Nivolumab as Second-Line Therapy Improves Survival in Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND: Limited data exists for the efficacy and outcomes of nivolumab as a second-line treatment for unresectable hepatocellular carcinoma (uHCC). We aimed to assess the efficacy and safety of nivolumab in patients with uHCC who experienced disease progression during sorafenib treatment. METHODS: In this retrospective, observational, multicenter study, adult Child-Turcotte-Pugh A/7B patients with uHCC who tolerated sorafenib therapy but showed disease progression switched to second-line intravenous nivolumab (n = 42). A similar number of consecutive, unselected patients who were maintained on sorafenib therapy, regardless of tumoral response or progression, served as historical controls (n = 38). The primary endpoint was overall survival (OS, defined as the time from starting sorafenib in either group up to death due to any cause) and analyzed by intention-to-treat. RESULTS: The mean age of the overall cohort was 72.4 ± 10.1 years, of whom 87.5% were males and 58.8% had underlying viral etiology. Patients in the two cohorts were similar, except those who received nivolumab had more co-morbidities (70.0% vs. 15.4%), ECOG-2 status (21.4% vs. 15.8%), BCLC stage C (81.0% vs. 47.4%), and extravascular invasion (54.4% vs. 21.8%) (p < 0.05 for all). More patients in the nivolumab arm were Child-Turcotte-Pugh B (35.7% vs. 21.1%, p = 0.15). Median OS was 22.2 months (95% CI: 8.9-49.8) on second-line nivolumab and 11.0 months (95% CI: 3.6-18.4) on sorafenib alone (HR 1.93; 95% CI: 1.1-3.3, p = 0.014). Median OS after starting nivolumab was 10.2 months, and time-to-progression was 4.9 months (95% CI: 3.2-6.3). CONCLUSION: Nivolumab is an effective second-line treatment option in patients with uHCC who progress on sorafenib, with significantly improved OS. These early real-life data offer encouraging results, similar to those shown in Phase I/IIa clinical trials. Further investigations are warranted for the use of nivolumab as a monotherapy.

Blue Toe Syndrome in Behçet's Disease: A Case Report.

BACKGROUND Vascular Behçet's disease (VBD) is a rare but potentially life-threatening subtype of Behçet's disease that is characterized by multisystemic vasculitis. It primarily affects males with ancestry traced back to regions along the ancient Silk Road. Both arteries and veins, regardless of size, may exhibit complications, including aneurysmal degeneration or occlusion. While venous involvement is observed in two-thirds of VBD cases, arterial complications are notably the most severe and lethal. Arterial aneurysmal degeneration is more common than occlusive complications, with larger arteries being predominantly affected in VBD. Data regarding isolated small-vessel arterial occlusive disease in VBD are limited. Given the rarity of this presentation in this patient population, it becomes mandatory to thoroughly evaluate such patients to differentiate small-vessel vasculitis from other similar diseases, such as Raynaud's phenomenon, which has a different etiology and management and generally has a more benign course. Here, we delineate the concept of isolated small-vessel vasculitis as a cause of blue toe syndrome in patients with VBD. CASE REPORT This report describes a distinctive case of vascular Behçet's disease in a 51-year-old man who initially exhibited unilateral blue toe syndrome, which swiftly progressed to dry gangrene of the toes. Despite reports of large-vessel involvement, there is a paucity of data on isolated small-vessel vasculitis-induced digital ischemia in VBD. CONCLUSIONS This atypical case underscores the necessity of clinical discernment in differentiating inflammatory microvascular occlusive disease from vasospastic Raynaud's syndrome, both of which can complicate Behçet's disease.

Complicated Spigelian hernia presenting with sigmoid colon strangulation: A unique clinical report.

INTRODUCTION AND IMPORTANCE: Spigelian hernias are rare, constituting about 1-2 % of all abdominal wall hernias. They present clinically significant challenges due to their potential for incarceration and strangulation. This case report highlights a unique presentation of a Spigelian hernia involving sigmoid colon strangulation, emphasizing the critical need for awareness and timely intervention. CASE PRESENTATION: A 60-year-old female with hypertension and diabetes presented with severe left abdominal pain, nausea, and vomiting. Examination revealed leukocytosis, neutrophilia, and signs of acute abdomen. CT imaging showed a complicated left lateral abdominal wall hernia containing the sigmoid colon. Surgical intervention included sigmoidectomy with colorectal anastomosis and hernia repair. Postoperative recovery was successful with subsequent elective ileostomy reversal. CLINICAL DISCUSSION: The rarity of Spigelian hernias and their atypical presentations can complicate diagnosis and management. This case was particularly challenging due to the strangulation of the sigmoid colon within the hernial sac. Surgical management was necessary to address the incarcerated bowel segment and prevent further complications. This case underscores the utility of CT scans in diagnosing complex cases and guiding surgical strategy. CONCLUSION: Despite their rarity, Spigelian hernias carry significant risks of strangulation. Prompt diagnosis and treatment are essential to avoid severe complications. This case highlights the importance of including Spigelian hernia in the differential diagnosis for acute abdominal symptoms, especially when they are nonspecific.

Findings on three endocommensal scuticociliates (Protista, Ciliophora) from freshwater mollusks, including their morphology and molecular phylogeny with descriptions of two new species.

Species of the ciliate genera Myxophyllum and Conchophthirus are found as endocommensals of terrestrial and freshwater mollusks, respectively. So far, there have been few studies of these genera and morphological data for most members are often incomplete. In the present work, two new species, Myxophyllum weishanense sp. nov. and Conchophthirus paracurtus sp. nov., and a known species, Conchophthirus lamellidens, were isolated from hosts in Lake Weishan Wetland, China. Taxonomic studies indicate that M. weishanense sp. nov. can be recognized mainly by the combination of about 60 somatic kineties on both ventral and dorsal sides and the presence of caudal cilia. Conchophthirus paracurtus sp. nov. differs from congeners in its body shape and size, having a glabrous area on the posterior right side, and having fewer somatic kineties. In addition, differences in their ITS2 (Internally Transcribed Spacer 2) secondary structures support the discrimination of the two new species from their highly similar congeners. An improved diagnosis for the poorly known species, C. lamellidens is also provided. Phylogenetic analyses reveal that members of the genus Myxophyllum belong to a fully supported clade that is sister to a large, poorly supported clade consisting of Hemispeiridae, Ancistridae, and several lineages of the nonmonophyletic Cyclidiidae. The Myxophyllum clade also includes Protophyra ovicola JQ956552, a possible misidentification. Sequences of the two new Conchophthirus species cluster with other congeners in a fully supported clade that is unrelated to either the 'typical' thigmotrichs or to pleuronematids, thus conflicting with the traditional classification, and may represent an orphan scuticociliate lineage. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-024-00230-4.

Isolated Neutrophilic Urticarial Dermatosis in a Previously Healthy Male: A Case Report.

Neutrophilic urticarial dermatosis (NUD), a variant falling under the larger umbrella of neutrophilic dermatoses (NDs), is characterized by distinctive clinical and histopathological attributes often associated with systemic conditions. This report presents a case of a 45-year-old male with no prior health issues who exhibits both clinical and pathological hallmarks of NUD without any concurrent systemic illness. This singular case illuminates the intricate aspects of NUD, emphasizing the necessity for accurate diagnostic methods and effective treatment strategies.

Study on Regio- and Diastereoselectivity of the 1,3-Dipolar Cycloaddition Reaction of Azomethine Ylide with 2-(Benzo[d]thiazol-2-yl)-3-(aryl)acrylonitrile: Synthesis, Spectroscopic, and Computational Approach.

An unprecedented and efficient three-component 1,3-dipolar cycloaddition reaction using (E)-2-(benzo[d]thiazol-2-yl)-3-(aryl)acrylonitriles 4a-g and an in situ generated azomethine ylide 3 from isatin and N-methylglycine is described. The reaction exhibits exclusive regioselectivity, resulting in the formation of 3'-(benzo[d]thiazol-2-yl)-1'-methyl-2-oxo-4'-(aryl)spiro[indoline-3,2'-pyrrolidine]-3'-carbonitriles regioisomers through exo/endo approaches. The diastereoselectivity of the reaction is highly dependent on the substitution pattern of the phenyl ring in dipolarophiles 4a-g, leading to the formation of exo-/endo-cycloadducts in varying ratios. To understand the stereoselectivity, the transition state structures were optimized using the TS guess geometry with the QST3-based method. The reaction mechanism and regioselectivity were elucidated by evaluating global and local electrophilicity and nucleophilicity descriptors at the B3LYP/cc-pVTZ level of theory, along with considerations based on the HSAB principle. The analysis of global electron density transfer (GEDT) showed that the reactions are polar and electron density fluxes from azomethine ylide 3 toward dipolarophile 4a-g. It was found from the molecular electrostatic potential map (MESP) that at the more favorable transition state, approach of reactants locates the oppositely charged regions over each other resulting in attractive forces between the two fragments. The computational results are consistent with the experimental observations, confirming that the reactions proceed through an asynchronous one-step mechanism.

Effects of nonlinear thermal radiation on the efficiency of building integrated photovoltaic systems with nanofluid cooling.

The nonlinear effects of thermal radiation on the free convection flow of certain nanofluids along a heated wall are studied numerically using an original finite-difference method. Nanofluids are used to improve the performance of flat and curved integrated photovoltaic modules. The partial differential equations governing the flow are difficult to solve due to the strong non-linearity of the radiative term. In contrast to previous studies, the problem is solved directly without linearization by Rosseland's nonlinear approximation. The proposed numerical method is validated with results from the literature. The effects of nonlinearity and various physical parameters such as time, volume fraction and radiation parameter on the velocity, temperature, Nusselt number and skin friction coefficient of the CuO-water nanofluid are analyzed and presented graphically. A comparative study between the solutions given by the linear and non-linear problems reveals that Rosseland's linear approximation is no longer valid when the effect of thermal radiation is significant. On the other hand, the non-linear model better reflects the physical phenomena involved in the cooling process. Finally, a comparison of the performance of five nanofluids (CuO, Ag, Al2O3, Cu and TiO2 in water) shows that the Cu-water nanofluid performs best, with a high heat transfer rate and low shear stresses.

Neuroprotective Effect of Brivaracetam and Perampanel Combination on Electrographic Seizures and Behavior Anomalies in Pentylenetetrazole-Kindled Mice.

Pentylenetetrazole (PTZ)-induced kindling is a broadly used experimental model to study the anticonvulsive potential of new and existing chemical moieties with the aim of discovering drugs hindering seizure progression and associated neurological comorbidities. In the present study, the impact of brivaracetam (BRV) (10 and 20 mg/kg) as monotherapy as well as in combination with 0.25 mg/kg of perampanel (PRP) was investigated on seizure progression with simultaneous electroencephalographic changes in PTZ kindling mouse model. Subsequently, mice were experimentally analyzed for anxiety, cognition, and depression after which their brains were biochemically evaluated for oxidative stress. The outcomes demonstrated that BRV alone delayed the kindling process, but BRV + PRP combination significantly (p < 0.0001) protected the mice from seizures of higher severity and demonstrated an antikindling effect. The PTZ-kindled mice exhibited anxiety, memory impairment, and depression in behavioral tests, which were remarkably less (p < 0.001) in animals treated with drug combination (in a dose-dependent manner) as these mice explored central, illuminated, and exposed zones of open-field test, light/dark box, and elevated plus maze. Moreover, memory impairment was demonstrated by kindled mice, which was significantly (p < 0.001) protected by BRV + PRP as animal's spontaneous alteration, object discrimination, and step-through latencies were increased in various tests employed for the assessment of cognitive abilities. The brains of PTZ-kindled mice had increased malondialdehyde and reduced antioxidant enzymes while treatment with BRV + PRP combination prevented kindling-induced elevation in oxidative markers. The outcomes of this study demonstrate that combining the PRP at low dose augmented the antiseizure properties of BRV as both drugs when administered simultaneously hindered the process of kindling by reducing PTZ-induced excessive electrical activity and oxidative stress in the brain.

Barriers to Seeking Mental Health Help in Saudi Arabia: A Systematic Review.

Globally, mental disorders have become a significant burden, affecting a substantial number of individuals. Accessing mental health services is crucial for effective treatment and improving outcomes. However, significant barriers to seeking health services can impede access and contribute to the treatment gap. This systematic review aims to identify and analyze the perceived barriers to seeking mental health services in Saudi Arabia. A comprehensive search was conducted among four databases (PubMed, Web of Science, ProQuest, and Science Direct) to identify relevant studies published between 2018 and 2023. Studies that investigated barriers that could prevent psychiatric patients from seeking mental health services in Saudi Arabia were included. Data extraction and synthesis were performed to identify common themes and barriers. The review included a total of six studies that examined barriers to seeking mental health services in Saudi Arabia. The identified barriers encompassed a range of factors, including stigma, lack of awareness, concerns about confidentiality, limited availability of services, negative attitudes toward professional help, and cultural and religious beliefs. The lack of knowledge, as well as the negative attitude toward mental health care, was a perceived barrier to help-seeking in most studies. Furthermore, stigma was consistently reported as a predominant barrier, preventing individuals from seeking mental health care. This systematic review highlights the barriers to seeking mental health services in Saudi Arabia. Addressing these barriers is essential for improving access to mental healthcare and reducing the treatment gap. Strategies should focus on destigmatization efforts, increasing awareness, ensuring confidentiality and privacy, providing culturally appropriate care, and addressing structural limitations. By implementing these strategies, healthcare systems can improve access to mental health care and the overall well-being of individuals experiencing mental disorders in Saudi Arabia.

Comprehensive pan-cancer analysis reveals VSIR as a candidate immunologic, diagnostic, and prognostic biomarker.

OBJECTIVES: Being a checkpoint, the expression level of V-set immunoregulatory receptor (VSIR) serves as an indicator of the extent of immunosuppression. Our objective was to undertake a pan-cancer analysis to examine the expression, genetic alterations, prognosis, and immunologic features associated with VSIR. METHODS: The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), GEPIA2, UALCAN, OncoDB, Human Protein Atlas (HPA), STRING, DAVID, cell culture, clinical sample collection, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were used. RESULTS: This study comprehensively assessed VSIR across 33 cancers using TCGA and GTEx databases. Differential expression analysis revealed elevated VSIR in several cancers, notably in cholangiocarcinoma, esophageal carcinoma, kidney renal cell carcinoma, and liver hepatocellular carcinoma, while decreased expression was observed in various others. Prognostic analysis highlighted its significant association with reduced overall survival (OS) in ESCA and LIHC. Investigation into cancer stages demonstrated a correlation between VSIR expression and stage in ESCA and LIHC. Promoter methylation analysis indicated decreased VSIR methylation levels in tumors, implicating a role in oncogenesis. Furthermore, subcellular localization predictions, Tumor Mutational Burden (TMB), and Microsatellite Instability (MSI) correlations revealed intriguing insight into VSIR's function. Notably, a positive correlation was identified between VSIR expression and various immune cells in both cancers. Protein-protein interaction (PPI) network construction and gene enrichment analysis elucidated VSIR-associated dysregulated pathways, emphasizing its possible involvement in diverse pathways. Finally, experimental validation using LIHC clinical samples and cell lines confirmed elevated VSIR expression, supporting its oncogenic role. CONCLUSION: Collectively, these findings present a comprehensive understanding of VSIR's diverse roles and potential clinical implications in ESCA and LIHC.

Exploring fluorine-substituted piperidines as potential therapeutics for diabetes mellitus and Alzheimer's diseases.

In the current study, a series of fluorine-substituted piperidine derivatives (1-8) has been synthesized and characterized by various spectroscopic techniques. In vitro and in vivo enzyme inhibitory studies were conducted to elucidate the efficacy of these compounds, shedding light on their potential therapeutic applications. To the best of our knowledge, for the first time, these heterocyclic structures have been investigated against α-glucosidase and cholinesterase enzymes. The antioxidant activity of the synthesized compounds was also assessed. Evaluation of synthesized compounds revealed notable inhibitory effects on α-glucosidase and cholinesterases. Remarkably, the target compounds (1-8) exhibited extraordinary α-glucosidase inhibitory activity as compared to the standard acarbose by several-fold. Subsequently, the potential antidiabetic effects of compounds 2, 4, 5, and 6 were validated using a STZ-induced diabetic rat model. Kinetic studies were also performed to understand the mechanism of inhibition, while structure-activity relationship analyses provided valuable insights into the structural features governing enzyme inhibition. Kinetic investigations revealed that compound 4 displayed a competitive mode of inhibition against α-glucosidase, whereas compound 2 demonstrated mixed-type behavior against AChE. To delve deeper into the binding interactions between the synthesized compounds and their respective enzyme targets, molecular docking studies were conducted. Overall, our findings highlight the promising potential of these densely substituted piperidines as multifunctional agents for the treatment of diseases associated with dysregulated glucose metabolism and cholinergic dysfunction.

Mycobacterium avium paratuberculosis Infection Suppresses Vitamin D Activation and Cathelicidin Production in Macrophages through Modulation of the TLR2-Dependent p38/MAPK-CYP27B1-VDR-CAMP Axis.

BACKGROUND: Vitamin D plays a vital role in modulating both innate and adaptive immune systems. Therefore, vitamin D deficiency has been associated with higher levels of autoimmune response and increased susceptibility to infections. CYP27B1 encodes a member of the cytochrome P450 superfamily of enzymes. It is instrumental in the conversion of circulating vitamin D (calcifediol) to active vitamin D (calcitriol). This is a crucial step for macrophages to express Cathelicidin Anti-microbial Peptide (CAMP), an anti-bacterial factor released during the immune response. Our recent study indicated that a Crohn's disease (CD)-associated pathogen known as Mycobacterium avium paratuberculosis (MAP) decreases vitamin D activation in macrophages, thereby impeding cathelicidin production and MAP infection clearance. The mechanism by which MAP infection exerts these effects on the vitamin D metabolic axis remains elusive. METHODS: We used two cell culture models of THP-1 macrophages and Caco-2 monolayers to establish the effects of MAP infection on the vitamin D metabolic axis. We also tested the effects of Calcifediol, Calcitriol, and SB203580 treatments on the relative expression of the vitamin D metabolic genes, oxidative stress biomarkers, and inflammatory cytokines profile. RESULTS: In this study, we found that MAP infection interferes with vitamin D activation inside THP-1 macrophages by reducing levels of CYP27B1 and vitamin D receptor (VDR) gene expression via interaction with the TLR2-dependent p38/MAPK pathway. MAP infection exerts its effects in a time-dependent manner, with the maximal inhibition observed at 24 h post-infection. We also demonstrated the necessity to have toll-like receptor 2 (TLR2) for MAP infection to influence CYP27B1 and CAMP expression, as TLR2 gene knockdown resulted in an average increase of 7.78 ± 0.88 and 13.90 ± 3.5 folds in their expression, respectively. MAP infection also clearly decreased the levels of p38 phosphorylation and showed dependency on the p38/MAPK pathway to influence the expression of CYP27B1, VDR, and CAMP which was evident by the average fold increase of 1.93 ± 0.28, 1.86 ± 0.27, and 6.34 ± 0.51 in their expression, respectively, following p38 antagonism. Finally, we showed that calcitriol treatment and p38/MAPK blockade reduce cellular oxidative stress and inflammatory markers in Caco-2 monolayers following macrophage-mediated MAP infection. CONCLUSIONS: This study characterized the primary mechanism by which MAP infection leads to diminished levels of active vitamin D and cathelicidin in CD patients, which may explain the exacerbated vitamin D deficiency state in these cases.

Aflatoxin B1 exposure deteriorates immune abnormalities in a BTBR T+ Itpr3tf/J mouse model of autism by increasing inflammatory mediators' production in CD19-expressing cells.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficiencies in communication, repetitive and stereotyped behavioral patterns, and difficulties in reciprocal social engagement. The presence of immunological dysfunction in ASD has been well established. Aflatoxin B1 (AFB1) is a prevalent mycotoxin found in food and feed, causing immune toxicity and hepatotoxicity. AFB1 is significantly elevated in several regions around the globe. Existing research indicates that prolonged exposure to AFB1 results in neurological problems. The BTBR T+ Itpr3tf/J (BTBR) mice, which were used as an autism model, exhibit the primary behavioral traits that define ASD, such as repeated, stereotyped behaviors and impaired social interactions. The main objective of this work was to assess the toxic impact of AFB1 in BTBR mice. This work aimed to examine the effects of AFB1 on the expression of Notch-1, IL-6, MCP-1, iNOS, GM-CSF, and NF-κB p65 by CD19+ B cells in the spleen of the BTBR using flow cytometry. We also verified the impact of AFB1 exposure on the mRNA expression levels of Notch-1, IL-6, MCP-1, iNOS, GM-CSF, and NF-κB p65 in the brain of BTBR mice using real-time PCR. The findings of our study showed that the mice treated with AFB1 in the BTBR group exhibited a substantial increase in the presence of CD19+Notch-1+, CD19+IL-6+, CD19+MCP-1+, CD19+iNOS+, CD19+GM-CSF+, and CD19+NF-κB p65+ compared to the mice in the BTBR group that were treated with saline. Our findings also confirmed that administering AFB1 to BTBR mice leads to elevated mRNA expression levels of Notch-1, IL-6, MCP-1, iNOS, GM-CSF, and NF-κB p65 in the brain, in comparison to BTBR mice treated with saline. The data highlight that exposure to AFB1 worsens immunological abnormalities by increasing the expression of inflammatory mediators in BTBR mice.

Pharmacological Potential of Kaempferol, a Flavonoid in the Management of Pathogenesis via Modulation of Inflammation and Other Biological Activities.

Natural products and their bioactive compounds have been used for centuries to prevent and treat numerous diseases. Kaempferol, a flavonoid found in vegetables, fruits, and spices, is recognized for its various beneficial properties, including its antioxidant and anti-inflammatory potential. This molecule has been identified as a potential means of managing different pathogenesis due to its capability to manage various biological activities. Moreover, this compound has a wide range of health-promoting benefits, such as cardioprotective, neuroprotective, hepatoprotective, and anti-diabetic, and has a role in maintaining eye, skin, and respiratory system health. Furthermore, it can also inhibit tumor growth and modulate various cell-signaling pathways. In vivo and in vitro studies have demonstrated that this compound has been shown to increase efficacy when combined with other natural products or drugs. In addition, kaempferol-based nano-formulations are more effective than kaempferol treatment alone. This review aims to provide detailed information about the sources of this compound, its bioavailability, and its role in various pathogenesis. Although there is promising evidence for its ability to manage diseases, it is crucial to conduct further investigations to know its toxicity, safety aspects, and mechanism of action in health management.

Epilepsy first aid awareness among healthcare workers in Saudi Arabia: A cross-sectional study.

Objectives: Epilepsy is a neurological disorder affecting more than 50 million human lives of all ages, its social, physical and psychological implications is of huge concern. The current study and as a continuation of epilepsy knowledge assessment projects conducted by our research team is aimed to assess the knowledge of healthcare workers regarding epilepsy first aid in Saudi Arabia. Methods: A cross-sectional questionnaire-based study was carried out from 2020 to 2021. Results: During the study period, 272 healthcare workers were recruited; participants were males and females from different nationalities in various Saudi Arabian cities, possess diverse qualifications, and belong to several healthcare-related professions. The question, "Did you witness an epileptic seizure"? was answered as "Yes" by 42% of participants, and in response to the question "If you know that this patient struggles during seizure attacks," 58% of respondents stated that they would not call an ambulance. Moreover, the question "Put something in his/her mouth to prevent tongue biting" was incorrectly answered as "Yes" by 42% of respondents, and the question "Try to catch him/her and stop his/her movement" in order to control the attack was answered "Yes" by 21% of respondents. Furthermore, almost 90% of healthcare participants do not know how to use the Vagus Nerve Stimulation device. The mean knowledge score among participants was 23.7; sex, as well as type of higher qualification obtained, was found to be significantly associated with the score of knowledge. Conclusion: Knowledge toward epilepsy and epilepsy first aid among healthcare workers in Saudi Arabia was found fragile. Further research is appreciated to support the current findings.

Unveiling the unexplored novel signatures for osteoporosis via a detailed bioinformatics and molecular experiments based approach.

BACKGROUND: Osteoporosis (OP) stands as a prevalent bone ailment affecting the elderly, globally. The identification of reliable diagnostic markers crucially aids OP clinical management. METHODS: Utilizing the GEO database (GSE35959), we acquired expression profiles for OP and normal samples. Differential expression genes (DEGs) and hub genes were pinpointed through STRING, GEO2R, and Cytoscape. The competing endogenous RNA (ceRNA) network was constructed using miRTarBase, miRDB, and MiRcode databases. Gene Ontology (GO) and KEGG pathway enrichment analyses were performed via DAVID. Validation involved clinical OP samples from the Pakistani population, with Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) assessing hub gene expression. RESULTS: A total of 2124 differentially expressed genes (DEGs) were identified between OP and normal samples in GSE35959. The selected hub genes among these DEGs were Splicing Factor 3a Subunit 1 (SF3A1), Ataxin 2 Like (ATXN2L), Heat Shock Protein 90 Beta Family Member 1 (HSP90B1), Cluster of Differentiation 74 (CD74), DExH-Box Helicase 29 (DHX29), ALG5 Dolichyl-Phosphate Beta-Glucosyltransferase (ALG5), NudC Domain Containing 2 (NUDCD2), and Ras-related protein Rab-2A (RAB2A). Expression validation of these genes on the Pakistani OP patients revealed significant up-regulation of SF3A1, ATXN2L, and CD74 and significant (P < 0.05) down-regulation of HSP90B1, DHX29, ALG5, NUDCD2, and RAB2A in OP patients. Receiver operating characteristic (ROC) analysis demonstrated that these hub genes displayed considerable diagnostic accuracy for detecting OP. The ceRNA network analysis of the hub genes revealed some important hub genes' regulatory miRNAs and lncRNAs. Via KEGG analysis, hub genes were found to be enriched in N-Glycan biosynthesis, Thyroid hormone synthesis, IL-17 signaling pathway, Prostate cancer, AMPK signaling pathway, Spliceosome, Estrogen signaling pathway, and Fluid shear stress and atherosclerosis, etc., pathways. CONCLUSION: The identified eight hub genes in the present study could reliably distinguish OP patients from normal individuals, which may provide novel insight into the diagnostic research of OP.

Improvement of phenolic profile and biological activities of wild mustard sprouts.

The current study aimed to assess the effect of the germination process of wild mustard seeds on the phenolic profile, antioxidant, antibacterial, and antidiabetic properties, and some relevant enzyme activities. The total phenolic and flavonoid contents increased 5- and 10-fold, respectively, and were maximized on 5-days sprouts. One new phenolic compound was identified on 5-days sprout extract using HPLC. The concentrations of the identified phenolic compounds increased 1.5-4.3 folds on 5-days sprouts compared with dry seeds. The total antioxidant activity multiplied 17- and 21-fold on 5-days sprouts using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) assays, respectively. The activity of carbohydrate-cleaving, phenolic-synthesizing and antioxidant enzymes also increased during germination. On 5-days sprouts, there was a substantial correlation between the highest ß-glucosidase and peroxidase activities with highest phenolic and flavonoid levels and maximum antioxidant activity. The phenolic extract of 5-days sprouts exhibited antimicrobial activities against Escherichia coli and Staphylococcus aureus and showed potent antidiabetic activity established by its inhibitory effect against α-amylase and α-glucosidase compared to dry seeds.

Dapagliflozin suppresses diabetes-induced oxidative DNA damage and hypermethylation in mouse somatic cells.

Diabetes mellitus is a complex metabolic disorder resulting from the interplay of environmental, genetic, and epigenetic factors that increase the risk of cancer development. However, it is unclear whether the increased cancer risk is due to poor glycemic control or the use of some antidiabetic medications. Therefore, we investigated the genetic and epigenetic changes in somatic cells in a mouse model of diabetes and studied whether multiple exposures to the antidiabetic medication dapagliflozin influence these changes. We also elucidated the mechanism(s) of these ameliorations. The micronucleus test and modified comet assay were used to investigate bone marrow DNA damage and methylation changes. These assays revealed that dapagliflozin is non-genotoxic in the tested regimen, and oxidative DNA damage and hypermethylation were significantly higher in diabetic mice. Spectrophotometry also evaluated oxidative DNA damage and global DNA methylation, revealing similar significant alterations induced by diabetes. Conversely, the dapagliflozin-treated diabetic animals significantly reduced these changes. The expression of some genes involved in DNA repair and DNA methylation was disrupted considerably in the somatic cells of diabetic animals. In contrast, dapagliflozin treatment significantly restored these disruptions and enhanced DNA repair. The simultaneous effects of decreased oxidative DNA damage and hypermethylation levels suggest that dapagliflozin can be used as a safe antidiabetic drug to reduce DNA damage and hypermethylation in diabetes, demonstrating its usefulness in patients with diabetes to control hyperglycemia and decrease the development of its subsequent complications.

MAFLD: an ideal framework for understanding disease phenotype in individuals of normal weight.

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is significant, impacting almost one-third of the global population. MAFLD constitutes a primary cause of end-stage liver disease, liver cancer and the need for liver transplantation. Moreover, it has a strong association with increased mortality rates due to various extrahepatic complications, notably cardiometabolic diseases. While MAFLD is typically correlated with obesity, not all individuals with obesity develop the disease and a significant percentage of MAFLD occurs in patients without obesity, termed lean MAFLD. The clinical features, progression and underlying physiological mechanisms of patients with lean MAFLD remain inadequately characterized. The present review aims to provide a comprehensive summary of current knowledge on lean MAFLD and offer a perspective on defining MAFLD in individuals with normal weight. Key to this process is the concept of metabolic health and flexibility, which links states of dysmetabolism to the development of lean MAFLD. This perspective offers a more nuanced understanding of MAFLD and its underlying mechanisms and highlights the importance of considering the broader metabolic context in which the disease occurs. It also bridges the knowledge gap and offers insights that can inform clinical practice.

A systematic review on the associations between the built environment and adult's physical activity in global tropical and subtropical climate regions.

BACKGROUND: Physical inactivity is a major public health concern, exacerbated in countries with a (sub)tropical climate. The built environment can facilitate physical activity; however, current evidence is mainly from North American and European countries with activity-friendly climate conditions. This study explored associations between built environment features and physical activity in global tropical or subtropical dry or desert climate regions. METHODS: A systematic review of four major databases (Web of Science, Scopus, PubMed, and SportDISCUS) was performed. To be included, studies had to investigate associations between perceived or objective built environment characteristics and adult's physical activity and had to be conducted in a location with (sub)tropical climate. Each investigated association was reported as one case and results were synthesized based upon perceived and objectively assessed environment characteristics as well as Western and non-Western countries. Study quality was evaluated using a tool designed for assessing studies on built environment and physical activity. RESULTS: Eighty-four articles from 50 studies in 13 countries with a total of 2546 built environment-physical activity associations were included. Design (connectivity, walking/cycling infrastructure), desirability (aesthetics, safety), and destination accessibility were the built environment characteristics most frequently associated with physical activity across the domains active transport, recreational physical activity, total walking and cycling, and moderate-to-vigorous physical activity, particularly if multiple attributes were present at the same time. Very few studies assessed built environment attributes specifically relevant to physical activity in (sub)tropical climates. Most studies were conducted in Western countries, with results being largely comparable with non-Western countries. Findings were largely generalizable across gender and age groups. Results from natural experiments indicated that relocating to an activity-friendly neighborhood impacted sub-groups differently. CONCLUSIONS: Built environment attributes, including destination accessibility, connectivity, walking and cycling infrastructure, safety, and aesthetics, are positively associated with physical activity in locations with (sub)tropical climate. However, few studies focus on built environment attributes specifically relevant in a hot climate, such as shade or indoor recreation options. Further, there is limited evidence from non-Western countries, where most of the urban population lives in (sub)tropical climates. Policy makers should focus on implementing activity-friendly environment attributes to create sustainable and climate-resilient cities.