Therapeutic potential of ghrelin/GOAT/GHSR system in gastrointestinal disorders.

Ghrelin, a peptide primarily secreted in the stomach, acts via the growth hormone secretagogue receptor (GHSR). It regulates several physiological processes, such as feeding behavior, energy homeostasis, glucose and lipid metabolism, cardiovascular function, bone formation, stress response, and learning. GHSR exhibits significant expression within the central nervous system. However, numerous murine studies indicate that ghrelin is limited in its ability to enter the brain from the bloodstream and is primarily confined to specific regions, such as arcuate nucleus (ARC) and median eminence (ME). Nevertheless, the central ghrelin system plays an essential role in regulating feeding behavior. Furthermore, the role of vagal afferent fibers in regulating the functions of ghrelin remains a major topic of discussion among researchers. In recent times, numerous studies have elucidated the substantial therapeutic potential of ghrelin in most gastrointestinal (GI) diseases. This has led to the development of numerous pharmaceutical agents that target the ghrelin system, some of which are currently under examination in clinical trials. Furthermore, ghrelin is speculated to serve as a promising biomarker for GI tumors, which indicates its potential use in tumor grade and stage evaluation. This review presents a summary of recent findings in research conducted on both animals and humans, highlighting the therapeutic properties of ghrelin system in GI disorders.

Propensity Score Matching Analysis of the Influence of Waiting Time Satisfaction on Community Resident's Satisfaction With Medical Institutions: An Extensive Survey of Outpatient Population in Shantou City of Southern China.

OBJECTIVE: This study was designed to perform a nuanced analysis of the multifaceted association between community residents' satisfaction and their perceived satisfaction concerning the visit duration at medical facilities, that could be harnessed to enhance and streamline the process of hierarchical diagnosis and treatment, thereby augmenting healthcare outcomes and patient experiences. METHODS: Respondents who had utilized services from medical institutions were invited to fill out questionnaires by scanning QR codes. Additionally, surveys also distributed questionnaires through WeChat groups of community residents in densely populated areas of the community, as well as WeChat groups for patients who had previously visited local hospitals. To balance differences between groups, propensity score matching was applied to analyze the contrast between residents satisfied and dissatisfied with their medical visits. After eliminating the interference of confounding factors, a comparative analysis was conducted on the relationship between resident satisfaction and medical institution experience.After eliminating the interference of confounding factors, a comparative analysis was conducted to delve deeply into the relationship between residents' satisfaction and their experiences at medical facilities. RESULTS: The study incorporated a large dataset encompassing 2356 community residents. Upon successful propensity score matching, logistic regression analysis elucidated several determinants of overall resident satisfaction. Notably, the grade of the medical institution (χ2 = 8.226, P < .05), satisfaction with the time invested in the registration process (χ2 = 11.04, P < .05), satisfaction with the waiting duration for consultation (χ2 = 15.759, P < .05), and satisfaction with the travel time to the hospital (χ2 = 45.157, P < .05) each exerted significant influence on the holistic satisfaction of residents with their medical experience. CONCLUSION: Factors such as the grade of the medical institution, satisfaction related to registration and waiting durations, and travel time to the hospital emerged as crucial determinants shaping community residents' holistic satisfaction with their medical encounters. These findings underscore the exigency for strategic allocation and optimization of medical resources, refinement of the classification system, and enhancement of public health education on the graded diagnosis and treatment schema. The study also demonstrates the value of employing advanced propensity score matching and predictive modelling techniques in health services research.

The New Challenge of Obesity - Obesity-Associated Nephropathy.

In recent years, obesity has become one of the major diseases that affect human health and consume human health resources, especially when it causes comorbidities such as hypertension, diabetes, cardiovascular disease and kidney disease. Many studies have demonstrated that obesity is associated with the development of chronic kidney disease and can exacerbate the progression of end-stage renal disease. This review described the mechanisms associated with the development of obesity-associated nephropathy and the current relevant therapeutic modalities, with the aim of finding new therapeutic targets for obesity-associated nephropathy. The mechanisms of obesity-induced renal injury include, in addition to the traditional alterations in renal hemodynamics, the involvement of various mechanisms such as macrophage infiltration in adipose tissue, alterations in adipokines (leptin and adiponectin), and ectopic deposition of lipids. At present, there is no "point-to-point" treatment for obesity-induced kidney injury. The renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors and bariatric surgery described in this review can reduce urinary protein to varying degrees and delay the progression of kidney disease. In addition, recent studies on the therapeutic effects of intestinal flora on obesity may reduce the incidence of obesity-related kidney disease from the perspective of primary prevention. Both of these interventions have their own advantages and disadvantages, so the continuous search for the mechanism of obesity-induced related kidney disease will be extremely helpful for the future treatment of obesity-related kidney disease.

Irbesartan ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing NLRP3 inflammasomes in vivo and in vitro.

OBJECTIVES: Diabetic nephropathy (DN) is characterized by albuminuria and renal dysfunction caused by diabetes. At present there is no specific treatment for DN. Irbesartan (IRB) is an angiotensin receptor inhibitor indicated for the treatment of hypertension and DN. However, the underlying molecular mechanisms of IRB on DN remains obscure. METHODS: RAW264.7 macrophages were incubated in RPMI-1640, cell viability was evaluated by CCK-8 assays, transcriptional level of proinflammatory cytokines and was measured by ELISA and qPCR, NLRP3 inflammasome and Nrf2/Keap1 related proteins were measured by Western blotting and immunohistochemistry. Streptozotocin (STZ)-induced diabetic male C57BL/6 mice were used to evaluate the therapeutic effect of IRB on DN. Key findings First, we found that IRB improved high glucose-induced cell inflammation by inhibiting the transcription of IL-1ß and IL-18. IRB activated the Nrf2/Keap1 pathway and decreased the release of reactive oxygen species (ROS). IRB also suppressed the expression of NLRP3 and caspase-1. IRB combined with the N-acetylcysteine (NAC) significantly inhibited the activation of NLRP3 inflammasomes. Conversely, IRB combined with the Nrf2-related inhibitor ML385 enhanced NLRP3 inflammasome activation, suggesting that IRB suppressed NLRP3 inflammasome via the Nrf2 pathway. In vivo study, HE staining and immunohistochemistry analysis further showed that IRB ameliorated high glucose-induced renal injury by elevating the expression of the Nrf2/Keap1 signaling pathway and suppressing the proinflammatory cytokine and NLRP3 inflammasome activation. CONCLUSIONS: Our results suggested that IRB ameliorates diabetic nephropathy by activating the Nrf2/Keap1 pathway and suppressing the NLRP3 inflammasomes in vivo and in vitro. These findings provide new therapeutic strategies of diabetic nephropathy.

Cytokines: The links between bone and the immune system.

Osteoporosis results from an imbalance in a highly balanced physiological process called bone remodeling, in which osteoclast-mediated bone resorption and osteoblast-mediated bone formation play important roles. Osteoimmunology is a newly discovered interdisciplinary research field that focuses on the relationship between bone and the immune system. Specifically, bone and the immune system interact through cytokines, immune cells secrete cytokines, and cytokines finely regulate bone metabolism by mediating the differentiation and activity of osteoclasts and osteoblasts. Therefore, understanding the influence of cytokines on bone metabolism is conducive for the development of novel targeted drugs against immune-related bone diseases. This review summarizes the pathophysiological functions of various common cytokines in bone and discusses the potential clinical value of multiple cytokines in immune-mediated bone diseases.

Efficacy of noiiglutide injection on body weight in obese Chinese adults without diabetes: A multicentre, randomized, double-blind, placebo-controlled, phase 2 trial.

AIM: To evaluate the effect of noiiglutide as an adjunct to lifestyle intervention on the reduction in body weight and tolerability in obese Chinese adults without diabetes. MATERIALS AND METHODS: In this 24-week, randomized, double-blind, placebo-controlled phase 2 trial, 254 obese adults with a body mass index of 28.0-40.0 kg/m2 and without diabetes were enrolled. Participants were initially randomized in a 1:1:1 ratio to one of three dose levels: 0.12, 0.24, or 0.36 mg of the study treatment. Within each dose level, participants were further randomized in a 3:1 ratio to receive either subcutaneous injection of noiiglutide or a matching placebo. The primary endpoint was the change in body weight from baseline to week 24. RESULTS: Across all noiiglutide dosage levels, least squares mean reductions in body weight from baseline to week 24 ranged from 8.03 to 8.50 kg, compared with 3.65 kg in the placebo group (all p-values <.0001). In the noiiglutide groups (0.12, 0.24, 0.36 mg/day), a significantly higher proportion of participants achieved a weight loss ≥5% (68.8%, 60.0%, 73.0%) and ≥10% (37.5%, 36.9%, 39.7%), compared with the pooled placebo group (≥5%: 29.0%; ≥10%: 8.1%). Gastrointestinal adverse events, such as nausea, diarrhoea and vomiting, were more common in all noiiglutide groups (15.4%-30.2%, 18.8%-22.2%, 15.6%-18.5%) than in the pooled placebo group (8.1%, 6.5%, 0%). CONCLUSIONS: In obese Chinese adults without diabetes, once-daily subcutaneous noiiglutide significantly reduced body week at week 24 compared with placebo, and had a manageable safety profile, primarily involving gastrointestinal disorders.

Case Report: Atrial myxoma combined with hyperthyroidism in an adolescent with literature review.

The most common primary cardiac tumors in adults are atrial myxomas, with adolescent-onset being uncommon. In this case report, a 15-year-old female was hospitalized with cerebrovascular embolism and later diagnosed with a left atrial myxoma. She had previously shown signs of distal vascular micro thrombosis, including recurring bilateral lower extremity rash, which are crucial for the early diagnosis and differential diagnosis of atrial mucinous neoplasm. We reviewed the various clinical symptoms and diagnostic approaches to identify left atrial mucinous neoplasm. This patient also had a combination of endocrine-related diseases. We reviewed the diagnostic approach for the Carney Complex (CNC) and discussed the role of thyroid disease in diagnosing CNC.

The combination of insulin and linezolid ameliorates Staphylococcus aureus pneumonia in individuals with diabetes via the TLR2/MAPKs/NLRP3 pathway.

Diabetes mellitus (DM) complicated with Staphylococcus aureus (S. aureus) infection lacks effective treatment strategies. In this study, we found that insulin combined with linezolid has potential to deal with the thorny problem. In vitro, our drug sensitivity assay, bacterial growth curve and hemolytic tests showed that a combination of insulin and linezolid exerted good antibacterial and anti-α-hemolysin activity, CCK8 experiment, glucose content and glycogen content determination showed that the combination of insulin and linezolid increased murine macrophage survival rate and reduced the extracellular glucose level of high glucose-treated MH-S cells and intracellular glycogen level, and Western blot showed that the combination inhibited TLR2/MAPKs/NLRP3-related inflammatory pathways in MH-S cells. The results of in vivo experiments showed that the combination therapy stabilized glucose level, remained body weight, ameliorated lung injury including improving pulmonary edema and decreasing lung wet/dry weight ratio, reduced the CFUs and inflammation in the lung tissue in a mouse model of diabetes with S. aureus pneumonia, and inhibited the expression of TLR2, MAPKs and NLRP3 inflammatory pathway. Overall, the combination of insulin and linezolid as autolytic inhibitor exhibited the effects of significant antibacterial and improving glucose level in vitro and in vivo, and also has an anti-inflammation activity via the TLR2/MAPKs/NLRP3 pathway, this paves the way for new treatments for diabetes mellitus complicated with S. aureus infection.

Association of Nirmatrelvir/Ritonavir Treatment on Upper Respiratory Severe Acute Respiratory Syndrome Coronavirus 2 Reverse Transcription-Polymerase Chain Reaction (SARS-Cov-2 RT-PCR) Negative Conversion Rates Among High-Risk Patients With Coronavirus Disease 2019 (COVID-19).

BACKGROUND: Acceleration of negative respiratory conversion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with coronavirus disease 2019 (COVID-19) might reduce viral transmission. Nirmatrelvir/ritonavir is a new antiviral agent recently approved for treatment of COVID-19 that has the potential to facilitate negative conversion. METHODS: A cohort of hospitalized adult patients with mild-to-moderate COVID-19 who had a high risk for progression to severe disease were studied. These patients presented with COVID-19 symptoms between 5 March and 5 April 2022. The time from positive to negative upper respiratory reverse transcription-polymerase chain reaction (RT-PCR) conversion was assessed by Kaplan-Meier plots and Cox proportional hazards regression with the adjustment for patients' baseline demographic and clinical characteristics. RESULTS: There were 258 patients treated with nirmatrelvir/ritonavir and 224 nontreated patients who had mild-to-moderate COVID-19. The median (interquartile range) time for patients who converted from positive to negative RT-PCR was 10 days (7-12 days) in patients treated ≤5 days after symptom onset and 17 days (12-21 days) in nontreated patients. The proportions of patients with a negative conversion at day 15 were 89.7% and 42.0% in treated patients and nontreated patients, corresponding to a hazard ratio of 4.33 (95% confidence interval, 3.31-5.65). Adjustment for baseline differences between the groups had little effect on the association. Subgroup analysis on treated patients suggests that time to negative conversion did not vary with the patients' baseline characteristics. CONCLUSIONS: This cohort study of high-risk patients with mild-to-moderate COVID-19 found an association between nirmatrelvir/ritonavir treatment and accelerated negative RT-PCR respiratory SARS-CoV-2 conversion that might reduce the risk of viral shedding and disease transmission.

Effectiveness of inactivated COVID-19 vaccines against mild disease, pneumonia, and severe disease among persons infected with SARS-CoV-2 Omicron variant: real-world study in Jilin Province, China.

It is critical to determine the real-world performance of vaccines against coronavirus disease 2019 (COVID-19) so that appropriate treatments and policies can be implemented. There was a rapid wave of infections by the Omicron variant in Jilin Province (China) during spring 2022. We examined the effectiveness of inactivated vaccines against Omicron using real-world data from this epidemic. This retrospective case-case study of vaccine effectiveness (VE) examined infected patients who were quarantined and treated from April 16 to June 8, 2022 and responded to an electronic questionnaire. Data were analyzed by univariable and multivariable analyses. A total of 2968 cases with SARS-CoV-2 infections (asymptomatic: 1061, mild disease: 1763, pneumonia: 126, severe disease: 18) were enrolled in the study. Multivariable regression indicated that the risk for pneumonia or severe disease was greater in those who were older or had underlying diseases, but was less in those who received COVID-19 vaccines. Relative to no vaccination, VE against the composite of pneumonia and severe disease was significant for those who received 2 doses (60.1%, 95%CI: 40.0%, 73.5%) or 3 doses (68.1%, 95%CI: 44.6%, 81.7%), and VE was similar in the subgroups of males and females. However, VE against the composite of all three classes of symptomatic diseases was not significant overall, nor after stratification by sex. There was no statistical difference in the VE of vaccines from different manufacturers. The inactivated COVID-19 vaccines protected patients against pneumonia and severe disease from Omicron infection, and booster vaccination enhanced this effect.

Inhibition of NLRP3 and Golph3 ameliorates diabetes-induced neuroinflammation in vitro and in vivo.

Golgi stress has been observed in various neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Whether Golgi stress participates in hyperglycemia-induced neuroinflammation, and how it is regulated remain unclear. First, we found that high glucose (HG) could induce dispersed Golgi apparatus (GA) in BV2 cells, which can be reversed by knockout of NLRP3. Next, we discovered that HG could promote the interaction of NLRP3 and VPS35 and then enhances the interaction of VPS35 and Golph3; knockout of NLRP3 suppressed the expression of VPS35 and Golph3; knockout of VPS35 reduced the expression of Golph3 but not NLRP3, indicating that HG induced the activation of NLRP3/VPS35/Golph3 pathway in BV2 cells. Further, we elucidated the signaling pathway that Golph3 mediated GA stress in HG condition. We used GST-pulldown and Co-IP experiments methods to show that HG promoted the interaction of Golph3 and Vimentin, knockout of Golph3 alleviated the expression of Vimentin. Knockout out of Golph3 and Vimentin both ameliorated HG induced dispersed Golgi apparatus. Collectively, our study demonstrated that HG regulates GA stress through NLRP3/VPS35/Golph3/Vimentin pathway. At last, we found that a combination of small molecular inhibitors targeting NLRP3 and Golph3 selected by molecular docking could alleviate HG-induced neuroinflammation in vitro and in vivo. Therefore, the molecular inhibitors targeting NLRP3 and Golph3 have great potential for use in the development of anti-diabetes neuroinflammatory therapies.

Construction of the coexpression network involved in the pathogenesis of thyroid eye disease via bioinformatics analysis.

BACKGROUND: Thyroid eye disease (TED) is the most common orbital pathology that occurs in up to 50% of patients with Graves' disease. Herein, we aimed at discovering the possible hub genes and pathways involved in TED based on bioinformatical approaches. RESULTS: The GSE105149 and GSE58331 datasets were downloaded from the Gene Expression Omnibus (GEO) database and merged for identifying TED-associated modules by weighted gene coexpression network analysis (WGCNA) and local maximal quasi-clique merger (lmQCM) analysis. EdgeR was run to screen differentially expressed genes (DEGs). Transcription factor (TF), microRNA (miR) and drug prediction analyses were performed using ToppGene suite. Function enrichment analysis was used to investigate the biological function of genes. Protein-protein interaction (PPI) analysis was performed based on the intersection between the list of genes obtained by WGCNA, lmQCM and DEGs, and hub genes were identified using the MCODE plugin. Based on the overlap of 497 genes retrieved from the different approaches, a robust TED coexpression network was constructed and 11 genes (ATP6V1A, PTGES3, PSMD12, PSMA4, METAP2, DNAJA1, PSMA1, UBQLN1, CCT2, VBP1 and NAA50) were identified as hub genes. Key TFs regulating genes in the TED-associated coexpression network, including NFRKB, ZNF711, ZNF407 and MORC2, and miRs including hsa-miR-144, hsa-miR-3662, hsa-miR-12136 and hsa-miR-3646, were identified. Genes in the coexpression network were enriched in the biological processes including proteasomal protein catabolic process and proteasome-mediated ubiquitin-dependent protein catabolic process and the pathways of endocytosis and ubiquitin-mediated proteolysis. Drugs perturbing genes in the coexpression network were also predicted and included enzyme inhibitors, chlorodiphenyl and finasteride. CONCLUSIONS: For the first time, TED-associated coexpression network was constructed and key genes and their functions, as well as TFs, miRs and drugs, were predicted. The results of the present work may be relevant in the treatment and diagnosis of TED and may boost molecular studies regarding TED.

Potential role of ghrelin in the regulation of inflammation.

Several diseases are caused or progress due to inflammation. In the past few years, accumulating evidence suggests that ghrelin, a gastric hormone of 28-amino acid residue length, exerts protective effects against inflammation by modulating the related pathways. This review focuses on ghrelin's anti-inflammatory and potential therapeutic effects in neurological, cardiovascular, respiratory, hepatic, gastrointestinal, and kidney disorders. Ghrelin significantly alleviates excessive inflammation and reduces damage to different target organs mainly by reducing the secretion of inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α), and inhibiting the nuclear factor kappa-B (NF-κB) and NLRP3 inflammasome signaling pathways. Ghrelin also regulates inflammation and apoptosis through the p38 MAPK/c-Jun N-terminal kinase (JNK) signaling pathway; restores cerebral microvascular integrity, and attenuates vascular leakage. Ghrelin activates the phosphoInositide-3 kinase (PI3K)/protein kinase B (Akt) pathway and inhibits inflammatory responses in cardiovascular diseases and acute kidney injury. Some studies show that ghrelin exacerbates colonic and intestinal manifestations of colitis. Interestingly, some inflammatory states, such as non-alcoholic steatohepatitis, inflammatory bowel diseases, and chronic kidney disease, are often associated with high ghrelin levels. Thus, ghrelin may be a potential new therapeutic target for inflammation-related diseases.

New Advances in Improving Bone Health Based on Specific Gut Microbiota.

The gut microbiota has been shown to play an important role in the pathogenesis of various diseases, including metabolic diseases, cardiovascular diseases, and cancer. Recent studies suggest that the gut microbiota is also closely associated with bone metabolism. However, given the high diversity of the gut microbiota, the effects of different taxa and compositions on bone are poorly understood. Previous studies demonstrated that the mechanisms underlying the effects of the gut microbiota on bone mainly include its modulation of nutrient absorption, intestinal permeability, metabolites (such as short-chain amino acids), immune responses, and hormones or neurotransmitters (such as 5-hydroxytryptamine). Several studies found that external interventions, such as dietary changes, improved bone health and altered the composition of the gut microbiota. This review summarises the beneficial gut bacteria and explores how dietary, natural, and physical factors alter the diversity and composition of the gut microbiota to improve bone health, thereby providing potential new insight into the prevention of osteoporosis.

Prediction of Synergistic Antibiotic Combinations by Graph Learning.

Antibiotic resistance is a major public health concern. Antibiotic combinations, offering better efficacy at lower doses, are a useful way to handle this problem. However, it is difficult for us to find effective antibiotic combinations in the vast chemical space. Herein, we propose a graph learning framework to predict synergistic antibiotic combinations. In this model, a network proximity method combined with network propagation was used to quantify the relationships of drug pairs, and we found that synergistic antibiotic combinations tend to have smaller network proximity. Therefore, network proximity can be used for building an affinity matrix. Subsequently, the affinity matrix was fed into a graph regularization model to predict potential synergistic antibiotic combinations. Compared with existing methods, our model shows a better performance in the prediction of synergistic antibiotic combinations and interpretability.

The change of gut microbiota-derived short-chain fatty acids in diabetic kidney disease.

BACKGROUND: Previous studies found the dysbiosis of intestinal microbiota in diabetic kidney disease (DKD), especially the decreased SCFA-producing bacteria. We aimed to investigate the concentration of the stool and serum short-chain fatty acids (SCFAs), gut microbiota-derived metabolites, in individuals with DKD and reveal the correlations between SCFAs and renal function. METHODS: A total of 30 participants with DKD, 30 participants with type 2 diabetes mellitus (DM), and 30 normal controls (NC) in HwaMei Hospital were recruited from 1/1/2018 to 12/31/2019. Participants with DKD were divided into low estimated glomerular filtration rate (eGFR)(eGFR<60ml/min, n=14) and high eGFR (eGFR≥60ml/min, n=16) subgroups. Stool and serum were measured for SCFAs with gas chromatograph-mass spectrometry. RESULTS: The DKD group showed markedly lower levels of fecal acetate, propionate, and butyrate versus NC (p<0.001, p<0.001, p=0.018, respectively) [1027.32(784.21-1357.90)]vs[2064.59(1561.82-2637.44)]µg/g,[929.53(493.65-1344.26)]vs[1684.57(1110.54-2324.69)]µg/g,[851.39(409.57-1611.65)] vs[1440.74(1004.15-2594.73)]µg/g, respectively, and the lowest fecal total SCFAs concentration among the groups. DKD group also had a lower serum caproate concentration than that with diabetes (p=0.020)[0.57(0.47-0.61)]vs[0.65(0.53-0.79)]µmol/L. In the univariate regression analysis, fecal and serum acetate correlated with eGFR (OR=1.013, p=0.072; OR=1.017, p=0.032). The correlation between serum total SCFAs and eGFR showed statistical significance (OR=1.019, p=0.024) unadjusted and a borderline significance (OR=1.024, p=0.063) when adjusted for Hb and LDL. The decrease in serum acetate and total SCFAs were found of borderline significant difference in both subgroups (p=0.055, p=0.050). CONCLUSION: This study provides evidence that in individuals with DKD, serum and fecal SCFAs levels (fecal level in particular) were lowered, and there was a negative correlation between SCFAs and renal function.

Microglia NLRP3 Inflammasomes Activation Involving Diabetic Neuroinflammation in Diabetic Mice and BV2 Cells.

BACKGROUND: Hyperglycemia-induced microglia activation can cause a continuous release of proinflammatory cytokines, which gradually damages neurons and contributes to central diabetic neuroinflammation. OBJECTIVE: This study aimed to illustrate the possible mechanism related to NLRP3 inflammasome and the aggravation of diabetes neuroinflammation. METHODS: The targeted proteins from BV2 cells and brain tissues were tested by Western blot or immunohistochemistry. Cytokines from cell supernatant and serum were detected by ELISA. Meanwhile, cytoplasm and mitochondria ROS were determined by DCFHDA and Mito sox Red, respectively. RESULTS: In vitro, BV2 cells were stimulated by different glucose concentrations (5.5 to 65 mM/L) above physiological values and maintained for different periods (12 to 48h). The proinflammatory cytokines IL-1ß, IL18, IL6, TNFα and cytoplasm ROS were significantly increased in a dose-dependent manner, while mitochondrial ROS was unaffected. NLRP3 inflammasomes, MAPKs, and NF-κB pathways were obviously activated at the concentration of 35 mM/L for 12h. Inhibition assay using specific inhibitors indicated that the treatment of glucose (35 mM/L for 12h) could stimulate NLRP3 inflammasome activation via ROS/JNK MAPKs/NF-κB pathway. In STZ induced diabetes mice models, microglia NLRP3, ASC, and caspase-1 proteins were highly expressed, and serum cytokines IL-1ß, IL6, IL18, and TNFα were remarkably increased. CONCLUSION: Microglia NLRP3 inflammasomes activation involves diabetic neuroinflammation in diabetic mice and BV2 cells via ROS/JNK MAPKs/NF-κB pathways.

Factors associated with fluoroscopy-guided placement of nasoenteral feeding tubes.

BACKGROUND: Feeding by nasoenteral tube (NET) is safe and effective for supporting the nutrition needs of patients with inadequate oral intake. However, during insertion of the NET with fluoroscopic guidance, both the professional staff and patients are exposed to radiation. To improve the success rate of NET placement and minimize radiation exposure, this retrospective study evaluated potential factors associated with successful fluoroscopy-guided NET placement and short total fluoroscopy time (TFT) among Chinese patients. METHODS: An assessment was conducted among patients (n = 348) who received NET placement by physicians under fluoroscopic guidance. Multivariate logistic regression models and linear models were used to validate factors that affected the success of placement and TFT. RESULTS: NET was placed successfully in 319 patients (91.7%), with a median TFT of 6.1 (interquartile range [IQR], 4.9-9.9) minutes. The median TFT of patients with unsuccessful placement was 15.4 (IQR, 12.7-20.9) minutes. Factors associated with successful placement included lack of upper gastrointestinal (GI) surgery history and normal peristalsis of the upper GI tract (P ≤ .015). The TFT was significantly influenced by upper GI surgery history and characteristics of the upper GI tract (P ≤ .025). The professional title or experience of the operators had no association with successful NET placement or TFT. CONCLUSIONS: NET placement under fluoroscopic guidance had a high success rate. Factors that are crucial for planning the approach include a history of upper GI surgery, the dynamic status of the upper GI tract, and features of the upper GI tract.

miR-3188 Regulates proliferation and apoptosis of granulosa cells by targeting KCNA5 in the polycystic ovary syndrome.

Abnormal proliferation of granulosa cells is implicated in ovarian dysfunction and dysregulated folliculogenesis in the polycystic ovary syndrome (PCOS). Aberrant microRNA (miRNA) expression might contribute to disordered folliculogenesis and granulosa cell proliferation in PCOS. This study aimed to investigate the roles of miR-3188 in ovarian dysfunction, as well as the mechanism involved in granulosa cell proliferation in PCOS. Firstly, peripheral blood samples were isolated from PCOS patients and healthy controls, and qRT-PCR analysis demonstrated a dramatic increase in miR-3188 in PCOS patients when compared to the healthy controls. Secondly, miR-3188 overexpression increased cell viability of the granulosa-like tumor cell line (KGN). However, cell viability of KGN was repressed by interference with miR-3188. MiR-3188 promoted cell cycle of KGN through increasing cyclinD1 and decreasing p21 levels. Moreover, cell apoptosis was suppressed by miR-3188 in KGN, indicated by enhanced Bcl-2, and reduced Bax and cleaved caspase-3 levels, whereas knockdown of miR-3188 resulted in opposite effects. Lastly, potassium voltage-gated channel subfamily A member 5 (KCNA5) was verified as a target of miR-3188. KCNA5 expression was decreased and displayed negative correlation with miR-3188 levels in PCOS patients. Overexpression of KCNA5 attenuated the promotive effects of miR-3188 on cell viability and cell cycle in KGN. In conclusion, miR-3188, a key miRNA enhanced in PCOS, promoted granulosa cell proliferation through down-regulation of KCNA5, providing a new therapeutic target for PCOS.

Two to Tango: Dialogue between Adaptive and Innate Immunity in Type 1 Diabetes.

Type 1 diabetes mellitus (T1DM) is a long-term and chronic autoimmune disorder, in which the immune system attacks the pancreatic ß-cells. Both adaptive and innate immune systems are involved in T1DM development. Both B-cells and T-cells, including CD4 + and CD8 + T-cells, as well as other T-cell subsets, could affect onset of autoimmunity. Furthermore, cells involved in innate immunity, including the macrophages, dendritic cells, and natural killer (NK) cells, could also accelerate or decelerate T1DM development. In this review, the crosstalk and function of immune cells in the pathogenesis of T1DM, as well as the corresponding therapeutic interventions, are discussed.