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Background Long-term exposure of pancreatic islets to fatty acids (FAs), common in obesity, metabolic syndrome, and type 2 diabetes, leads to a compensatory hyperactivity followed by inflammation, apoptosis, dysfunctional beta cells, and results in insulin dependence of the patient. Restriction of fatty uptake by islet beta cells may protect them from lipotoxicity. Purpose Pancreatic islet beta cells express the fatty acid binding protein 3 (FABP3) to bind FAs and to orchestrate lipid signals. Based on this, we investigated whether downregulation of FABP3, by Fabp3 silencing, might slow lipid metabolism and protect against lipotoxicity in insulin-secreting cells. Results Neither Fabp3 silencing, nor overexpression affected the glucose-stimulated insulin secretion in absence of FAs. Fabp3 silencing decreased FA-uptake, lipid droplets formation, and the expression of the lipid accumulation-regulating gene Dgat1 in Ins1E cells. It reduced FA-induced inflammation by deactivation of NF-κB, which was associated with upregulation of IκBα and deactivation of the NF-κB p65 nuclear translocation, and the downregulation of the cytokines ILl-6, IL-1β, and TNFα. Ins1E cells were protected from the FA-induced apoptosis as assessed by different parameters including DNA degradation and cleaved caspase-3 immunoblotting. Furthermore, FABP3 silencing improved the viability, Pdx1 gene expression, and the insulin-secreting function in cells long-term cultured with palmitic acid. All results were confirmed by the opposite action rendered by FABP3 overexpression. Conclusion The present data reveals that pancreatic beta cells can be protected from lipotoxicity by inhibition of FA-uptake, intracellular utilization and accumulation. FABP3 inhibition, hence, may be a useful pharmaceutical approach in obesity, metabolic syndrome, and type 2 diabetes.

The gut microbiome plays a crucial role in human health by influencing various physiological functions through complex interactions with the endocrine system. These interactions involve the production of metabolites, signaling molecules, and direct communication with endocrine cells, which modulate hormone secretion and activity. As a result, the microbiome can exert neuroendocrine effects and contribute to metabolic regulation, adiposity, and appetite control. Additionally, the gut microbiome influences reproductive health by altering levels of sex hormones such as estrogen and testosterone, potentially contributing to conditions like polycystic ovary syndrome (PCOS) and hypogonadism. Given these roles, targeting the gut microbiome offers researchers and clinicians novel opportunities to improve overall health and well-being. Probiotics, such as Lactobacillus and Bifidobacterium, are live beneficial microbes that help maintain gut health by balancing the microbiota. Prebiotics, non-digestible fibers, nourish these beneficial bacteria, promoting their growth and activity. When combined, probiotics and prebiotics form synbiotics, which work synergistically to enhance the gut microbiota balance and improve metabolic, immune, and hormonal health. This integrated approach shows promising potential for managing conditions related to hormonal imbalances, though further research is needed to fully understand their specific mechanisms and therapeutic potential.

Bone marrow-derived mesenchymal stem cells (BM-MSCs) represent an interesting alternative to liver or hepatocyte transplantation to treat liver injuries. Many studies have reported that MSCs can treat several diseases, including liver damage, just by injection into the bloodstream, without evidence of differentiation. The improvements were attributed to the organotrophic factors, low immunogenicity, immunomodulatory, and anti-inflammatory effects of MSCs, rather than their differentiation. The aim of the present study was to answer the question of whether the presence of BM-MSCs in the hepatic microenvironment will lead to their differentiation to functional hepatocyte-like cells. The hepatic microenvironment was mimicked in vitro by culture for 21 d with liver extract. The resulted cells expressed marker genes of the hepatic lineage including AFP, CK18, and Hnf4a. Functionally, they were able to detoxify ammonia into urea, to store glycogen as observed by PAS staining, and to synthesize glucose from pyruvate/lactate mixture. Phenotypically, the expression of MSC surface markers CD90 and CD 105 decreased by differentiation. This evidenced differentiation into hepatocyte-like cells was accompanied by a downregulation of the stem cell marker genes sox2 and Nanog and the cell cycle regulatory genes ANAPC2, CDC2, Cyclin A1, and ABL1. The present results suggest a clear differentiation of BM-MSCs into functional hepatocyte-like cells by the extracted liver microenvironment. This differentiation is confirmed by a decrease in the sternness and mitotic activities. Tracking transplanted BMMSCs and proving their in vivo differentiation remains to be elucidated.

Aquilaria malaccensis has been traditionally used to treat several medical disorders including inflammation. However, the traditional claims of this plant as an anti-inflammatory agent has not been substantially evaluated using modern scientific techniques. The main objective of this study was to evaluate the anti-inflammatory effect of Aquilaria malacensis leaf extract (ALEX-M) and potentiate its activity through nano-encapsulation. The extract-loaded nanocapsules were fabricated using water-in-oil-in-water (w/o/w) emulsion method and characterized via multiple techniques including DLS, TEM, FTIR, and TGA. The toxicity and the anti-inflammatory activity of ALEX-M and the extract-loaded nanocapsules (ALEX-M-PNCs) were evaluated in-vitro on RAW 264.7 macrophages and in-vivo on zebrafish embryos. The nanocapsules demonstrated spherical shape with mean particle diameter of 167.13 ± 1.24 nm, narrow size distribution (PDI = 0.29 ± 0.01), and high encapsulation efficiency (87.36 ± 1.81%). ALEX-M demonstrated high viability at high concentrations in RAW 264.7 cells and zebrafish embryos, however, ALEX-M-PNCs showed relatively higher cytotoxicity. Both free and nanoencapsulated extract expressed anti-inflammatory effects through significant reduction of the pro-inflammatory mediator nitric oxide (NO) production in LPS/IFNγ-stimulated RAW 264.7 macrophages and zebrafish embryos in a concentration-dependent manner. The findings highlight that ALEX-M can be recognized as a potential anti-inflammatory agent, and its anti-inflammatory activity can be potentiated by nano-encapsulation. Further studies are warranted toward investigation of the mechanistic and immunomodulatory roles of ALEX-M.

The Aquilaria malaccensis species of the genus Aquilaria is an abundant source of agarwood resin and many bioactive phytochemicals. Recent data regarding the chemical constituents and biological activities of Aquilaria leaves led us to attempt to qualitatively profile the metabolites of Aquilaria malaccensis leaves from a healthy, noninoculated tree through phytochemical screening, GC-MS, and LC/Q-TOF-MS. The present work is also the first to report the antilipoxygenase activity of A. malaccensis leaves from healthy noninoculated tree and investigate its toxicity on oral mucosal cells. A total of 53 compounds were tentatively identified in the extract, some of which have been described in literature as exhibiting anti-inflammatory activity. A number of compounds were identified for the first time in the extract of A. malaccensis leaf, including quercetin, quercetin-O-hexoside, kaempferol-O-dirhamnoside, isorhamnetin-O-hexoside, syringetin-O-hexoside, myricetin, tetrahydroxyflavanone, hesperetin, sissotrin, and lupeol. The antilipoxygenase assay was used to determine the lipoxygenase (LOX) inhibitory potential of the extract, while a WST-1 assay was conducted to investigate the effect of the extract on oral epithelial cells (OEC). The extract implied moderate anti-LOX activity with IC50 value of 71.6 µg/mL. Meanwhile, the cell viability of OEC ranged between 92.55% (10 µg/mL)–76.06% ± (100 µg/mL) upon treatment, indicating some potential toxicity risks. The results attained encourage future studies of the isolation of bioactive compounds from Aquilaria malaccensis leaves, as well as further investigation on the anti-inflammatory mechanisms and toxicity associated with their use.

Bulk zinc oxide (ZnO-BPs) and its nanoparticles (ZnO-NPs) are frequently used in various products for humans. Helisoma duryi embryos can serve as effective model organisms for studying the toxicity of NPs. This study aimed to compare the teratogenic potency of ZnO-BPs and ZnO NPs in the embryonic stages of H. duryi to evaluate the utility of this snail as a bioindicator for ZnO-NPs in the aquatic environment. The mechanisms of teratogenesis were evaluated by determination of the LC 50 , studying the effect of sub-lethal concentrations of both ZnO forms on the embryos, and studying their enzyme activity, oxidative stress, and biochemical analysis. The SDS-PAGE electrophoresis was undertaken to assess the effect of ZnO-BPs and ZnO NPs on protein synthesis. The results revealed that the veliger stage of H. duryi is the specific stage for bulk and nano ZnO. ZnO-NPs proved to be more toxic to snails’ embryos than ZnO-BPs. Exposure to ZnO influences specific types of defects in development, which in the case of BPs are far less drastic than those caused by NPs. Thus, the toxicity of ZnO-NPs in embryonic development is due to their unique physicochemical properties. The observed malformations include mainly hydropic malformation, exogastrulation, monophthalmia, shell misshapen, and cell lyses. Almost all tested oxidative biomarkers significantly changed, revealing that ZnONPs display more oxidative stress than ZnO-BPs. Also, the low concentration of ZnO induces many disturbances in the organic substances of veliger larvae, such as a decrease in the total protein and total lipid levels and an increase in the glycogen level. The results indicated that ZnO-BPs increase the number of protein bands. Conversely, ZnO-NPs concealed one band from treated egg masses, which was found in the control group. Embryos of snail are an appropriate model to control freshwater snails. This study demonstrates that H. duryi embryos can serve as effective model organisms to study the toxicity of ZnO-NPs.

Heterozygous pathogenic variants in SLC12A2 are reported in patients with nonsyndromic hearing loss. Recently, homozygous loss-of-function variants have been reported in two patients with syndromic intellectual disability, with or without hearing loss. However, the clinical and molecular spectrum of SLC12A2 disease has yet to be characterized and confirmed. Using whole-exome sequencing, we detected a homozygous splicing variant in four patients from two independent families with severe developmental delay, microcephaly, respiratory abnormalities, and subtle dysmorphic features, with or without congenital hearing loss. We also reviewed the reported cases with pathogenic variants associated with autosomal dominant and recessive forms of the SLC12A2 disease. About 50% of the cases have syndromic and nonsyndromic congenital hearing loss. All patients harboring the recessive forms of the disease presented with severe global developmental delay. Interestingly, all reported variants are located in the c-terminal domain, suggesting a critical role of this domain for the proper function of the encoded co-transporter protein. In conclusion, our study provides an additional confirmation of the autosomal recessive SLC12A2 disease.

Actinopyga maur itiana , Bohadschia marmorata , Holothuria leucospilota , H . edulis , H. atra and H. polii are the abundant sea - cucumbers inhabiting either Red or Mediterranean Sea shore in Egypt. The aim of this study was to elucidate the metabolic content in the tegument of the selected sea - cucumbers using ultra-performance liquid chromatography coupled to high-resolution mass spectrometry (UPLC/HRMS). The identified metabolites included sulfated saponins such as holothurin B1 and 24-dehydroechinoside A and non-sulfated saponins such as bivittoside C and D. Our results showed that B. marmorata is substantially different from all the other species and occupies alone one taxon. Consequently, it can be suggested to reclassify the family Holothuriidae into three subfamilies. The first suggested comprising the genera, Holothuria and Actinopyga , the second includes only genus Bohadschia , whereas the third includes only genus Pearsonothuria . Lipidomic analysis of sea-cucumbers showed high variation in saturated and unsaturated fatty acids (USFAs) between the collected species. H. edulis and B. marmorata showed the highest amount of all identified SFAs. Among the USFAs, palmitoleic, docosatrienoic and linoleic acid were detected in varied amount in most species.

Purpose Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD. Methods We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia. Results The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively. Conclusion Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.

Sickle cell disease (SCD) is associated with alterations in immune phenotypes. CD4+CD28null T lymphocytes have pro-inflammatory functions and are linked to vascular diseases. To assess the percentage of CD4+CD28null T lymphocytes, natural killer cells (NK), and IFN-gamma levels, we compared 40 children and adolescents with SCD with 40 healthy controls and evaluated their relation to disease severity and response to therapy. Patients with SCD steady state were studied, focusing on history of frequent vaso-occlusive crisis, hydroxyurea therapy, and IFN-gamma levels. Analysis of CD4+CD28null T lymphocytes and NK cells was done by flow cytometry. Liver and cardiac iron overload were assessed. CD4+CD28null T lymphocytes, NK cells, and IFN-gamma levels were significantly higher in patients than controls. Patients with history of frequent vaso-occlusive crisis and those with vascular complications had higher percentage of CD4+CD28null T lymphocytes and IFN-gamma while levels were significantly lower among hydroxyurea-treated patients. CD4+CD28null T lymphocytes were positively correlated to transfusional iron input while these cells and IFN-gamma were negatively correlated to cardiac T2* and duration of hydroxyurea therapy. NK cells were correlated to HbS and indirect bilirubin. Increased expression of CD4+CD28null T lymphocytes highlights their role in immune dysfunction and pathophysiology of SCD complications.