Dexmedetomidine Prolongs Lidocaine Intravenous Regional Anesthesia in Rats by Blocking the Hyperpolarization-Activated Cation Current.

Purpose: Intravenous regional anesthesia (IVRA) using lidocaine provides effective localized analgesia but its duration is limited. The mechanism by which dexmedetomidine enhances lidocaine IVRA is unclear but may involve modulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Materials and Methods: Lidocaine IVRA with varying dexmedetomidine concentrations was performed in the tails of Sprague-Dawley rats. Tail-flick and tail-clamping tests assessed IVRA analgesia and anesthesia efficacy and duration. Contributions of α2 adrenergic receptors and HCN channels were evaluated by incorporating an α adrenergic receptor antagonist, the HCN channel inhibitor ZD7288, and the HCN channel agonist forskolin. Furthermore, whole-cell patch clamp electrophysiology quantified the effects of dexmedetomidine on HCN channels mediating hyperpolarization-activated cation current (Ih) in isolated dorsal root ganglion neurons. Results: Dexmedetomidine dose-dependently extended lidocaine IVRA duration and analgesia, unaffected by α2 receptor blockade. The HCN channel inhibitor ZD7288 also prolonged lidocaine IVRA effects, while the HCN channel activator forskolin shortened effects. In dorsal root ganglion neurons, dexmedetomidine concentration-dependently inhibited Ih amplitude and shifted the voltage-dependence of HCN channel activation. Conclusion: Dexmedetomidine prolongs lidocaine IVRA duration by directly inhibiting HCN channel activity, independent of α2 adrenergic receptor activation. This HCN channel inhibition represents a novel mechanism underlying the anesthetic and analgesic adjuvant effects of dexmedetomidine in IVRA.

Profiles in neglect of older adult care workers in a long-term care facility: a latent profile analysis.

Background: Neglect is a common form of abuse, and long-term care facilities record higher incidences of this abuse. Given that older adult care workers are the main workforce in these facilities, their neglectful behavior requires public health attention. Internal individual characteristics can lead to older adult abuse, and managing workers who abuse older adults may require various methods. This study aimed to identify the profiles of neglect among older adult care workers in long-term care facilities and explore the influencing factors of neglect. Methods: In this cross-sectional study, a convenience sample of older adult care workers from 15 long-term care facilities in Shandong Province (N = 421) completed a questionnaire on the characteristics associated with neglect. Latent profile analysis was used to identify distinct neglect profiles and promote the understanding of individual characteristics associated with varying levels of neglect. One-way analysis of variance and multivariate logistic regression analyses were used to examine the population characteristic differences. Results: Older adult care workers exhibited three neglect profiles, namely, the "low-risk group," "medium-risk group," and "high-risk group." Males, participants with no employment qualification certificate, and those who did not attend regular training represented the majority of those in the "high-risk group." Participants with a monthly income of more than ¥ 4,000 and nursing 1-2 older adults simultaneously represented the majority of those in the "low-risk group." Conclusion: Long-term care facility administrators should tailor interventions to individual care worker profiles to reduce neglect behaviors and improve care levels.

Glucose Fluctuation Inhibits Nrf2 Signaling Pathway in Hippocampal Tissues and Exacerbates Cognitive Impairment in Streptozotocin-Induced Diabetic Rats.

Background: This research investigated whether glucose fluctuation (GF) can exacerbate cognitive impairment in streptozotocin-induced diabetic rats and explored the related mechanism. Methods: After 4 weeks of feeding with diets containing high fats plus sugar, the rat model of diabetes mellitus (DM) was established by intraperitoneal injection of streptozotocin (STZ). Then, GF was triggered by means of alternating satiety and starvation for 24 h. The weight, blood glucose level, and water intake of the rats were recorded. The Morris water maze (MWM) test was carried out to appraise the cognitive function at the end of week 12. Moreover, the morphological structure of hippocampal neurons was viewed through HE and Nissl staining, and transmission electron microscopy (TEM) was performed for ultrastructure observation. The protein expression levels of Nrf2, HO-1, NQO-1, Bax, Bcl-2, and Caspase-3 in the hippocampal tissues of rats were measured via Western blotting, and the mRNA expressions of Nrf2, HO-1, and NQO-1 were examined using qRT-PCR. Finally, Western blotting and immunohistochemistry were conducted to detect BDNF levels. Results: It was manifested that GF not only aggravated the impairment of spatial memory in rats with STZ-induced type 2 DM but also stimulated the loss, shrinkage, and apoptosis of hippocampal neurons. Regarding the expressions in murine hippocampal tissues, GF depressed Nrf2, HO-1, NQO-1, Bcl-2, and BDNF but boosted Caspase-3 and Bax. Conclusions: GF aggravates cognitive impairment by inhibiting the Nrf2 signaling pathway and inducing oxidative stress and apoptosis in the hippocampal tissues.

A case of hypophysis with HIV negative cryptococcal meningitis. / 垂体功能减退症伴HIV阴性的隐球菌性脑膜炎1例.

The clinical mortality of cryptococcal meningitis (CM) is high. There is no report of hypopituitarism associated with HIV negative CM so far. The patients with hypopituitarism complicated with CM are easy to be misdiagnosed and mistreated. A patient with hypopituitarism and HIV negative CM was admitted to Weihai Municipal Hospital on August 27, 2021. The patient was treated for 18 years after craniopharyngioma with headache for more than 2 months, nausea and vomiting for 4 days. MRI showed abnormal enhancement of the right basal ganglia, edema of surrounding tissue, and multiple striated enhancement of the bilateral cerebellar hemisphere. The smear of cerebrospinal fluid showed a large number of fungi and Cryptococcus. Culture of cerebrospinal fluid showed positive in Cryptococcus. The patient's HIV and syphilis antibodies were negative. The condition of the patient was improved after active antifungal therapy. The clinician should make a definite diagnosis and give early treatment as soon as possible.

Incidence, prevalence and characteristics of multimorbidity in different age groups among urban hospitalized patients in China.

The aim of the study was to investigate the incidence, prevalence and characteristics of multimorbidity in urban inpatients of different age groups. This study used data from the National Insurance Claim for Epidemiology Research (NICER) to calculate the overall incidence, prevalence, geographic and age distribution patterns, health care burden, and multimorbidity patterns for multimorbidity in 2017. According to our study, the overall prevalence of multimorbidity was 6.68%, and the overall prevalence was 14.87% in 2017. The prevalence of multimorbidity increases with age. The pattern of the geographic distribution of multimorbidity shows that the prevalence of multimorbidity is relatively high in South East China. The average annual health care expenditure of patients with multimorbidity increased with age and rose rapidly, especially among older patients. Patients with cancer and chronic kidney disease have higher treatment costs. Patients with hypertension or ischemic heart disease had a significantly higher relative risk of multimorbidity than other included noncommunicable diseases (NCDs). Hyperlipidemia has generated the highest number of association rules, which may suggest that hyperlipidemia may be both a risk factor for other NCDs and an outcome of them.

Development and Validation of a Clinical Prediction Model for Venous Thromboembolism Following Neurosurgery: A 6-Year, Multicenter, Retrospective and Prospective Diagnostic Cohort Study.

BACKGROUND: Based on the literature and data on its clinical trials, the incidence of venous thromboembolism (VTE) in patients undergoing neurosurgery has been 3.0%~26%. We used advanced machine learning techniques and statistical methods to provide a clinical prediction model for VTE after neurosurgery. METHODS: All patients (n = 5867) who underwent neurosurgery from the development and retrospective internal validation cohorts were obtained from May 2017 to April 2022 at the Department of Neurosurgery at the Sanbo Brain Hospital. The clinical and biomarker variables were divided into pre-, intra-, and postoperative. A univariate logistic regression (LR) was applied to explore the 67 candidate predictors with VTE. We used a multivariable logistic regression (MLR) to select all significant MLR variables of MLR to build the clinical risk prediction model. We used a random forest to calculate the importance of significant variables of MLR. In addition, we conducted prospective internal (n = 490) and external validation (n = 2301) for the model. RESULTS: Eight variables were selected for inclusion in the final clinical prediction model: D-dimer before surgery, activated partial thromboplastin time before neurosurgery, age, craniopharyngioma, duration of operation, disturbance of consciousness on the second day after surgery and high dose of mannitol, and highest D-dimer within 72 h after surgery. The area under the curve (AUC) values for the development, retrospective internal validation, and prospective internal validation cohorts were 0.78, 0.77, and 0.79, respectively. The external validation set had the highest AUC value of 0.85. CONCLUSIONS: This validated clinical prediction model, including eight clinical factors and biomarkers, predicted the risk of VTE following neurosurgery. Looking forward to further research exploring the standardization of clinical decision-making for primary VTE prevention based on this model.

Relationship between acute glucose variability and cognitive decline in type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Cognitive decline is one of the most widespread chronic complications of diabetes, which occurs in more than half of the patients with type 2 diabetes (T2DM). Emerging evidences have suggested that glucose variability (GV) is associated with the pathogenesis of diabetic complications. However, the influence of acute GV on cognitive dysfunction in T2DM is still controversial. The aim of the study was to evaluate the association between acute GV and cognitive defect in T2DM, and provide a most recent and comprehensive summary of the evidences in this research field. METHODS: PubMed, Cochrane library, EMBASE, Web of science, Sinomed, China National Knowledge Infrastructure (CNKI), and Wanfang were searched for articles that reported on the association between acute GV and cognitive impairment in T2DM. RESULTS: 9 eligible studies were included, with a total of 1263 patients with T2DM involved. Results showed that summary Fisher's z value was -0.23 [95%CI (-0.39, -0.06)], suggesting statistical significance (P = 0.006). Summary r value was -0.22 [95%CI (-0.37, -0.06)]. A lower cognitive performance was found in the subjects with greater glucose variation, which has statistical significance. Mean amplitude of glycemic excursions (MAGE) was associated with a higher risk of poor functional outcomes. Fisher's z value was -0.35 [95%CI (-0.43, -0.25)], indicating statistical significance (P = 0.011). Sensitivity analyses by omitting individual studies showed stability of the results. CONCLUSIONS: Overall, higher acute GV is associated with an increased risk of cognitive impairment in patients with T2DM. Further studies should be required to determine whether targeted intervention of reducing acute GV could prevent cognitive decline.

The accelerated organ senescence and proteotoxicity in thyrotoxicosis mice.

The mechanism of aging has always been the focus of research, because aging is related to disease susceptibility and seriously affects people's quality of life. The diseases also accelerate the aging process, especially the pathological changes of substantive organs, such as cardiac hypertrophy, severely shortened lifespan. So, lesions in organs are both a consequence and a cause of aging. However, the disease in a given organ is not in isolation but is a systemic problem. Our previous study found that thyrotoxicosis mice model has aging characteristics including immunosenescence, lipotoxicity, malnutrition. But all these characteristics will lead to organ senescence, therefore, this study continued to study the aging changes of important organs such as heart, liver, and kidney in thyrotoxicosis mice using tandem mass tags (TMT) proteomics method. The results showed that the excess thyroxine led to cardiac hypertrophy. In the liver, the ability to synthesize functional proteins, detoxify, and metabolism were declined. The effect on the kidney was the decreased ability of detoxify and metabolism. The main finding of the present study was that the acceleration of organ senescence by excess thyroxine was due to proteotoxicity. The shared cause of proteotoxicity in the three organs included the intensify of oxidative phosphorylation, the redundancy production of ribosomes, and the lack of splicing and ubiquitin proteasome system function. Totally, proteotoxicity was another parallel between thyrotoxicosis and aging in addition to lipotoxicity. Our research provided a convenient and appropriate animal model for exploring aging mechanism and antiaging drugs.

Study on the influence of patient safety culture on the pain and turnover intention of Chinese nurses in adverse nursing events.

AIM: Exploring the influence of patient safety culture on nurses' pain and turnover intention the job as a second victim. DESIGN: The study employed a cross-sectional design. METHODS: From July 2020 to August 2020, a convenience sampling method was used to select 1525 clinical nurses from hospitals of different levels in Shandong Province as the research subjects, and the general data survey method, patient safety culture scale and the assessment entries on pain in the second victim experience and support scale, using a convenience sampling method. RESULTS: Patient safety culture is an influencing factor that affects the second-victim pain and turnover intention. Among them, the non-punitive response to errors, open communication, cooperation between different departments, organizational learning and promotion has a statistically significant influence on the second-victim pain and turnover intention.

Systematic evaluation of combined herbal adjuvant therapy for proliferative diabetic retinopathy.

Objective: To evaluate the efficacy and safety of combined traditional Chinese medicine in the adjuvant treatment of proliferative diabetic retinopathy (PDR) by Meta-analysis. Methods: PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang databases were searched by computer. Random controlled clinical trials (RCTS) using traditional Chinese medicine as adjuvant therapy for proliferative diabetic retinopathy were screened, and Stata16.0 software was used to perform meta-analysis on the final included literatures. Results: A total of 18 studies involving 1392 patients were included. Meta-analysis showed that the clinical effective rate OR=2.99 (CI: 2.18-4.10, I2 = 42.7%, P<0.05); Visual acuity MD=0.10(CI: 0.06-0.13, I2 = 0%, P<0.05); Fundus efficacy OR=5.47 (CI: 1.33-22.51, I2 = 71.4%, P<0.05); Neovascularisation regression rate OR=8 (CI: 3.83-16.71, I2 = 30.1%, P<0.05); Macular foveal thickness MD=-44.24 (CI: -84.55-3.93, I2 = 95.6%, P<0.05); Absorption of vitreous hemorrhage OR=4.7 (CI: 2.26-9.77, I2 = 0%, P<0.05); Fasting blood glucose MD=-0.23, (CI: -0.38-0.07, I2 = 0%, P<0.05); 2h postprandial blood glucose MD=-0.19 (CI: -0.52-0.14, I2 = 0%, P=0.25). From the results, the combined Chinese medicine adjuvant therapy showed better efficacy than the control group. A total of 69 kinds of traditional Chinese medicine were involved in 18 studies, among which the top four applied frequencies were Panax notoginseng, Rehmannia rehmannii, Astragalus membranaceus and Poria cocos. Most of the medicines were sweet and bitter in taste, the qi tended to be slight cold and cold, and the meridian tropism belongs to the liver meridian. Conclusion: The combination of traditional Chinese medicine adjuvant therapy has a good curative effect on PDR patients. However, the relevant clinical trials are few and more high-quality clinical trials are still needed, what's more the attention should be paid to the exploration of its safety.

Hsa_circ_0008500 inhibits apoptosis of adipose-derived stem cells under high glucose through hsa-miR-1273h-5p/ELK1 axis.

Preliminary researches have confirmed that the number of apoptosis of adipose tissue-derived stem cells (ADSCs) in patients with diabetes is significantly increased, leading to a difficult healing wound. Increasing researches revealed that circular RNAs (circRNAs) can control apoptosis. However, it is still unclear whether and how circRNAs are critical for regulating ADSCs apoptosis. In this study, we utilized in vitro model in which ADSCs were cultivated with normal glucose (NG) (5.5 mM) or high glucose (HG) (25 mM) medium, respectively, and found that more apoptotic ADSCs were observed in HG medium comparing to ADSCs in NG medium. Furthermore, we found that hsa_circ_0008500 attenuated HG-mediated ADSCs apoptosis. In addition, Hsa_circ_0008500 could directly interact with hsa-miR-1273h-5p, acting as a miRNA sponge, which subsequently suppressed Ets-like protein-1(ELK1) expression, the downstream target of hsa-miR-1273h-5p. Thus, these results indicated that targeting the hsa_circ_0008500/hsa-miR-1273h-5p/ELK1 signaling pathway in ADSCs may be a potential target for repairing diabetic wounds.

The efficacy and safety of Chinese herbal medicine in the treatment of painful diabetic neuropathy: A systematic review and meta-analysis.

Objective: The objective of this systematic review and meta-analysis is to assess the effectiveness and security of Chinese herbal medicine (CHM) in the therapy of painful diabetic neuropathy (PDN). Methods: We searched databases for randomized controlled trials (RCTs) of CHM in the treatment of PDN. Outcome indicators included nerve conduction velocity, clinical efficiency, pain score, TCM syndrome score, and adverse events. Stata 16.0 was used to carry out the Meta-analysis. Results: A total of 21 RCTs with 1,737 participants were included. This meta-analysis found that using CHM as adjuvant treatment or as monotherapy for PDN can improve SCV of median nerve [mean difference (MD) = 3.56, 95% Confidence interval (CI) (2.19, 4.92) ], MCV of median nerve [ MD = 3.82, 95% CI (2.51, 5.12) ], SCV of common peroneal nerve [ MD = 4.16, 95% CI (1.62, 6.70) ], MCV of common peroneal nerve [ MD = 4.37, 95% CI (1.82, 6.93) ], SCV of gastrocnemius nerve [ MD = 4.95, 95% CI (3.52, 6.37) ], SCV of tibial nerve [ MD = 3.17, 95% CI (-2.64, 8.99) ], MCV of tibial nerve [MD = 6.30, 95%CI (5.00, 7.60)] and clinical effective rate [ odds ratio (OR) = 4.00, 95% CI (2.89, 5.52) ] and reduce pain score [standardized mean difference (SMD) = -2.23, 95% CI (-3.04, -1.41) ], TCM syndrome score [ MD = -4.70, 95% CI (-6.61, -2.80) ]. In addition, compared to the control group, adverse events of Chinese medicine intervention occurred less. Conclusion: CHM as adjuvant therapy or single treatment has a good curative effect and is safe for patients with PDN, which is worthy of clinical promotion and use, however; higher quality clinical studies are still needed to prove. Systematic Review Registration: https://www.crd.york.ac.uk/, identifier CRD42022327967.

Efficacy and safety of prophylaxis for venous thromboembolism in brain neoplasm patients undergoing neurosurgery: a systematic review and Bayesian network meta-analysis.

Neurosurgeons often face this dilemma. Brain neoplasm patients undergoing neurosurgery are at a high risk of venous thrombosis. However, antithrombotic drugs may induce bleeding complications. Therefore, we compared the efficacy and safety of prophylaxis for venous thromboembolism (VTE) in brain neoplasm patients undergoing neurosurgery. We searched Cochrane Central Register of Controlled Trials, Ovid MEDLINE(R), and Embase from inception to January 2022 for randomized controlled trials (RCTs) comparing the prophylactic measures efficacy and safety for VTE in brain neoplasm patients undergoing neurosurgery. The main efficacy outcome was symptomatic or asymptomatic VTE. The safety outcomes included major bleeding, minor bleeding, all occurrences of bleeding, and all-cause mortality. We used (Log) odds ratio (OR) of various chemoprophylaxis regimens to judge the safety and effectiveness of VTE. Additionally, all types of intervention were ranked by the Surface Under the Cumulative Ranking (SUCRA) value. We included 10 RCTs with 1128 brain neoplasm patients undergoing neurosurgery. For symptomatic or asymptomatic VTE and proximal DVT or PE, DOACs, compared with placebo, can significantly reduce the events. DOACs were superior to all other interventions in the rank plot of these events. For major bleeding reduction, unfractionated heparin (SUCRA value = 0.21) demonstrated better safety efficacy than others. For minor bleeding reduction, DOACs had a significantly higher risk of minor bleeding compared with placebo [Log OR 16.76, 95% CrI (1.53, 61.13)], LMWH [Log OR 15.68, 95% CrI (0.26, 60.10)] and UFH [Log OR 15.93, 95% CrI (0.22, 60.16)] respectively. Except for placebo (SUCRA values of 0.13), UFH (SUCRA values of 0.37) depicted better safety efficacy than others. For all-cause mortality, we found UFH always had significantly lower all-cause mortality compared with low-molecular-weight heparin (LMWH) [Log OR = 14.17, 95% CrI (0.05, 48.35)]. UFH plus intermittent pneumatic compression (IPC) (SUCRA value of 0.12) displayed the best safety for all-cause mortality. In our study, DOACs were more effective as prophylaxis for VTE in brain neoplasm patients undergoing neurosurgery. Regarding the safety of prophylaxis for VTE, UFH of chemoprophylaxis consistently demonstrated better safety efficacy, involving either major bleeding, minor bleeding, bleeding, or all-cause mortality.

Transcriptome and Pathway Analysis Reveals that Adipose-derived Stem Cells Target Inflammatory Factors and Delay the Progression of Diabetic Liver Disease.

BACKGROUND: Diabetic liver disease is one of the main complications that leads to the aggravation of diabetes, but it has not received sufficient attention. This study aimed to provide a better understanding of the altered molecular networks in in diabetic rats with liver damage after stem cell therapy. To a certain extent, our research would be instructive, since almost no studies of this kind have been performed on patients with diabetic liver disease after stem cell therapy. METHODS: Streptozotocin-induced diabetic rats were treated with adipose-derived stem cells. RNA-Seq analysis was performed on the liver tissues of these animals, and key pathway factors were further identified and validated. RESULTS: RNA-Seq analysis revealed numerous affected signaling pathways and functional categories. The results showed that the network of dual specificity phosphatase 1 (DUSP1), an oxidative stress-related gene, was prominently activated in the liver after stem cell therapy, and the enrichment of genes associated with liver damage, steatosis and fibrosis was also detected. The extracellular regulated protein kinase (ERK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway may be involved in this process by regulating the nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. CONCLUSIONS: These data provide novel insights into liver biology, suggest common alterations in the molecular networks during diabetic liver damage, and show the advantages of stem cell therapy, indicating its further application potential for early treatment of diabetic liver damage and delaying the progression of liver fibrosis in the later stage.

The anti-aging effects of Renshen Guben on thyrotoxicosis mice: Improving immunosenescence, hypoproteinemia, lipotoxicity, and intestinal flora.

With the rapid aging of the population, the control of age-related disease susceptibility and prognosis faces greater challenges. There is an urgent need for a strategy to maintain the vitality of elderly people. In this study, the effect of Renshen Guben (RSGB) oral liquid was investigated on an accelerated aging mice model of thyrotoxicosis by conventional detection methods combined with multiomics technology. The results showed that RSGB increased the number of neutrophils and lymphocytes, enhanced the function of lymphocytes, and increased the levels of complement and antimicrobial peptides, which indicated that RSGB improved the immunity of thyrotoxicosis mice at the cellular and molecular levels. RSGB corrected malnutrition in thyrotoxicosis mice by improving anemia, hypoalbuminemia, ion transporters, and vitamin-binding proteins. RSGB significantly reduced the lipotoxicity by reducing the level of fatty acids, triglyceride, sphingolipids, and glucocorticoids, thus increasing the level of docosapentaenoic acid (DPA) and bile acids, which contributed to improve immunosenescence. The intestinal defense ability of thyrotoxicosis mice was enhanced with the increase of bile acids and lactic acid bacteria by the RSGB treatment. The plant metabolomics analysis showed that there were various active components in RSGB oral liquid and medicated serum, including terpenoids, phenolic acids, flavonoids, tannin, alkaloids, organic acids, phenolamines, amino acids, and others. They have antioxidant, immune regulation, and anti-aging effects, which was the material basis of RSGB. Totally, RSGB protected the thyrotoxicosis mice against aging by improving immunosenescence, hypoproteinemia, lipotoxicity, and the intestinal flora. It will be beneficial for improving the disease susceptibility and prognosis of the elderly.

The Aging Features of Thyrotoxicosis Mice: Malnutrition, Immunosenescence and Lipotoxicity.

The problem of aging is mainly the increase of age-related diseases, and elderly patients have longer hospitalization and worse prognosis. Poorer nutritional status and immunosenescence may be predisposing and severe factors. The mechanism of the high incidence of diseases and poor prognosis behind aging is complex. Finding suitable aging models is of great significance to find strategies to prevent aging related events. In this study, the relationship between thyrotoxicosis and aging was investigated in mice. The results of routine blood tests and flow cytometry showed that immunosenescence occurred in thyrotoxicosis mice, which was characterized by a significant decrease in neutrophils, lymphocytes, CD4+/CD8+ and CD4+IFN-γ+ lymphocytes. Biochemical examination results showed that there were hypocholesterolemia, hypolipoproteinemia, and hyperlipidemia in thyrotoxicosis mice. Serum proteomics analysis showed that the downregulation of complement and coagulation proteins was another manifestation of declined immunity. Moreover, proteomics analysis showed that many downregulated proteins were related to homeostasis, mainly transport proteins. Their downregulation led to the disturbance of osmotic pressure, ion homeostasis, vitamin utilization, lipid transport, hyaluronic acid processing, and pH maintenance. Serum metabolomics analysis provided more detailed evidence of homeostasis disturbance, especially lipid metabolism disorder, including the downregulation of cholesterol, vitamin D, bile acids, docosanoids, and the upregulation of glucocorticoids, triglycerides, sphingolipids, and free fatty acids. The upregulated lipid metabolites were related to lipotoxicity, which might be one cause of immunosenescence and many aging related syndromes. This study provides evidence for the aging model of thyrotoxicosis mice, which can be used for exploring anti-aging drugs and strategies.

Krüppel-Like Factor 15 Reduces Ischemia-Induced Apoptosis Involving Regulation of p38/MAPK Signaling.

Cardiomyocyte apoptosis is a characteristic of a variety of cardiac diseases, including myocardial infarction (MI). Krüppel-like factor 15 (KLF15) is a transcription factor of Krüppel family that plays an important part in cardiovascular diseases. However, the function and the underlying mechanism of KLF15 in MI remain unknown. The expression of KLF15 was downregulated both in ischemic myocardium of MI mice model and hypoxia-treated neonatal rat ventricular myocytes (NRVCs). KLF15 overexpression mediated by adeno-associated virus significantly abrogated the ischemia-induced cardiac dysfunction, increased the survival rate, and reduced infarct size after MI. Meanwhile, KLF15 overexpression dramatically reduced the myocardial apoptosis, regulated apoptosis-related genes, such as Bcl2 and Bax, diminished the activities of caspase-9/3, and inactivated p38/MAPK signaling in the border zone. Similar results were observed in NRVCs exposed to hypoxia. We demonstrated for the first time that KLF15 overexpression could reduce cardiomyocyte apoptosis and improve cardiac dysfunction in MI mice at least partially by inhibiting p38/MAPK signaling pathway.

Qindan Capsule Attenuates Myocardial Hypertrophy and Fibrosis in Pressure Overload-Induced Mice Involving mTOR and TGF-ß1/Smad Signaling Pathway Inhibition.

Qindan capsule (QC), a traditional Chinese medicine compound, has been used to treat hypertension in the clinic for over 30 years. It is still not known about the effects of QC on pressure overload-induced cardiac remodeling. Hence, this study aims to investigate the effects of QC on pressure overload-induced cardiac hypertrophy, fibrosis, and heart failure in mice and to determine the possible mechanisms. Transverse aortic constriction (TAC) surgery was used to induce cardiac hypertrophy and heart failure in C57BL/6 mice. Mice were treated with QC or losartan for 8 weeks after TAC surgery. Cardiac function indexes were evaluated with transthoracic echocardiography. Cardiac pathology was detected using HE and Masson's trichrome staining. Cardiomyocyte ultrastructure was detected using transmission electron microscopy. Hypertrophy-related fetal gene expression was investigated using real-time RT-PCR. The expression of 8-OHdG and the concentration of MDA and Ang-II were assessed by immunohistochemistry stain and ELISA assay, respectively. The total and phosphorylated protein levels of mTOR, p70S6K, 4EBP1, Smad2, and Smad3 and the expression of TGF-ß1 and collagen I were measured using western blot. The results showed that low- and high-dose QC improved pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction. QC inhibited ANP, BNP, and ß-MHC mRNA expression in failing hearts. QC improved myocardial ultrastructure after TAC surgery. Furthermore, QC downregulated the expression of 8-OHdG and the concentration of MDA, 15-F2t-IsoP, and Ang-II in heart tissues after TAC surgery. We also found that QC inhibited the phosphorylation of mTOR, p70S6K, and 4EBP1 and the expression of TGF-ß1, p-Smad2, p-Smad3, and collagen I in pressure overload-induced failing hearts. These data indicate that QC has direct benefic effects on pressure overload-induced cardiac hypertrophy, fibrosis, and dysfunction. The protective effects of QC involve prevention of increased oxidative stress injury and Ang-II levels and inhibition of mTOR and TGF-ß1/Smad pathways in failing hearts.

TGM6 might not be a specific causative gene for spinocerebellar ataxia resulting from genetic analysis and functional study.

OBJECTIVE: To investigate whether TGM6 is a specific causative gene for spinocerebellar ataxia type 35 (SCA35). MATERIALS AND METHODS: The next-generation sequencing (NGS) data consisted of 47 SCA, 762 non-SCA patients and 2827 normal controls were analyzed. The allele frequencies of low frequent and deleterious TGM6 variants were compared. Functional studies were performed in five widely distributed variants (V314M, R342Q, P347L, V391M, L517W). RESULTS: Two TGM6 detrimental variants were identified in one SCA patient, 14 in non-SCA patients and 43 in normal controls, the allele frequencies of TGM6 variants did not differ among the SCA and other controls. Seven reported pathogenic variants (c.7 + 1G > T, c.331C > T, c.1171G > A, c.1478C > T, c.1528G > C, c.1550 T > G and c.1722_1724delAGA) were identified in patients with various neurologic diseases or normal controls. All the 5 widely distributed variants led to destabilization and significantly reduction of enzymatic activity of TG6 as the reported pathogenic mutations. CONCLUSIONS: TGM6 might not be a specific causative gene for SCA35, the relevant clinical consult or diagnostic should be pay more attention.

Inhibition of Aurora-A improves insulin resistance by ameliorating islet inflammation and controlling interleukin-6 in a diabetic mouse model.

Aurora-A kinase, a serine/threonine mitotic kinase, is reportedly upregulated in skin tissues of individuals with type 2 diabetes mellitus , although its function in diabetes is unclear. C57BL/6 J mice were utilized to establish a type 2 diabetic model and explore the functions of Aurora-A in diabetes. Aurora-A was highly expressed in the pancreas of the diabetic mice as confirmed by western blot. Inhibition of Aurora-A did not affect fasting blood glucose and body weight, but did improve insulin resistance, as indicated by improved oral glucose tolerance, insulin tolerance, and the Homoeostasis Model Assessment-Insulin Resistance index. Blockade of Aurora-A dramatically decreased the number of infiltrating macrophages in the pancreas in parallel with decreases in the levels of serum insulin and interleukin-6 (IL-6) mRNA. The levels of phosphorylated forms of protein kinase B, which are the key mediators of in insulin resistance, were not induced in liver, adipocyte tissues, and skeletal muscle by alisertib treatment. Our findings indicate that suppression of Aurora-A could at least partially enhance insulin sensitivity by decreasing the number of infiltrating macrophages and IL-6 level in a type 2 diabetic mouse model.