Development Of Disease Research Articles

#1895 Elucidating Asprosin's role as an intracellular metabolism regulator in diabetes and obesity-induced renal damage

Abstract Background and Aims Asprosin, an adipokine with a multifaceted function that encompasses inducing insulin resistance, promoting inflammation, and stimulating appetite, is the focus of our investigation. We seek to establish its pivotal role as a mediator in regulating cellular energy metabolism, particularly in the context of renal damage induced by diabetes and obesity. Method We conducted experiments using type 2 diabetic db/db mice and obesity-induced high-fat diet mice. These animal models were categorized into two groups: one received Asprosin neutralizing antibodies (250 μg/mouse/21 days), targeting the 28-amino acid peptide located proximal to Asprosin's C-terminus (KKKELNQLEDRYDKDYLSGELGDNLKMK), while the other received an AMPK activator (Metformin) associated with the regulation of Asprosin receptors (OLFR734/G proteins-cAMP-PKA). Additionally, we cultured renal constituent cells (mesangial cells, glomerular endothelial cells) in high glucose and palmitic acid conditions and silencing Asprosin expression using siRNA. We assessed the levels of Asprosin, AMPK, and their respective downstream signaling pathways. Results Asprosin was found to be overexpressed in the serum and kidney tissues of both db/db mice and high-fat diet mice, as well as in renal constituent cells cultured under high glucose and palmitic acid conditions. Interfering with Asprosin led to reduced body and liver weight in mice, improved glucose tolerance, and mitigated renal injury in vivo. Asprosin knockdown ameliorated lipid accumulation and inflammatory infiltration, both in vitro and in vivo. Moreover, Asprosin absence activated the AMPK/Sirts/mTOR signaling pathway, while the AMPK activator Metformin reversed the effects of Asprosin on lipid accumulation and inflammatory response, confirming Asprosin's direct role in intracellular lipid metabolism. Conclusion The mechanism of intracellular energy metabolism regulation mediated by Asprosin presents promising potential for targeted organ therapy in the development and prevention of diabetic kidney disease. Inhibiting Asprosin suppressed lipid accumulation and inflammation in diabetic kidney disease through the activation of AMPK-associated signaling pathway.

#1425 Anemia in patients with IgA nephropathy: an impact on the prognosis of IgA nephropathy

Abstract Background and Aims Immunoglobulin A Nephropathy (IgAN) has several well-known predictors of renal outcomes, including persistent proteinuria, hypertension, and baseline eGFR at the time of diagnosis. However, the effect of hemoglobin (Hb) levels on the progression of IgAN is rarely reported. This study aims to evaluate the impact of Hb levels on the prognosis of IgAN and to identify risk factors for anemia in patients with IgAN. Method A retrospective analysis of the data of 855 patients diagnosed with IgAN at Kyungpook National University Hospital between January 2002 and December 2021 was performed. We obtained the data on clinical parameters and pathological findings according to the Oxford classification at the time of the kidney biopsy. Univariate and multivariate logistic regression analyses were used to evaluate the risk factors for anemia, and a Cox proportional hazard model was used to estimate the effects of anemia on the development of end-stage kidney disease (ESKD). Results Lower serum albumin, lower eGFR, severe interstitial fibrosis, and tubular atrophy were associated with anemia in patients with IgAN. The Kaplan-Meier survival curve revealed that patients with anemia had worse renal survival than those without anemia. The multivariable Cox analysis showed that anemia was an independent risk for the progression to ESKD (HR 2.86, confidence interval 1.58–5.17, p = 0.001). In a sex-specific analysis, only the female sex showed a significant and higher risk for ESKD (hazard ratio 4.07, confidence interval 1.53–10.8, p = 0.005). Conclusion A low Hb level at the time of biopsy, even if subclinical, was an independent risk factor for the development of ESKD in patients with IgAN. Therefore, it is necessary to monitor Hb levels at the time of diagnosis and take proactive measures to reduce the risk of disease progression.

Dose-response relationship between physical activity and the morbidity and mortality of cardiovascular disease among individuals with diabetes: A meta-analysis of prospective cohort studies.

Diabetes, a chronic condition affecting various organs, is frequently associated with abnormal lipid metabolism, notably increased cholesterol and triglyceride levels. These lipid abnormalities are closely linked to the development and advancement of cardiovascular disease (CVD). Although regular physical activity (PA) has consistently shown benefits in reducing CVD risk in the general population, its precise influence on CVD risk among diabetic patients remains uncertain, particularly regarding dose-response relationships. This study aimed to summarize the evidence from prospective studies on the association between PA and CVD morbidity and mortality in individuals with diabetes, and to explore the optimal levels for public health recommendation. We systematically reviewed prospective cohort studies in PubMed, EMBASE, and Web of Science up to December 2022, with inclusion criteria specifying the studies published in English and included adult participants diagnosed with diabetes. A random-effects model was used to pool the relative risk (RR) with the corresponding 95% confidence interval (CI) comparing the highest with the lowest PA categories in each study for qualitative evaluation. In addition, linear and spline regression analyses were used to estimate dose-response associations. The meta-analysis included 12 prospective cohort studies, involving a total of 109,820 participants with diabetes. The combined results revealed that higher levels of PA were associated with a reduced risk of CVD. The RR of CVD for the highest compared with the lowest PA category was 0.62 (95% CI, 0.51-0.73). In addition, there were four studies describing leisure-time physical activity (LTPA) and the pooled RR was 0.68 (95% CI, 0.52-0.83) for the highest versus the lowest activity. The linear regression model revealed that each 10 MET-h/week of incrementally higher PA was associated with a 19.0% (95% CI, 11.6%-25.7%) and a 6.9% (95% CI, 4.5%-9.3%) reduction in CVD morbidity and mortality. Additionally, spline regression curves showed nonlinear relationships between PA levels and the risk of CVD and CVD mortality (both P-nonlinearity <0.001), with a limited reduction in CVD risk and some further reduction in CVD mortality above 20 MET-h per week of PA levels. For patients with diabetes, especially type 2 diabetes, there was a dose-response relationship between increased PA and reduced risk of CVD morbidity and mortality. The observed PA threshold is consistent with the recommended level for the general population. Gradually moving from inactivity to a guideline-recommended PA level could therefore significantly reduce the burden of CVD in patients with diabetes.

#970 The impact of VEGF signalling pathway inhibitors and/or immune checkpoint inhibitors on kidney function over time

Abstract Background and Aims Treatment with vascular endothelial growth factor signalling pathway inhibitors (VSPI) and immune checkpoint inhibitors (ICI) has transformed outcomes in advanced kidney cancer. VSPI and ICI can both independently cause side effects that are risk factors for development or progression of chronic kidney disease (CKD). We analysed estimated glomerular filtration rate (eGFR) decline in people with kidney cancer following treatment with VSPI or ICI. Methods We linked routine healthcare databases in the West of Scotland, UK (spanning 2010–2020, population 1.4 million) to identify adults with advanced kidney cancer who received a VSPI and/or ICI. In the two years following therapy initiation, eGFR slope (defined as annualised rate of change in eGFR) was modelled using linear mixed-effects models for the whole group and subgroups of people who had nephrectomy, metastatic cancer and a baseline eGFR &amp;lt;60 mL/min/1.73 m² prior to systemic therapy. Additional outcomes were studied using competing risk regression considering the competing risk of death: 40% decline in eGFR, de-novo proteinuria (urine albumin creatinine ratio &amp;gt;3 mg/mmol), and progression to eGFR &amp;lt;15 mL/min/1.73 m2. The risk of all-cause mortality was estimated with Cox regression models. Results We studied 357 adults (62.5% male; median age 63.0 years, IQI 55.0-71.0) with kidney cancer who were treated with either VSPI and/or ICI. The median baseline eGFR before systemic therapy was 74.6 mL/min/1.73 m² (58.3-91.9) and most received VSPI monotherapy (86.0%). On average, eGFR remained relatively stable over time (average annual increase +1.03 mL/min/1.73 m²/year: 95% CI −1.64 to +3.70, p = 0.2). People who had nephrectomy prior to systemic therapy demonstrated the largest average increase in eGFR (+2.30 mL/min/1.73 m²/year: 95% CI −1.66 to + 6.26). People with baseline eGFR &amp;lt;60 mL/min/1.73 m² prior to systemic therapy had a small decline (−1.02 mL/min/1.73 m²/year: 95% CI −6.55 to +4.50) in eGFR (Fig. 1). A ≥40% decline in eGFR occurred in 82 people (23.0%) within one year of starting systemic therapy. People with diabetes were more likely to experience a ≥40% decline in eGFR (subdistribution HR 1.89: 95% CI 1.05-3.41, p = 0.04). A decline in eGFR to &amp;lt;15 mL/min/1.73 m² or kidney failure with replacement therapy was found in 4 (1.1%) people. Among the 75 people assessed for proteinuria, 30.2% developed de-novo microalbuminuria. Median overall survival was 1.36 years (IQI 1.11-1.75 years), but this was longer in people who had nephrectomy prior to systemic therapy: 2.13 years (IQI 1.82–2.57 years). A 40% acute or chronic decline in eGFR was not associated with increased hazards of death on univariable or multivariable analysis (adjusted HR: 1.11: 95% CI 0.85-1.46, p = 0.4). Conclusion Despite case series and prescribing guidelines highlighting adverse impact of VSPI/ICI therapy on kidney function, our results demonstrate that there is no significant impact on the average change in eGFR but highlights that people with diabetes are at higher risk of clinically significant renal events. With appropriate monitoring, more widespread use of these agents in patients with renal impairment may be warranted.

#1493 Upregulated miR-205 as a biomarker of diet-induced obesity-related glomerulopathy

Abstract Background and Aims Obesity is a modifiable risk factor for the development and progression of chronic kidney disease (CKD). Pathways through which obesity might cause renal disease are not completely understood, as not all obese subjects develop CKD. In terms of deepening the knowledge of the preliminary steps of obesity-related renal damage, our group has developed a diet-induced obese murine model with obesity related glomerulopathy (ORG). The objective of this study was to investigate ORG at a cellular, structural and transcriptomic level as a way to discover the triggering pathogenic phenomena of ORG and evaluate potential biomarkers. Method Thirty Wistar rats were randomized into two groups: control rats (n = 15), which were fed with standard diet (SD) and study rats (n = 15), which were fed with high-fat diet (HFD). After 10 weeks, weight, parameters of kidney function, renal histological features, transcriptomic changes, miRNA and mRNA isolation were compared. Results HFD gained significantly more weight (55.8%) than SD(29.2%), p = 0.001. Albuminuria was also significantly higher in HFD (10,384.04) compared with SD (5,845.45), p = 0.001. HFD rats showed typical lesions of early-stages of ORG, with a predominance of mesangial matrix increase (MMI) and podocyte hypertrophy (PH). All histologic lesions correlated with genes differentially expressed (DE) in kidneys of HFD group and, both MMI and PH, also correlated with specific miRNAs DE in the urine of HFD group. The functional analysis showed 4 miRNAs DE in the kidneys of HFD group that negatively regulates PTEN gene, which promotes podocyte endocytosis of lipids in ORG. The electronic microscope confirmed the spaces of lipid vacuoles in the podocytes of HFD rats. Between those 4 miRNAs DE, miR-205 was also found to be upregulated in the urine of HFD group. Conclusion Wistar rats fed with HFD for 10 weeks developed early-stages of ORG, with a specific targetome of miRNAs and gene expression. The upregulation of miR-205 in kidney and its isolation in urine is associated with lipid endocytosis of podocytes, which takes place in the early-stages of ORG and could become a plausible biomarker of early-stages of ORG and open new avenues for future therapeutics research.

#1841 Trimethylamine N-oxide (TMAO) induces the formation of endothelial extracellular vesicles

Abstract Background and Aims Endothelial dysfunction caused by the accumulation of uremic toxins is an important contributor to the development of cardiovascular disease in patients with chronic kidney disease (CKD). The uremic toxin trimethylamine n-oxide (TMAO) is associated with oxidative stress, vascular calcification, and inflammation, triggering the release of several proinflammatory molecules and Extracellular Vesicles (EVs). Clinical studies have shown that patients with CKD have high levels of circulating EVs, however, their role is still poorly understood. In this dysfunctional scenario, EVs can be used as damage biomarkers for CKD, as they carry information from their cells of origin. Here, we aim to elucidate the formation of EVs in endothelial cells exposed to TMAO. Method Human endothelial cells (EA.hy926, ATCC CRL-2922) were exposed for 24 h with TMAO at uremic concentrations (7.49 mg/L). EVs were isolated by differential ultracentrifugation. Protein concentration was analyzed by Pierce™ BCA Protein Assay Kit, and particle size and particle concentration were analyzed by NanoParticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM), and Scanning Electron Microscopy (SEM). EVs were stained with calcein and their internalization in endothelial cells was analyzed with Fluorescence Confocal Microscopy. Results TMAO treatment at uremic concentration induced the formation of EVs with a size of 202.8 ± 3.1 nm (image 1B) and 1.09 × 109 ± 2.68 × 107 particles/mL and a total protein concentration of 88.57 µg/mL. The morphological features of EVs are shown in images 1C-1F. TMAO-induced EVs were incorporated by endothelial cells, being dispersed in the cytoplasm or perinuclear regions (images 1G and end 1H). Conclusion TMAO was able to induce the formation of EVs in endothelial cells, with characteristics morphological features. When compared to control EVs (image 1A), TMAO-EVs have a more heterogeneous size, which indicate a change in the size pattern, and thus the nature of the EVs induced by TMAO. TMAO-EVs were able to be internalized by human endothelial cells. This uptake can be closely related to the effects of EVs in endothelial cells, but more experiments need to be performed. Taken together, these data could contribute to understanding how the formation and uptake of TMAO-EVs by the endothelium occurs, relating their effects to the cardiovascular complications of CKD.

Menthol-Modified Quercetin Liposomes with Brain-Targeting Function for the Treatment of Senescent Alzheimer's Disease.

Oxidative stress and neuroinflammation in the aging brain are correlated with the development of neurodegenerative diseases, such as Alzheimer's disease (AD). The blood-brain barrier (BBB) poses a significant challenge to the effective delivery of therapeutics for AD. Prior research has demonstrated that menthol (Men) can augment the permeability of the BBB. Consequently, in the current study, we modified Men on the surface of liposomes to construct menthol-modified quercetin liposomes (Men-Qu-Lips), designed to cross the BBB and enhance quercetin (Qu) concentration in the brain for improved therapeutic efficacy. The experimental findings indicate that Men-Qu-Lips exhibited good encapsulation efficiency and stability, successfully crossed the BBB, improved oxidative stress and neuroinflammation in the brains of aged mice, protected neurons, and enhanced their learning and memory abilities.

#1029 Factors associated with chronic kidney disease in patients with recurrent kidney stones: a case-control study

Abstract Background and Aims Kidney stones have been described in multiple studies as an independent risk factor for chronic kidney disease (CKD). However, this relationship remains partially understood, and there is limited local, regional, and national information available. While common factors contribute to both kidney stones and CKD development, other factors favoring CKD occurrence in patients with recurrent renal lithiasis have been reported. This study aimed to identify factors associated with chronic kidney disease in patients with recurrent renal lithiasis in the city of Cartagena, Colombia. Method This was an observational nested case-control study within a cohort, where cases were patients diagnosed with recurrent kidney stones who developed CKD during follow-up, and controls were patients with recurrent kidney stones without CKD during follow-up. The cohort comprised all adult patients with recurrent kidney stones between 2010 and 2019, without an initial diagnosis of CKD, and with a minimum follow-up period of two years or more. Data on demographic variables (age, gender, type of insurance), clinical factors (overweight, history of hyperuricemia, diabetes mellitus, hypertension, dyslipidemia, alcohol consumption, smoking, exercise habits), and variables related to recurrent kidney stones (course of kidney stones, onset time of CKD, metabolic disorders, history of renal colic, stone localization, number, and size) were collected. Variables associated with the development of chronic kidney disease were identified using association measures via the chi-square test. Variables of clinical and statistical significance were further analyzed for association using multivariable logistic regression. Results The study included 31 cases and 39 controls, with mean ages of 65.2±11.5 and 51.8±14.6 years, respectively (p=0.00002). The duration of recurrent kidney stones was 174.7±148.6 and 163.3±129.5 months for cases and controls (p=0.738). The onset time of CKD was 61.1±35.4 months. Among cases, 93.5% were men, 77.4% were hypertensive, and 67.9% had dyslipidemia, significantly differing from the controls (see Table 1). There were no differences between cases and controls concerning the duration of recurrent kidney stones, type of health insurance, overweight status, hyperuricemia, diabetes mellitus, exercise habits, metabolic study alterations, history of renal colic, renal stone localization, number, and size. The difference was borderline for alcohol consumption and smoking habits. Multivariable logistic regression, incorporating variables with statistical significance (age, gender, hypertension, alcohol consumption, smoking habit) into the model, revealed that higher age corresponds to a greater risk of CKD (Odds ratio 1.052; 95% CI, 1.003 to 1.103). Furthermore, the male gender exhibited a 5.5 times higher likelihood of suffering from CKD (Odds ratio 5.5; 95% CI, 1.2 to 26.5). Conclusion In patients with recurrent kidney stones, higher age, and male gender were identified as factors associated with the development of CKD.

#1442 Retrospective evaluation of etiology, clinical and laboratory findings in patients diagnosed with secondary and genetic FSGS

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a glomerulonephritis characterized by segmental sclerosis in at least one of the glomeruli and may develop due to primary, secondary, genetic etiology. We compared clinical, histopathological, and laboratory findings, treatment options, and response to treatment in patients with secondary and genetic FSGS. Method This study analyzed 172 patients with secondary and genetic FSGS at our Glomerular Diseases Clinic (1987-2022). Criteria included at least 16 weeks of follow-up, absence of other primary glomerular diseases, and age over 18. Retrospective data were collected on demographics, diagnosis, renal biopsies, genetic tests, imaging, treatments, treatment responses, end-stage renal disease (ESRD) development, and transplantation. The focus was on predicting genetic FSGS and ESRD. Results 103 of our patients were female (59.8%), and the mean age at diagnosis was 38.46 ± 13.75 years. Of these patients, 29 were diagnosed with genetic FSGS and 141 with non-genetic secondary FSGS. Forty-one patients with non-genetic secondary FSGS were obese, and 21 had a single kidney. The patients had a median follow-up of 78 (38-134) months. 28 patients developed ESRD during follow-up, 16 of whom underwent renal transplantation. Familial renal disease (p &amp;lt; 0.001), familial ESRD (p &amp;lt; 0.001), and hematuria at diagnosis (p = 0.005) were more common in patients with genetic FSGS. Comparison of genetic FSGS and non-genetic secondary FSGS patients shown in Figure 1. The number of glomeruli with global sclerosis (p = 0.006) and C3 accumulation (p = 0.048) on renal biopsy was more frequent in patients with ESRD. Comparison of ESRD and non-ESRD patients are shown in Figure 2. Conclusion Differentiating genetic and non-genetic secondary FSGS is vital in clinical practice. For those with a family history of renal disease, hematuria, or unresponsive to immunosuppressive therapy, consider genetic FSGS and request genetic testing. Patients with secondary FSGS, diagnosed with high creatinine, a substantial presence of sclerosing glomeruli on biopsy, and C3 accumulation, should be closely monitored for ESRD.

The Effects of Bacillus amyloliquefaciens SC06 on Behavior and Brain Function in Broilers Infected by Clostridium perfringens

Poultry studies conducted on Clostridium perfringens (CP) mainly focus on the effects of intestinal health and productive performance. Notably, the probiotic Bacillus amyloliquefaciens SC06 (BaSC06) is known to play a role in preventing bacterial infection. However, whether CP could induce the changes in brain function and behaviors and whether BaSC06 could play roles in these parameters is yet to be reported. The aim of this study was to evaluate the effects of BaSC06 on stress-related behaviors and gene expression, as well as the brain morphology and mRNA sequence of the hypothalamus in broiler chickens. A total of 288 one-day-old chicks were randomly divided into four groups: (1) a control group with no treatment administered or infection; (2) birds treated with the BaSC06 group; (3) a CP group; and (4) a BaSC06 plus CP (Ba_CP) group. The results showed that stress and fear-related behaviors were significantly induced by a CP infection and decreased due to the treatment of BaSC06. CP infection caused pathological damage to the pia and cortex of the brain, while BaSC06 showed a protective effect. CP significantly inhibited hypothalamic GABA and promoted HTR1A gene expression, while BaSC06 promoted GABA and decreased HTR1A gene expression. The different genes were nearly found between the comparisons of control vs. Ba group and Ba vs. CP group, while there were a great number of different genes between the comparisons of control vs. Ba_CP as well as CP vs. Ba_CP. Several different gene expression pathways were found that were related to disease, energy metabolism, and nervous system development. Our results will help to promote poultry welfare and health, as well as provide insights into probiotics to replace antibiotics and reduce resistance in the chicken industry.

#971 Effects of arsenic trioxide on MMP9/IL-17A expression in lupus nephritis—results from bioinformatics analysis and in vitro studies

Abstract Background and Aims Previous research has indicated that ATO treatment at low doses may decrease the likelihood of flares in active systemic lupus erythematosus (SLE) patients, but the pharmacological mechanisms of such effect have not been studied. Method Machine learning and network pharmacology analysis were employed to explore the potential targets from differentially expressed genes (DEGs) of human SLE and LN peripheral blood mononuclear cells (PBMCs) microarray datasets and pharmacological databases. GO and KEGG analyses were performed, and the protein-protein interaction (PPI) network was constructed. The association of these characteristic genes and immune cells were further examined and validated. Results Three machine learning models (RF, SVM, and XGB) were utilized to identify five immunoregulatory genes in SLE among twelve intersection DEGs. Among these genes, MMP9 exhibited the highest ROC AUC (0.92) in predicting disease development. KEGG analysis revealed significant associations with the IL-17 signaling pathway (p = 1.67E-18). Furthermore, ssGSEA analysis indicated positive correlations between MMP9 and macrophages (correlation coefficient 0.88) as well as neutrophils (correlation coefficient 0.66). In vitro treatment of PBMCs from lupus nephritis (LN) patients with ATO resulted in downregulation of MMP9 and IL-17A, validating our bioinformatics findings. Conclusion ATO has the potential to mitigate the MMP/IL-17A pathways in PBMCs in LN patients, and hence maybe a promising and innovative therapeutic alternative.

Species-level characterization of saliva and dental plaque microbiota reveals putative bacterial and functional biomarkers of periodontal diseases in dogs.

Periodontal diseases are among the most common bacterial-related pathologies affecting the oral cavity of dogs. Nevertheless, the canine oral ecosystem and its correlations with oral disease development are still far from being fully characterized. In this study, the species-level taxonomic composition of saliva and dental plaque microbiota of 30 healthy dogs was investigated through a shallow shotgun metagenomics approach. The obtained data allowed not only to define the most abundant and prevalent bacterial species of the oral microbiota in healthy dogs, including members of the genera Corynebacterium and Porphyromonas, but also to identify the presence of distinct compositional motifs in the two oral micro-niches as well as taxonomical differences between dental plaques collected from anterior and posterior teeth. Subsequently, the salivary and dental plaque microbiota of 18 dogs affected by chronic gingival inflammation and 18 dogs with periodontitis were compared to those obtained from the healthy dogs. This analysis allowed the identification of bacterial and metabolic biomarkers correlated with a specific clinical status, including members of the genera Porphyromonas and Fusobacterium as microbial biomarkers of a healthy and diseased oral status, respectively, and genes predicted to encode for metabolites with anti-inflammatory properties as metabolic biomarkers of a healthy status.

The effect of enriched versus depleted housing on eucalyptus smoke-induced cardiovascular dysfunction in mice.

Objectives: Living conditions play a major role in health and well-being, particularly for the cardiovascular and pulmonary systems. Depleted housing contributes to impairment and development of disease, but how it impacts body resiliency during exposure to environmental stressors is unknown. This study examined the effect of depleted (DH) versus enriched housing (EH) on cardiopulmonary function and subsequent responses to wildfire smoke. Materials and Methods: Two cohorts of healthy female mice, one of them surgically implanted with radiotelemeters for the measurement of electrocardiogram, body temperature (Tco) and activity, were housed in either DH or EH for 7 weeks. Telemetered mice were exposed for 1 h to filtered air (FA) and then flaming eucalyptus wildfire smoke (WS) while untelemetered mice, which were used for ventilatory assessment and tissue collection, were exposed to either FA or WS. Animals were continuously monitored for 5-7 days after exposure. Results: EH prevented a decrease in Tco after radiotelemetry surgery. EH mice also had significantly higher activity levels and lower heart rate during and after FA and WS. Moreover, EH caused a decreased number of cardiac arrhythmias during WS. WS caused ventilatory depression in DH mice but not EH mice. Housing enrichment also upregulated the expression of cardioprotective genes in the heart. Conclusions: The results of this study indicate that housing conditions impact overall health and cardiopulmonary function. More importantly, depleted housing appears to worsen the response to air pollution. Thus, non-chemical factors should be considered when assessing the susceptibility of populations, especially when it comes to extreme environmental events.

Regulatory roles of long non-coding RNAs in short-term heat stress in adult worker bees

Long non-coding RNAs (lncRNAs) are crucial modulators of post-transcriptional gene expression regulation, cell fate determination, and disease development. However, lncRNA functions during short-term heat stress in adult worker bees are poorly understood. Here, we performed deep sequencing and bioinformatic analyses of honeybee lncRNAs. RNA interference was performed by using siRNA targeting the most highly expressed lncRNA. The silencing effect on lncRNA and the relative expression levels of seven heat shock protein (HSP) genes, were subsequently examined. Overall, 7,842 lncRNAs and 115 differentially expressed lncRNAs (DELs) were identified in adult worker bees following heat stress exposure. Structural analysis revealed that the overall expression abundance, length of transcripts, exon number, and open reading frames of lncRNAs were lower than those of mRNAs. GO analysis revealed that the target genes were mainly involved in “metabolism,” “protein folding,” “response to stress,” and “signal transduction” pathways. KEGG analysis indicated that the “protein processing in endoplasmic reticulum” and “longevity regulating pathway-multiple species” pathways were most enriched. Quantitative real-time polymerase chain reaction (qRT-PCR) detection of the selected DELs confirmed the reliability of the sequencing data. Moreover, the siRNA experiment indicated that feeding siRNA yielded a silencing efficiency of 77.51% for lncRNA MSTRG.9645.5. Upon silencing this lncRNA, the expression levels of three HSP genes were significantly downregulated (p < 0.05), whereas those of three other HSP genes were significantly upregulated (p < 0.05). Our results provide a new perspective for understanding the regulatory mechanisms of lncRNAs in adult worker bees under short-term heat stress.

Identification of plasma protein markers of allergic disease risk: a mendelian randomization approach to proteomic analysis

BackgroundWhile numerous allergy-related biomarkers and targeted treatment strategies have been developed and employed, there are still signifcant limitations and challenges in the early diagnosis and targeted treatment for allegic diseases. Our study aims to identify circulating proteins causally associated with allergic disease-related traits through Mendelian randomization (MR)-based analytical framework.MethodsLarge-scale cis-MR was employed to estimate the effects of thousands of plasma proteins on five main allergic diseases. Additional analyses including MR Steiger analyzing and Bayesian colocalisation, were performed to test the robustness of the associations; These findings were further validated utilizing meta-analytical methods in the replication analysis. Both proteome- and transcriptome-wide association studies approach was applied, and then, a protein-protein interaction was conducted to examine the interplay between the identified proteins and the targets of existing medications.ResultsEleven plasma proteins were identified with links to atopic asthma (AA), atopic dermatitis (AD), and allergic rhinitis (AR). Subsequently, these proteins were classified into four distinct target groups, with a focus on tier 1 and 2 targets due to their higher potential to become drug targets. MR analysis and extra validation revealed STAT6 and TNFRSF6B to be Tier 1 and IL1RL2 and IL6R to be Tier 2 proteins with the potential for AA treatment. Two Tier 1 proteins, CRAT and TNFRSF6B, and five Tier 2 proteins, ERBB3, IL6R, MMP12, ICAM1, and IL1RL2, were linked to AD, and three Tier 2 proteins, MANF, STAT6, and TNFSF8, to AR.ConclusionEleven Tier 1 and 2 protein targets that are promising drug target candidates were identified for AA, AD, and AR, which influence the development of allergic diseases and expose new diagnostic and therapeutic targets.

Factors and clinical prediction score for complication development after cellulitis diagnosis in adult patients.

Cellulitis is defined as a bacterial infection of the skin and subcutaneous tissue that can cause multiple complications, such as sepsis and necrotizing fasciitis. In extreme cases, it may lead to multiorgan failure and death. We sought to analyze the clinical factors that contribute to the development of complicated disease, including demographics, clinical presentation, initial vital signs, and laboratory studies. Our study is a retrospective cohort study carried out in a university-based tertiary care hospital in Bangkok, Thailand. Adult patients who presented with cellulitis from January 1, 2018, to December 31, 2022, were evaluated for eligibility and inclusion in this study. All related variables for both outcomes, bacteremia and necrotizing fasciitis, were gathered from electronic medical records and analyzed using multivariable logistic regression analysis. Of the 1,560 visits to this hospital, 47 cases reported at least one complication, with bacteremia noted in 27 visits (1.73%) and necrotizing fasciitis in 20 visits (1.27%). From the multivariable logistic regression analysis, six variables emerge as predictors of cellulitis complications. These are: Age ≥ 65 years, Body Mass Index ≥ 30kg/m2, diabetes mellitus, body temperature ≥ 38°C, systolic blood pressure ≤ 100 mmHg, and involvement of lower extremities. The predictive score was developed from these factors and was named the Ramathibodi Necrotizing Fasciitis/Bacteremia (RAMA-NFB) Prediction Score. Our predictive score has an accuracy of 82.93% (95% CI, 0.77-0.89). Patients in the high-risk group (RAMA NFB score > 6) have a likelihood ratio of 8.75 (95% CI, 4.41-18.12; p < 0.001) times to develop complications of cellulitis. In our study, the RAMA-NFB Prediction Score predicts complications of necrotizing fasciitis and bacteremia in adult patients who present with cellulitis. External validation of this predictive score is still needed for further practical application.

Epigenetics of hypertension as a risk factor for the development of coronary artery disease in type 2 diabetes mellitus

Hypertension, a multifaceted cardiovascular disorder influenced by genetic, epigenetic, and environmental factors, poses a significant risk for the development of coronary artery disease (CAD) in individuals with type 2 diabetes mellitus (T2DM). Epigenetic alterations, particularly in histone modifications, DNA methylation, and microRNAs, play a pivotal role in unraveling the complex molecular underpinnings of blood pressure regulation. This review emphasizes the crucial interplay between epigenetic attributes and hypertension, shedding light on the prominence of DNA methylation, both globally and at the gene-specific level, in essential hypertension. Additionally, histone modifications, including acetylation and methylation, emerge as essential epigenetic markers linked to hypertension. Furthermore, microRNAs exert regulatory influence on blood pressure homeostasis, targeting key genes within the aldosterone and renin-angiotensin pathways. Understanding the intricate crosstalk between genetics and epigenetics in hypertension is particularly pertinent in the context of its interaction with T2DM, where hypertension serves as a notable risk factor for the development of CAD. These findings not only contribute to the comprehensive elucidation of essential hypertension but also offer promising avenues for innovative strategies in the prevention and treatment of cardiovascular complications, especially in the context of T2DM.

Resident Microbiome of Kidney Tumors

Emerging research has uncovered the significance of microbiota in carcinogenesis, with specific bacterial infectious agents linked to around 15% of malignant tumors. This review is focused on the resident kidney microbiome, its composition, and alterations in various diseases. Recent studies have shown that bacteria can infiltrate the kidney, with differences between normal and tumor tissue. These studies have identified distinctive microorganisms unique to both conditions, hinting at their potential clinical relevance. Research into the kidney microbiome diversity reveals differences in tumor tissue, with specific taxa associated with different histological types. Notably, the alpha diversity indices suggest variations in bacterial content between tumor and normal tissue, offering insights into potential diagnostic and prognostic use of these markers. Better studied is the impact of the gut microbiome on therapy efficacy in malignant kidney tumors. Antibiotics, which can alter the gut microbiome, have been linked to survival outcomes in patients receiving targeted therapy and immunotherapy. The findings suggest that the uncontrolled use of antibiotics may not only contribute to bacterial resistance but also disrupt the normal microbiome, potentially influencing the development of oncological diseases. In-depth investigation into the resident kidney microbiome is essential for addressing fundamental and practical aspects of kidney tumor development.

Effectiveness of structured exercise program on insulin resistance and quality of life in type 2 diabetes mellitus-A randomized controlled trial.

Impaired glucose control & Insulin resistance are reported to be risk factors for the development of cardiovascular diseases. To find the effects of a structured exercise program on insulin resistance, glycaemic control, functional capacity, and quality of life in patients with Type 2 diabetes mellitus. Randomized, controlled trial. Diabetic Foot Clinic, Department of Physiotherapy & Department of General Medicine, Kasturba Hospital in Manipal, Karnataka, India. 160 participants aged between 30-65 years with Type 2 diabetes mellitus. A set of structured exercise programs (aerobic, resistance, and combined) along with the standard hospital care was performed 3-5 times weekly for 12 weeks. Fasting Insulin Level, Homa-IR, Six-minute walk test (6MWT), and WHOQOL-BREF questionnaire at baseline and 12th week. Body composition analysis, Fasting Blood Sugar, Postprandial Blood Sugar, Glycated Haemoglobin (HbA1c), and GPAQ questionnaire at baseline and 12th week. Significant differences have been observed in Homeostasis model assessment for insulin resistance (Homa-IR) (F (1, 144) = 89.29, p < 0.001); Fasting insulin (FI) (F (1, 144) = 129.10, p < 0.001); Fasting blood sugar (FBS) (F (1, 144) = 12.193, p< 0.001); Post prandial blood sugar (PPBS) (F (1, 144) = 53.015, p< 0.001); glycated haemoglobin (HbA1c) (F (1, 144) = 80.050, p < 0.001); WHOQOL-Physical health (F (1, 144) = 20.008, p< 0.001), Psychological (F (1, 144) = 77.984, p< 0.001), Social relationship (F (1, 144) = 44.866, p< 0.001); Environmental (F (1, 144) = 69.974, p< 0.001); Six minute walk test (6MWT) (F (1, 144) = 84.135, p< 0.001) in the study group when compared with the control group from baseline to 12th week. The study reveals that a 12-week structured exercise training program effectively reduces insulin resistance, improves quality of life, enhances functional capacity, and improves glycaemic control in type 2 diabetes mellitus.

The association of serum uric acid level with metabolic risk factors in patients with type 2 diabetes and their relation to eGFR status

BackgroundThe importance of uric acid has been increasingly appreciated because of its association with the development of diabetes mellitus and related diseases, and with the increasing incidence of diabetes, studying the impact of hyperuricemia in patients with diabetes type 2 is necessary. So we aimed to measure serum uric acid (SUA) levels in patients with diabetes type 2 and to assess the relation between the estimated glomerular filtration rate (eGFR) and the SUA in patients with type 2 diabetes (T2DM).Subjects and methodsThis study is a cross-sectional conducted on 142 adult patients who attended the Outpatients Diabetes Clinic and Endocrinology Center in the Department of Internal Medicine, Assiut University Hospitals, in the period from the 1st of November 2021 up to October 2022. We measured serum uric acid level, serum creatinine, cholesterol, low- and high-density lipoproteins, triglycerides, and eGFR.ResultsOverall, 142 patients were enrolled in the study; all patients had type 2 diabetes. The mean age of the participants was 61.08 ± 9.73 years. Based on SUA level, 46 (32.4%) patients had normal SUA and 96 (67.6%) patients had high SUA. Sixty-nine (48.6%) patients had normal eGFR and 73 (51.4%) patients had reduced eGFR. We found that serum uric acid had a positive significant correlation with the number of metabolic syndrome criteria, cholesterol, low-density lipoproteins, and triglycerides. Meanwhile, it had a negative significant correlation with eGFR and high-density lipoproteins.ConclusionSerum uric acid was strongly associated with metabolic syndrome components and reduced eGFR in patients with T2DM.