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Emerging evidence indicates group-specific component (GC) variants are associated with ethnicity. We aimed to investigate the association of GC variants and protein expression level with T2DM and diabetic nephropathy (DN) in Saudi patients. A total of 200 participants (120 T2DM/80 controls) were genotyped for GC-rs7041/GC-rs4588 by real-time polymerase chain reaction. Serum GC was assessed by ELISA and in silico analysis was executed. GC-rs7041 frequency distribution showed no difference between the study groups, while GC-rs4588 showed association with T2DM under all genetic models. rs4588*AA variant was correlated with higher serum GC globulin, albuminuria, and poor glycaemic control. A higher frequency of rs7041*TT and rs4588*AA was evident in macroalbuminuria vs. normoalbuminuria group. Carrying GC-2 haplotype was 2.5 more likely to develop diabetes and correlated with the levels of albuminuria. GC variants could have independent effects on the risk of T2DM and DN in the study population. [ABSTRACT FROM AUTHOR]

The current study investigated the immunomodulating and osteoblast differentiation potential of the natural compounds from Leea macrophylla (LMN). Immunomodulatory effects have been investigated by the phagocytosis of Candida albicans using polymorphonuclear neutrophil cells in the in vitro slide method. A bioactivity‐guided fractionation technique was used to evaluate the stimulating effect of L. macrophylla methanol extract on osteoblast differentiation using mouse osteoblastic cells. A low dose of LMN was found to stimulate the phagocytic effect better than a higher dose. The natural compounds from L. macrophylla have significantly increased alkaline phosphatase (ALP) and osteocalcin activities. The LMN promoted the osteoblast differentiation through upregulation of ALP, osteocalcin, and type 1 collagen in a dose‐dependent manner. These natural compounds also upregulated ALP, osteocalcin, and type 1 collagen gene expressions. The data suggest that LMN has potential anabolic sequel on bone formation and osteoblast differentiation. [ABSTRACT FROM AUTHOR]

Antipsychotics (APs) are widely used medications with reported diabetogenic side effects. This study investigated the effect of commonly used APs, namely chlorpromazine (CPZ), haloperidol (HAL) and clozapine, on the bioenergetics of male CD1 mice isolated pancreatic beta cells as an underlying mechanism of their diabetogenic effects. The effect of APs on Alamar blue reduction, adenosine triphosphate (ATP) production and glucose‐stimulated insulin secretion (GSIS) of isolated beta cells was evaluated. Then, the effects of APs on the activities of mitochondrial complexes and their common coding genes expression, oxygen consumption rate (OCR), mitochondrial membrane potential (MMP) and lactate production were investigated. The effects of APs on the mitochondrial membrane fluidity (MMF) and mitochondrial membrane fatty acid composition were also examined. Results showed that the tested APs significantly decreased cellular ATP production and GSIS of the beta cells. The APs significantly inhibited the activities of mitochondrial complexes and their coding gene expression, MMP and OCR of the treated cells, with a parallel increase in lactate production to different extents with the different APs. CPZ and HAL showed increased MMF and mitochondrial membrane polyunsaturated fatty acid content. In conclusion, the tested APs‐induced mitochondrial disruption can play a role in their diabetogenic side effect. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) is a major risk factor for end-stage renal disease (ESRD). MicroRNAs (miRNAs/miRs) and their variants may be implicated in health and disease, including DN. The present study aimed to investigate the association of the miRNA-499a gene (MIR499A) A/G seed region variant (rs3746444) with DN-associated ESRD susceptibility in patients with diabetes mellitus, and to determine whether there was an association between the different genotypes and the patients' laboratory and clinical data. A case-control pilot study was conducted on 180 adult patients with type 2 diabetes mellitus. A total of 90 patients with ESRD on regular hemodialysis were considered as the cases, and 90 age-, sex- and ethnicity-matched diabetic patients with normo-albuminuria were considered as the controls. MIR499A genotyping was performed using a TaqMan Real-Time allele discrimination assay. Results demonstrated that the MIR499A rs3746444*G variant conferred susceptibility to the development of ESRD under co-dominant [(odds ratio (95% confidence interval): 2.49 (1.41-3.89) and 2.41 (1.61-6.68) for heterozygous and homozygous comparison, respectively], dominant [2.30 (1.18-3.90)] and allelic [1.82 (1.17-2.83)] models. Different genotypes of the specified variant did not exhibit significant associations with the clinic-laboratory data of the studied patients or the circulating miR-499a plasma levels. In conclusion, results of the present study suggested that MIR499A rs3746444 may be a susceptibility variant for DN-associated ESRD in the study population. However, larger sample size studies with different ethnicities are warranted to verify these findings. [ABSTRACT FROM AUTHOR]

Background: The antiretroviral protease inhibitor drug, lopinavir (LPV), is used to treat HIV-1 infection. LPV is known to have limited oral bioavailability, which may be attributed to its poor aqueous solubility, low efficacy and high first-pass metabolism. Self-nanoemulsifying drug delivery systems (SNEDDS) for LPV have been developed and optimised to counter the current issues., Methods: The titration method was used to prepare LPV-loaded SNEDDS (LPV-SNEDDS). Six different pseudo-ternary phase diagrams were constructed to identify the nanoemulsifying region. The developed formulations were chosen in terms of globule size < 100 nm, dispersity ≤ 0.5, dispersibility (Grade A) and% transmittance > 85. Heating-cooling cycle, freeze-thaw cycle, and centrifugation studies were performed to confirm the stability of the developed SNEDDS., Results: The final LPV-SNEDDS (L-14) droplet size was 58.18 ± 0.62 nm, with polydispersity index, zeta potential, and entrapment efficiency (EE%) values of 0.326 ± 0.005, -22.08 ± 1.2 mV, and 98.93 ± 1.18%, respectively. According to high-resolution transmission electron microscopy (HRTEM) analysis, the droplets in the optimised formulation were < 60 nm in size. The selected SNEDDS released nearly 99% of the LPV within 30 min, which was significantly (p < 0.05) higher than the LPV-suspension in methylcellulose (0.5% w/v). It indicates the potential use of SNEDDS to enhance the solubility of LPV, which eventually could help improve the oral bioavailability of LPV. The Caco-2 cellular uptake study showed a significantly (p < 0.05) higher LPV uptake from the SNEEDS (LPV-SNEDDS-L-14) than the free LPV (LPV-suspension)., Conclusion: The LPV-SNEDDS could be a potential carrier for LPV oral delivery., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

MicroRNA machinery genes Argonaute 1 ( AGO1 ) and 2 ( AGO2 ) are associated with several hallmarks of cancer. They play a key role in transcriptomic silencing, regulation of the immune system, cell differentiation, and angiogenesis processes. The present pilot study aims to explore the impact of genetic variants rs636832 and rs2977490 of AGO1 and AGO2 , respectively, on breast cancer (BC) risk in a sample of Mediterranean population. TaqMan genotyping assay of 93 consecutive breast cancer female patients and age- as well as ethnicity-matched controls, was done by Real-Time allele discrimination polymerase chain reaction. Association with the available clinical, histopathological and immunohistochemistry assessments was applied. In silico data analysis was also executed. Although allele and genotype frequencies distribution of both study variants were comparable in BC and healthy control cohorts, AGO1*G variant conferred a significant BC risk under recessive model [adjusted odds ratio (95% confidence interval); 4.90 (1.03-23.39), P = 0.024], and was significantly associated with lymph node infiltration ( P = 0.037), distant metastasis ( P = 0.019), advanced clinical stage ( P < 0.001), recurrence ( P = 0.032), and shorter overall survival ( P = 0.001). Furthermore, AGO2*G/G genotype showed an association with poor pathological grade ( P = 0.029). Our results suggested for the first time that rs636832 and rs2977490 variants of the miRNA-machinery genes AGO1 and 2 , respectively, may impact susceptibility and/or clinical outcomes of BC patients in the study population., Competing Interests: None., (AJTR Copyright © 2020.)