mouse models.

Stem cell transplantation in cerebrovascular accidents: A global bibliometric analysis (2000-2023).

BACKGROUND: Cerebrovascular accident (CVA) is a major global contributor to death and disability. As part of its medical management, researchers have recognized the importance of promising neuroprotective strategies, where stem cell transplantation (SCT) is thought to confer advantages via trophic and neuroprotective effects. AIM: To evaluate the current state of research on SCT in patients with CVA, assess key trends and highlight literature gaps. METHODS: PubMed was screened for SCT in CVA-related articles in October 2023, for each country during the period between 2000 and 2023. Using the World Bank data, total population and gross domestic product were collected for comparison. VOSviewer_1.6.19 was used to create the VOS figure using the results of the same query. Graphs and tables were obtained using Microsoft Office Excel. RESULTS: A total of 6923 studies were identified on SCT in CVA, making 0.03% of all published studies worldwide. Approximately, 68% were conducted in high-income countries, with a significant focus on mesenchymal stem cells. The journal "Stroke" featured the largest share of these articles, with mesenchymal SCT having the highest rate of inclusion, followed by hematopoietic SCT. Over time, there has been a noticeable shift from in vitro studies, which assess stem cell proliferation and neurogenesis, to in vivo studies aimed at evaluating efficacy and safety. Additionally, the number of reviews increased along this approach. CONCLUSION: This bibliometric analysis provides a comprehensive guide for physicians and researchers in the field through an objective overview of research activity, and highlights both current trends and gaps. Having a potential therapeutic role in CVA, more research is needed in the future to focus on different aspects of SCT, aiming to reach a better treatment strategy and improve life quality in patients.

The Mechanism and Potential Therapeutic Effects of Cyclosporin, Cyclophilin, Probiotics and Syndecan-1 in an Animal Model of Inflammatory Bowel Disease.

Background: Inflammatory bowel diseases (IBDs) have several treatment modalities including immunoregulators, like cyclosporine A, an immunosuppressant that interacts with cytoplasmic cyclophilin A, and probiotics. Aims: This study explored and compared the possible role of syndecan-1 in the IBD pathogenic process as well as the effectiveness of cyclophilin A, cyclosporine A, and their combination in the management of IBDs in the presence of probiotics. Methodology: IBD was induced in a total of 112 mice equally divided between syndecan-1 knock-out (KO) and Balb/c wild-type mice, using 2% dextran sulfate sodium (DSS) followed by intraperitoneal treatment with cyclosporine A, cyclophilin A, or a combination of both. In addition, a daily dose of probiotics was given in their drinking water. The animals were monitored for clinical signs and symptoms and checked for gross pathologies in the abdomen after 3 weeks. Descending and sigmoid colon biopsies were collected and fixed for routine microscopy or frozen for protein extraction and molecular testing for IL-6, CD3, CD147, and beta 1 integrins as well as pAkt expression. Results: The data showed that the induction of IBD in the syndecan-1 KO mice was more severe at the clinical, histological, and molecular levels than in the wild type. The combined CypA-CyA treatment showed no added inhibitory effect compared to single-drug treatment in both strains. Probiotics added to the combination was more effective in the wild type and, when used alone, its inhibition of IL-6 was the highest. As for the CD147 marker, there were more suppressions across the various groups in the KO mice except for the probiotics-alone group. Concerning CD3, it was significantly increased by the CypA-CyA complex, which led to more inflammation in the KO mice. Probiotics had little effect with the combination. In relation to beta 1 integrins, the CypA-CyA combination made no significant difference from CyA alone, and adding probiotics to the combination resulted in higher beta 1 integrin expression in the KO mice. As for pAkt, it was very well expressed and upregulated in both strains treated with DSS, but the effect was much larger in the KO mice. In brief, the CypA-CyA complex showed a decrease in the expression of pAkt, but there was no added effect of both drugs. Probiotics along with the complex had a similar reduction effects in both strains, with a greater effect in the wild-type mice, while probiotics alone led to a similar reduction in pAkt expressions in both strains. Conclusions: The differential effects of CyA, CypA, probiotics, and their combinations on the various inflammatory markers, as well as the histological alterations and clinical signs and symptoms, speak in favor of a clear role of syndecan-1 in reducing inflammation. However, probiotics need to be considered after more explorations into the mechanisms involved in the presence of CypA and CyA especially since pAkt is less active in their presence.

Probiotics, gut microbiome, and cardiovascular diseases: An update.

Cardiovascular diseases (CVD) are one of the most challenging diseases and many factors have been demonstrated to affect their pathogenesis. One of the major factors that affect CVDs, especially atherosclerosis, is the gut microbiota (GM). Genetics play a key role in linking CVDs with GM, in addition to some environmental factors which can be either beneficial or harmful. The interplay between GM and CVDs is complex due to the numerous mechanisms through which microbial components and their metabolites can influence CVDs. Within this interplay, the immune system plays a major role, mainly based on the immunomodulatory effects of microbial dysbiosis and its resulting metabolites. The resulting modulation of chronic inflammatory processes was found to reduce the severity of CVDs and to maintain cardiovascular health. To better understand the specific roles of GM-related metabolites in this interplay, this review presents an updated perspective on gut metabolites related effects on the cardiovascular system, highlighting the possible benefits of probiotics in therapeutic strategies.

Mechanism of Action of Melatonin as a Potential Adjuvant Therapy in Inflammatory Bowel Disease and Colorectal Cancer.

Inflammatory bowel disease (IBD), a continuum of chronic inflammatory diseases, is tightly associated with immune system dysregulation and dysbiosis, leading to inflammation in the gastrointestinal tract (GIT) and multiple extraintestinal manifestations. The pathogenesis of IBD is not completely elucidated. However, it is associated with an increased risk of colorectal cancer (CRC), which is one of the most common gastrointestinal malignancies. In both IBD and CRC, a complex interplay occurs between the immune system and gut microbiota (GM), leading to the alteration in GM composition. Melatonin, a neuroendocrine hormone, was found to be involved with this interplay, especially since it is present in high amounts in the gut, leading to some protective effects. Actually, melatonin enhances the integrity of the intestinal mucosal barrier, regulates the immune response, alleviates inflammation, and attenuates oxidative stress. Thereby, the authors summarize the multifactorial interaction of melatonin with IBD and with CRC, focusing on new findings related to the mechanisms of action of this hormone, in addition to its documented positive outcomes on the treatment of these two pathologies and possible future perspectives to use melatonin as an adjuvant therapy.

Impaired DNA Double-Strand Break Repair in Irradiated Sheep Lung Fibroblasts: Late Effects of Previous Irradiation of the Spinal Thecal Sac.

Children with cancer previously treated with radiotherapy face the likelihood of side effects that can be debilitating or fatal. This study aimed to assess the long-term effect of medulloblastoma radiotherapy on the DNA double-strand break (DSB) repair capability of primary fibroblasts derived from lung biopsies of previously irradiated young sheep. This study included biopsies from three control and five irradiated sheep. The treated sheep had previously received spinal radiotherapy at a total dose of 28 Gy, which is equivalent to pediatric medulloblastoma treatment. Lung biopsies were taken 4 years post-irradiation from high-dose (HD, >18 Gy) and low-dose (LD, <2 Gy) regions. Fifteen cell lines were extracted (six control, four LD and five HD). The cells were irradiated, and DNA DSB repair was analyzed by immunofluorescence. Clonogenic, trypan blue and micronuclei assays were performed. Both the HD and LD cell lines had a significantly higher number of residual γH2AX foci 24 h and a significant decrease in pATM activity post-irradiation compared to the control. There was no statistically significant difference in the clonogenic assay, trypan blue and micronuclei results. Our study showed that a previous irradiation can impair the DNA DSB repair mechanism of ovine lung fibroblasts.

The Effects of Endosomal Toll-like Receptor Inhibitors in an EBV DNA-Exacerbated Inflammatory Bowel Disease Mouse Model.

Epstein-Barr virus (EBV), a Herpesviridae family member, is associated with an increased risk of autoimmune disease development in the host. We previously demonstrated that EBV DNA elevates levels of the pro-inflammatory cytokine IL-17A and that inhibiting Toll-like receptor (TLR) 3, 7, or 9 reduces its levels. Moreover, this DNA exacerbated colitis in a mouse model of inflammatory bowel disease (IBD). In the study at hand, we examined whether inhibition of TLR3, 7, or 9 alleviates this exacerbation. Mice were fed 1.5% dextran sulfate sodium (DSS) water and administered EBV DNA. Then, they were treated with a TLR3, 7, or 9 inhibitor or left untreated. We also assessed the additive impact of combined inhibition of all three receptors. Mice that received DSS, EBV DNA, and each inhibitor alone, or a combination of inhibitors, showed significant improvement. They also had a decrease in the numbers of the pathogenic colonic IL-17A+IFN-γ+ foci. Inhibition of all three endosomal TLR receptors offered no additive benefit over administering a single inhibitor. Therefore, inhibition of endosomal TLRs reduces EBV DNA exacerbation of mouse colitis, offering a potential approach for managing IBD patients infected with EBV.

A modulating effect of epigallocatechin gallate (EGCG), a tea catechin, on the bladder of rats exposed to water avoidance stress.

AIMS: To examine the effect of epigallocatechin gallate (EGCG), a green tea catechin, on the bladder of rats exposed to water avoidance stress (WAS). METHODS: Twenty female Sprague-Dawley rats were divided into four groups of five. The first group was exposed to WAS for7 days. The second group was pretreated with EGCG 1 mg/kg intraperitoneally (IP) for 7 days before exposure to WAS. The treatment was continued till the end of the experiment. The third group was placed on the platform in a container without water for 2 hr daily for 7 days (Sham WAS). The fourth group was pretreated with saline I.P. for 7 days before being exposed to sham WAS. PRIMARY OUTCOME: Bladder wall evaluation for signs of inflammation and total and activated mast cell counts. Secondary outcome: fecal pellet output and micturition frequency at baseline, day 1 and day 7. RESULTS: Bladder walls from rats exposed to WAS revealed significantly higher inflammation score, total and degranulated mast cell counts compared to the sham WAS group. EGCG administration had an obvious protective effect on the bladder mucosa, as the inflammation score, total and degranulated mast cell counts were all significantly lower than in the WAS group. In the WAS group, fecal pellet output and micturition frequency increased above baseline throughout the experiment. Comparison of sham WAS group versus sham WAS with saline revealed no statistically significant difference in any parameter. CONCLUSIONS: EGCG given at 1 mg/kg I.P to rats has a significant protective effect against bladder degenerative changes following WAS.

Nerve growth factor and burn wound healing: Update of molecular interactions with skin cells.

Burn wound healing is a very intricate and complex process that conventionally includes three interrelated and overlapping stages of hemostasis/inflammation, proliferation and remodeling. This review aims to explore the molecular interactions of NGF with the most prominent cell types in the skin and their respective secretory products during wound healing, particularly burn wound healing. Different types of cells such as, nerve cells, endothelial cells, mast cells, macrophages, neutrophils, keratinocytes and fibroblasts all come into play through a plethora of cytokines and growth factors including nerve growth factor (NGF). NGF is a pleiotropic molecule that exerts its effects on all the aforementioned cells using two types of receptors (TrkA and p75) and affects wound healing by decreasing healing time and improving the quality of the scar. Both receptors mediate cellular proliferation, survival and apoptosis through complex signaling molecules. During the inflammatory phase, macrophages and mast cells secrete ample cytokines and growth factors, including NGF, which participate in the inflammatory reaction and induction of other cells targeting a homeostatic state. The proliferative phase follows, and NGF promotes angiogenesis through VEGF and FGF expression in endothelial cells. NGF also stimulates keratinocyte proliferation and neurite extension through the TrkA-PI3K/Akt pathway. Other molecules such as TGF-ß1, IL-1ß and TNF-α increase NGF expression in fibroblasts through dynamic interactions with Smads and MAPK molecules. Stimulated fibroblasts induce new collagen production to form the granulation tissue. In the remodeling phase, NGF regulates fibroblasts and induces their differentiation into myofibroblasts ultimately leading to wound contracture. In addition, NGF stimulates melanocytes and enhances hair growth and pigmentation. Such data depict the mechanisms of action of NGF implicated in the various stages of the healing process and support its applicability as a new targeted therapeutic molecule effective in burn wound healing but with some limitations.

Highlights on two decades with microbiota and inflammatory bowel disease from etiology to therapy.

Inflammatory Bowel diseases (IBDs) constitute a complex panel of disorders characterized with chronic inflammation affecting the alimentary canal along with extra intestinal manifestations. Its exact etiology is still unknown; however, it seems to be the result of uncharacterized environmental insults in the intestine and their immunological consequences along with dysbiosis, in genetically predisposed individuals. It was the main target of our team since 2002 to explore the etiology of IBD and the related role of bacteria. For almost two decades, our laboratory, among others, has been involved in the reciprocal interaction between the host gastrointestinal lining and the homing microbiota. In the first decade, the attention of scientists focused on the possible role of enteropathogenic E. coli and its relationship to the mechanistic pathways involved in IBD induced in both rats and mice by chemicals like Iodoacetamide, Dextran Sodium Sulfate, Trinitrobenzene, thus linking microbial alteration to IBD pathology. A thorough characterization of the various models was the focus of research in addition to exploring how to establish an active homeostatic composition of the commensal microbiota, including its wide diversity by restoration of gut microbiota by probiotics and moving from dysbiosis to eubiosis. In the last six years and in order to effectively translate such findings into clinical practice, it was critical to explore their relationship to colorectal cancer CRC both in solid tumors and chemically induced CRC. It was also critical to explore the degree of intestinal dysbiosis and linking to IBD, CRC and diabetes. Remarkably, the active mechanistic pathways were proposed as well as the role of microbiota or bacterial metabolites involved. This review covers two decades of investigations in our laboratory and sheds light on the different aspects of the relationship between microbiota and IBD with an emphasis on dysbiosis, probiotics and the multiple mechanistic pathways involved.

VEGF-A: A Novel Mechanistic Link Between CYP2C-Derived EETs and Nox4 in Diabetic Kidney Disease.

Diabetes is associated with decreased epoxyeicosatrienoic acid (EET) bioavailability and increased levels of glomerular vascular endothelial growth factor A (VEGF-A) expression. We examined whether a soluble epoxide hydrolase inhibitor protects against pathologic changes in diabetic kidney disease and whether the inhibition of the VEGF-A signaling pathway attenuates diabetes-induced glomerular injury. We also aimed to delineate the cross talk between cytochrome P450 2C (CYP2C)-derived EETs and VEGF-A. Streptozotocin-induced type 1 diabetic (T1D) rats were treated with 25 mg/L of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) in drinking water for 6 weeks. In parallel experiments, T1D rats were treated with either SU5416 or humanized monoclonal anti-VEGF-A neutralizing antibody for 8 weeks. Following treatment, the rats were euthanized, and kidney cortices were isolated for further analysis. Treatment with AUDA attenuated the diabetes-induced decline in kidney function. Furthermore, treatment with AUDA decreased diabetes-associated oxidative stress and NADPH oxidase activity. Interestingly, the downregulation of CYP2C11-derived EET formation is found to be correlated with the activation of the VEGF-A signaling pathway. In fact, inhibiting VEGF-A using anti-VEGF or SU5416 markedly attenuated diabetes-induced glomerular injury through the inhibition of Nox4-induced reactive oxygen species production. These findings were replicated in vitro in rat and human podocytes cultured in a diabetic milieu. Taken together, our results indicate that hyperglycemia-induced glomerular injury is mediated by the downregulation of CYP2C11-derived EET formation, followed by the activation of VEGF-A signaling and upregulation of Nox4. To our knowledge, this is the first study to highlight VEGF-A as a mechanistic link between CYP2C11-derived EET production and Nox4. ARTICLE HIGHLIGHTS: Diabetes is associated with an alteration in cytochrome P450 2C11 (CYP2C11)-derived epoxyeicosatrienoic acid (EET) bioavailability. Decreased CYP2C11-derived EET bioavailability mediates hyperglycemia-induced glomerular injury. Decreased CYP2C11-derived EET bioavailability is associated with increased reactive oxygen species production, NADPH oxidase activity, and Nox4 expression in type 1 diabetes. Decreased CYP2C11-derived EET formation mediates hyperglycemia-induced glomerular injury through the activation of the vascular endothelial growth factor A (VEGF-A) signaling pathway. Inhibiting VEGF signaling using anti-VEGF or SU5416 attenuates type 1 diabetes-induced glomerular injury by decreasing NADPH oxidase activity and NOX4 expression.

Probiotics Properties: A Focus on Pregnancy Outcomes.

A healthy microbiome plays an important role in the prevention of illness and maintenance of overall health, including reproductive health. Although the therapeutic advantages of probiotics have been shown to run across multiple organ systems, their role in pregnancy is not well explored. The aim of this review is to highlight the potential advantages and adverse effects of probiotics in pregnancy. Data were collected from the literature over the past decade using PubMed, Medline, Google Scholar, Ovid, Scopus, and Science Direct. A total of 40 articles were utilized in this review. Collected data indicated that prenatal and post-natal supplementation with lactobacilli alone or lactobacilli with Bifidobacterium spp. seems to be protective. Probiotics may improve insulin resistance and consequently reduce the risk of gestational diabetes. Probiotics may also reduce anxiety and depression by influencing brain activity. Additionally, they interfere with vaginal flora to make it friendlier to beneficial bacteria, and enhance anti-inflammatory or reduce pro-inflammatory cytokines. They may also decrease eczema in breastfed infants and prevent allergic reactions by downregulating Th2 responses to specific allergens from mid to late gestation. Leveraging the cervicovaginal microbiota could promote a number of positive pregnancy-related health outcomes. Caution should be exercised in the selection, dosing, and monitoring of probiotics administration. More comprehensive randomized clinical trials are needed to reach a more meaningful evidence-based clinical knowledge.

Chemopreventive effects of wild carrot oil against 7,12-dimethyl benz(a)anthracene-induced squamous cell carcinoma in mice.

CONTEXT: Daucus carota L. ssp. carota (Apiacea) is widely distributed throughout the world and has many uses in traditional medicine. OBJECTIVE: The present study investigates the chemopreventive effects of oil extract of D. carota umbels on 7,12-dimethyl benz(a)anthracene (DMBA)-induced skin cancer in mice. MATERIALS AND METHODS: D. carota oil extract (DCOE) was prepared by extracting the dried umbels with 50:50 acetone:methanol. Skin papilloma were initiated by DMBA and promoted by 12-O-tetradecanoyl phorobol-13-acetate (TPA). The extract was administered to animals via gavage (0.02 mL of 100% oil), intraperitoneal (0.3 mL of 2% oil), and topical (0.2 mL of 5, 50, and 100% oil) routes for 20 weeks. Tumor appearance, incidence, yield, and volume were compared with those of a non-treated control group. RESULTS: Topical 100% treatment delayed tumor appearance, and inhibited tumor incidence and yield by 40 and 89%, respectively. Topical 50% treatment inhibited tumor incidence and yield by 30 and 83%, respectively, whereas the 5% treatment inhibited tumor yield by 36%. Tumor volume was decreased by 99, 91, and 70% following topical treatments with 100, 50, and 5% oil, respectively. Intraperitoneal treatment inhibited tumor yield by 43%, and decreased tumor volume by 85%, whereas gavage treatment showed minimal effects on both. Intraperitoneal and topical treatment decreased infiltration and hyperplasia with an increase in the level of hyperkeratosis. CONCLUSION: These findings demonstrate that DCOE has remarkable antitumor activity against DMBA-induced skin cancer compared with non-treated animals paving the ground for further investigations.