USP38 exacerbates pressure overload-induced left ventricular electrical remodeling.

BACKGROUND: Ubiquitin-specific protease 38 (USP38), belonging to the USP family, is recognized for its role in controlling protein degradation and diverse biological processes. Ventricular arrhythmias (VAs) following heart failure (HF) are closely linked to ventricular electrical remodeling, yet the specific mechanisms underlying VAs in HF remain inadequately explored. In this study, we examined the impact of USP38 on VAs in pressure overload-induced HF. METHODS: Cardiac-specific USP38 knockout mice, cardiac-specific USP38 transgenic mice and their matched control littermates developed HF induced by aortic banding (AB) surgery. After subjecting the mice to AB surgery for a duration of four weeks, comprehensive investigations were conducted, including pathological analysis and electrophysiological assessments, along with molecular analyses. RESULTS: We observed increased USP38 expression in the left ventricle of mice with HF. Electrocardiogram showed that the USP38 knockout shortened the QRS interval and QTc, while USP38 overexpression prolonged these parameters. USP38 knockout decreased the susceptibility of VAs by shortening action potential duration (APD) and prolonging effective refractory period (ERP). In addition, USP38 knockout increased ion channel and Cx43 expression in ventricle. On the contrary, the increased susceptibility of VAs and the decreased expression of ventricular ion channels and Cx43 were observed with USP38 overexpression. In both in vivo and in vitro experiments, USP38 knockout inhibited TBK1/AKT/CAMKII signaling, whereas USP38 overexpression activated this pathway. CONCLUSION: Our data indicates that USP38 increases susceptibility to VAs after HF through TBK1/AKT/CAMKII signaling pathway, Consequently, USP38 may emerge as a promising therapeutic target for managing VAs following HF.

Precise Regulation in Chain-Edge Structural Microenvironments of 1D Covalent Organic Frameworks for Photocatalysis.

Covalent organic frameworks (COFs) constitute a promising research topic for photocatalytic reactions, but the rules and conformational relationships of 1D COFs are poorly defined. Herein, the chain edge structure is designed by precise modulation at the atomic level, and the 1D COFs bonded by C, O, and S elements is directionally prepared for oxygen-tolerant photoinduced electron transfer-atom transfer radical polymerization (PET-ATRP) reactions. It is demonstrated that heteroatom-type chain edge structures (─O─, ─S─) lead to a decrease in intra-plane conjugation, which restricts the effective transport of photogenerated electrons along the direction of the 1D strip. In contrast, the all-carbon type chain edge structure (─C─) with higher intra-plane conjugation not only reduces the energy loss of photoexcited electrons but also enhances the carrier density, which exhibits the optimal photopolymerization performance. This work offers valuable guidance in the exploitation of 1D COFs for high photocatalytic performance. This work offers valuable guidance in the exploitation of 1D COFs for high photocatalytic performance.

Laparoscopic Ureteric Reconstruction After Partial Ureterectomy for Locally Advanced and Recurrent Pelvic Malignancies (with Video).

BACKGROUND: The urinary tract is one of the most frequently involved organs in advanced non-urologic pelvic malignances. Extensive resection of ureteric organs is mandatory during a curative surgery. Urinary reconstruction after partial ureterectomy, the most challenging situation, is associated with a higher incidence of complication than cystectomy, especially when performed with laparoscopy. Furthermore, to date, no generally accepted strategy for urinary reconstruction after extensive tumor resection with partial ureterectomy has been established. METHODS: The study identified and scrutinized intraoperative videos and clinical records of patients with locally advanced or recurrent pelvic malignancies who underwent segmental ureterectomy during en bloc resection of advanced tumors between February 2020 and February 2024. RESULTS: The study enrolled nine patients, including four cases managed by ureteroureteral anastomosis, two cases managed by ureteroneocystomy, two cases managed by Boari flap reconstruction, and one case managed by ileal interposition. In all nine cases, R0 margins were obtained, and no case needed conversion to laparotomy. No clinical evidence of postoperative urinary leakage was identified. The median follow-up period was 14 months (range, 5-19 months). In three of the nine cases, recurrence was identified, at the 3rd, 18th, and 19th month follow-up evaluations, respectively. One patient died of systemic metastasis. CONCLUSIONS: Laparoscopic ureteric reconstruction is feasible for patients who undergo segmental ureterectomy during extensive surgery for locally advanced or recurrent pelvic malignancies. A low anastomotic leakage rate and favorable postoperative renal function could be achieved in this study when anastomosis was performed laparoscopically.

Dapansutrile Ameliorates Atrial Inflammation and Vulnerability to Atrial Fibrillation in HFpEF Rats.

BACKGROUND: Numerous studies have demonstrated that NLRP3 inflammasomes are key players in the progression of atrial fibrillation (AF) in heart failure with preserved ejection fraction (HFpEF). This study aimed to analyse the effect of pharmacological inhibition of NLRP3 inflammasomes using dapansutrile (DAPA), an oral NLRP3-specific inhibitor. METHODS: Dahl salt-sensitive rats were fed a high-salt diet (HSD, 8% NaCl) to induce HFpEF. Either DAPA (200 mg/kg/day) or saline was administered daily via gavage for 4 weeks. Electrophysiological studies were performed to assess the AF inducibility. Confocal fluorescence microscopy and western blot analysis were used to study calcium handling. RESULTS: The DAPA-treated HFpEF rats were less prone to AF induction by programmed electrical stimulation. Atrial fibrosis and inflammation were attenuated in DAPA-treated HFpEF hearts. Dapansutrile treatment showed an increase in the Ca2+ transient sarcoplasmic reticulum-Ca2+ load, and protein expression of SERCA2; NCX1 and phosphorylation of PLB at Thr17 were decreased following DAPA treatment. The increased frequency of spontaneous Ca2+ spark in the HFpEF rats was related to the hyperphosphorylation of RyR2 at Ser2814, which was blunted in DAPA treatment. Dapansutrile treatment also decreased the phosphorylation of CaMKII expression in the HFpEF rats. Mechanistically, DAPA exerts an anti-arrhythmic effect, mainly by inhibiting activation of the NLRP3 inflammasome. CONCLUSION: These data provide evidence that the beneficial cardiac effects of DAPA are associated with reduced atrial inflammation and improved CaMKII-dependent Ca2+-handling abnormalities via blunting activation of the NLRP3 inflammasome, and DAPA may be beneficial in a rat model of HFpEF-induced AF.

Identification of hydrochemical fingerprints, quality and formation dynamics of groundwater in western high Himalayas.

Identifying hydrochemical fingerprints of groundwater is a challenge in areas with complex geological settings. This study takes the Gilgit-Baltistan, a complex geological area in west high Himalayas, Pakistan, as the study area to get insights into the hydrochemcial genesis and quality of groundwater in complex geological mountainous regions. A total of 53 samples were collected across the area to determine the hydrochemical characteristics and formation of groundwater. Results revealed groundwater there is characterized by slightly alkaline and soft fresh feature. Groundwater is dominated by the hydrochemical facies of HCO3·SO4-Ca·Mg type. The factor method yields three components (PCs) of principal component analysis, which together explain 75.71% of the total variances. The positive correlation of EC, TDS, Ca2+, SO42-, K+ in PC1, and NO3-, Cl- in PC2 indicate that a combination of natural and anthropogenic activities influences groundwater hydrochemistry. Water-rock interaction is the main mechanism governing the natural hydrochemistry of groundwater. The negative correlation of Cl-, SO42-, Ca2+, and Na+ with NDVI attributes to inorganic salt uptake by plant roots. Groundwater chemical composition is also affected by the type of land use. Groundwater is characterized as excellent and good water quality based on the entropy-weighted water quality index assessment, and is suitable for drinking purposes except for very few samples, while aqueous fluoride would pose potential health threats to water consumers in western high Himalayas, and infants are most at risk compared to other populations. This study will help to deepen the hydrochemial formation mechanism and exploitation suitability of groundwater resources in the mountainous areas that undergone the combined actions of nature and human activities, and provide insights into the characteristics of water environmental quality in western Himalayas area.

Balancing adipocyte production and lipid metabolism to treat obesity-induced diabetes with a novel proteoglycan from Ganoderma lucidum.

Obesity is often accompanied by metabolic disorder and insulin resistance, resulting in type 2 diabetes. Based on previous findings, FYGL, a natural hyperbranched proteoglycan extracted from the G. lucidum fruiting body, can decrease blood glucose and reduce body weight in diabetic mice. In this article, the underlying mechanism of FYGL in ameliorating obesity-induced diabetes was further investigated both in vivo and in vitro. FYGL upregulated expression of metabolic genes related to fatty acid biosynthesis, fatty acid ß-oxidation and thermogenesis; downregulated the expression of insulin resistance-related genes; and significantly increased the number of beige adipocytes in db/db mice. In addition, FYGL inhibited preadipocyte differentiation of 3T3-L1 cells by increasing the expression of FABP-4. FYGL not only promoted fatty acid synthesis but also more significantly promoted triglyceride degradation and metabolism by activating the AMPK signalling pathway, therefore preventing fat accumulation, balancing adipocyte production and lipid metabolism, and regulating metabolic disorders and unhealthy obesity. FYGL could be used as a promising pharmacological agent for the treatment of metabolic disorder-related obesity.

The effect of posterior cruciate ligament tibial avulsion fracture on functional outcomes in knees with concomitant ipsilateral lower limb fractures: a matched-cohort analysis.

BACKGROUND: At present, the optimal treatment for posterior cruciate ligament tibial avulsion fracture (PCLTAF) combined with concomitant ipsilateral lower limb fractures remains unclear. The present study aimed to assess the preliminary outcomes of treatment for PCLTAF with concomitant ipsilateral lower limb fractures by open reduction and internal fixation (ORIF). MATERIALS AND METHODS: The medical records of patients who sustained PCLTAF with concomitant ipsilateral lower limb fractures between March 2015 and February 2019 and underwent treatment at a single institution were retrospectively reviewed. Imaging examinations performed at the time of injury were applied to identify concomitant ipsilateral lower limb fractures. We used 1:2 matching between patients with PCLTAF combined with concomitant ipsilateral lower limb fractures (combined group; n = 11) and those with isolated PCLTAF (isolated group; n = 22). Outcome data were collected, including the range of motion (ROM) and visual analogue scale (VAS), Tegner, Lysholm, and International Knee Documentation Committee (IKDC) scores. At the final follow-up, the clinical outcomes were compared between the combined and isolated groups and between patients who underwent early-stage surgery and those who underwent delayed treatment for PCLTAF. RESULTS: Thirty-three patients (26 males, 7 females) were included in this study, with eleven patients having PCLTAF and concomitant ipsilateral lower limb fractures and a follow-up of 3.1 to 7.4 years (average, 4.8 years). Compared to patients in the isolated group, patients in the combined group demonstrated significantly worse Lysholm scores (85.7 ± 5.8 vs. 91.5 ± 3.9, p = 0.040), Tegner scores (4.4 ± 0.9 vs. 5.4 ± 0.8, p = 0.006), and IKDC scores (83.6 ± 9.3 vs. 90.5 ± 3.0, p = 0.008). Inferior outcomes were found in patients with delayed treatment. CONCLUSIONS: Inferior results were found in patients with concomitant ipsilateral lower limb fractures, while better outcomes were obtained in patients with PCLTAF through early-stage ORIF using the posteromedial approach. The present findings may help determine the prognoses of patients with PCLTAF combined with concomitant ipsilateral lower limb fractures treated through early-stage ORIF.

Laparoscopic Pelvic Exenteration with Bladder Sparing for Men with Locally Advanced Rectal Cancer (with Video).

OBJECTIVE: The aim of this article was to introduce a fascial space priority approach for laparoscopic pelvic exenteration (PE) with bladder-sparing for men with locally advanced rectal cancer. METHODS: We present a video of bladder-sparing laparoscopic PE with fascial space priority approach in a 70-year old man. The systematic de-arterialization of the prostate on the basis of complete separation of the avascular lateral pelvic spaces is introduced in detail. RESULTS: The operation time was 360 min and the estimated intraoperative blood loss was 50 mL. The postoperative course was uneventful and the patient was discharged on postoperative day 14. Histopathological examination showed all margins to be tumor-free. CONCLUSIONS: Bladder-sparing laparoscopic PE using a fascial space priority approach is a feasible and safe procedure that can be performed in well-selected patients following neoadjuvant chemoradiotherapy. Extensive multivisceral resection is possible without a permanent stoma.

Fascial space priority approach for laparoscopic total pelvic exenteration in patients with locally advanced rectal cancer.

BACKGROUND: Total pelvic exenteration (TPE) with intent to achieve a pathological R0 resection is now considered as the only chance of a long-term survival for locally advanced rectal cancer (LARC) invading into adjacent organs. Lately, laparoscopic total pelvic exenteration (LTPE) is performed and achieved in several specialized centers and showed a promising application prospect. Although this is universally realized by surgeons, there are only few specialized centers to perform this complex surgery, due to concerns about the high morbidity and mortality. The techniques associated need to be disclosed and facilitated. OBJECTIVE: The aim of this article is to introduce a fascial space priority approach for laparoscopic TPE step by step (with video). METHODS: We describe here a fascial space priority approach for LTPE in highly selected patients with locally advanced rectal cancer. The main principle of this approach is that all of the pelvic organs are considered as a whole, the non-vascular spaces surrounding it are separated in the first place, the vascular pedicle and nerve pedicle of pelvic organs can be isolated and then transected precisely. Meanwhile, the associated key landmarks of this approach are disclosed (see the video). RESULTS: The ureterohypogastric nerve fascia (UHGNF) and the vesicohypogastric fascia (VHGF) are two vital embryological planes on the lateral compartment of pelvis. The spaces on either side of them together with the retrorectal space, the space of Retzius, are all non-vascular spaces, and dissection of these spaces in LTPE surgery can be achieved simply and practicably. The ureter, the umbilical artery, the arcus tendinous fasciae pelvis (ATFP), piriformis and the puboprostatic ligament (PPL) are all important landmarks during surgery. Step-by-step illustration with precise anatomical landmarks in the present video may lead to less intraoperative blood loss and complications. CONCLUSIONS: LTPE with fascial space priority approach might be a standard surgical procedure for total pelvic exenteration with clear anatomy and reduced blood loss.

Inhibition on α-Glucosidase Activity and Non-Enzymatic Glycation by an Anti-Oxidative Proteoglycan from Ganoderma lucidum.

The prevention of postprandial hyperglycemia and diabetic complications is crucial for diabetes management. Inhibition of α-glucosidase to slow carbohydrate metabolism is a strategy to alleviate postprandial hyperglycemia. In addition, suppression of non-enzymatic glycation can diminish the advanced glycation end products and reduce the oxidative stress and inflammation, thereby preventing the diabetic complications. In this study, an anti-oxidative proteoglycan (named FYGL) extracted from Ganoderma lucidum was investigated in vitro for its inhibitory effect on α-glucosidase and non-enzymatic glycation using molecular kinetics, intrinsic fluorescence assay, and bovine serum albumin glycation models. The molecular kinetics and fluorescence assay revealed that FYGL decreases α-glucosidase activity by forming a FYGL-α-glucosidase complex. To evaluate the anti-glycation effect, fructose-glycated and methylglyoxal-glycated BSA models were analyzed by spectroscopic and SDS-PAGE methods. Results showed that FYGL inhibited the glycation at every stage and suppressed glycoxidation, possibly due to its anti-oxidative capacity and FYGL-BSA complex formation. Furthermore, we demonstrated in vivo that FYGL could alleviate postprandial hyperglycemia in db/db mice as well as AGE accumulation and vascular injury in diabetic rats. Overall, FYGL possesses anti-postprandial hyperglycemia and anti-glycation functions and would be potentially used in clinic for diabetes and related complication management.

Influence of the Building Unit on Covalent Organic Frameworks in Mediating Photo-induced Energy-Transfer Reversible Complexation-Mediated Radical Polymerization (PET-RCMP).

Two imine-based covalent organic framework photocatalysts with different building units, TPB-DMTA-COF and TAT-DMTA-COF, for photo-induced energy transfer reversible complexation-mediated radical polymerization (PET-RCMP) were developed and investigated, producing ideal polymers with accurate molecular weight and moderate dispersity under visible light irradiation. The chain extension and spatiotemporal control experiments revealed the high chain-end fidelity of polymers and the compatibility of RCMP processes in both bulk and aqueous system. Moreover, density functional theory (DFT) calculations verified that heteroatom-doped TAT-DMTA-COF exhibits higher activities for weakening C-I bond energy barrier, which promotes PET-RCMP polymerization performance. This work demonstrates that rational adjustment of building block for constructing COF heterogeneous photocatalyst can enhance the catalytic performance of PET-RCMP, providing a design methodology for the development of polymeric organic photoelectric semiconductor catalysts to mediate RCMP.

Exosomes-mediated transfer of long noncoding RNA LINC01133 represses bladder cancer progression via regulating the Wnt signaling pathway.

Bladder cancer (BC), as one of the most common malignant cancers of the urinary system, has a high incidence and mortality rates. Recently, increasing studies have indicated that exosomes can mediate cellular communication in assorted cancers, including BC. Long noncoding RNAs (lncRNAs) have also been confirmed to take part in the regulation of many cancers. Long intergenic non-protein coding RNA 1133 (LINC01133) is an lncRNA and its roles in several cancers have been revealed. However, the functions of exosomes and LINC01133 in BC are still not elucidated. In our research, functional assays were conducted to evaluate the function of LINC01133, as well as the influence of exosomes and LINC01133 on BC cells. Western blot assay, immunofluorescence assay, electron microscope, and nanoparticle tracking analysis were applied for detecting the characteristics of exosomes. Bioinformatics tools and quantitative reverse-transcription polymerase chain reaction were performed to test the expression of LINC01133 in BC cells and exosomes of the immortalized human uroepithelial cell line (SV-HUC-1). Luciferase reporter assay was performed to measure the activity of the Wnt pathway. We discovered that LINC01133 expression was high in exosomes of SV-HUC-1 and low in that of BC cells. Additionally, exosomes restrained cell viability, proliferation, migration, and invasion. Similarly, LINC01133 exerted the same function on BC cells. In addition, the Wnt signaling pathway could be inactivated by LINC01133. Finally, in vivo experiments demonstrated that cell growth could be suppressed by overexpressed LINC01133. In short, exosomes-mediated transfer of lncRNA LINC01133 repressed BC progression via regulating the Wnt signaling pathway.

Visible Light-Regulated Heterogeneous Catalytic PET-RAFT by High Crystallinity Covalent Organic Framework.

Covalent organic frameworks (COFs) are a class of promising photocatalysts for conversing light energy into chemical energy. Based on the tunable building blocks, COFs can be well-designed as photocatalyst for mediating reversible addition-fragmentation chain-transfer (RAFT) polymerization. Herein, 1,3,6,8-tetrakis(4-formylphenyl)pyrene (TFPPy) and 2,2″-bipyridine-5,5″-diamine (Bpy) are chosen to construct imine-based TFPPy-Bpy-COFs for catalyzing RAFT polymerization of methacrylates under white light irradiation. The well-defined polymers with precise molecular weight and narrow molecular weight distribution are obtained. The switch on/off light experiments suggest excellent temporal control toward RAFT polymerization system and the chain-extension reaction indicates high chain-end fidelity of macro-initiators. Mechanism study clarifies that the electron transfer between excited state of TFPPy-Bpy-COFs and RAFT agent can form living radicals to mediate polymerization. This methodology provides a novel platform for reversible-deactivation radical polymerization using COFs as heterogeneous catalysts.

MD1 deletion exaggerates cardiomyocyte autophagy induced by heart failure with preserved ejection fraction through ROS/MAPK signalling pathway.

In our previous studies, we reported that myeloid differentiation protein 1 (MD1) serves as a negative regulator in several cardiovascular diseases. However, the role of MD1 in heart failure with preserved ejection fraction (HFpEF) and the underlying mechanisms of its action remain unclear. Eight-week-old MD1-knockout (MD1-KO) and wild-type (WT) mice served as models of HFpEF induced by uninephrectomy, continuous saline or d-aldosterone infusion and a 1.0% sodium chloride treatment in drinking water for 4 weeks to investigate the effect of MD1 on HFpEF in vivo. H9C2 cells were treated with aldosterone to evaluate the role of MD1 KO in vitro. MD1 expression was down-regulated in the HFpEF mice; HFpEF significantly increased the levels of intracellular reactive oxygen species (ROS) and promoted autophagy; and in the MD1-KO mice, the HFpEF-induced intracellular ROS and autophagy effects were significantly exacerbated. Moreover, MD1 loss activated the p38-MAPK pathway both in vivo and in vitro. Aldosterone-mediated cardiomyocyte autophagy was significantly inhibited in cells pre-treated with the ROS scavenger N-acetylcysteine (NAC) or p38 inhibitor SB203580. Furthermore, inhibition with the autophagy inhibitor 3-methyladenine (3-MA) offset the aggravating effect of aldosterone-induced autophagy in the MD1-KO mice and cells both in vivo and in vitro. Our results validate a critical role of MD1 in the pathogenesis of HFpEF. MD1 deletion exaggerates cardiomyocyte autophagy in HFpEF via the activation of the ROS-mediated MAPK signalling pathway.

miR-146b Reverses epithelial-mesenchymal transition via targeting PTP1B in cisplatin-resistance human lung adenocarcinoma cells.

Epithelial-mesenchymal transformation (EMT) is associated with drug resistance in human lung adenocarcinoma cells, but its specific mechanism has not been clarified. In this study, we investigated the effect of miRNA-146b on EMT in cisplatin (DDP) resistant human lung adenocarcinoma cells and the corresponding mechanism. Cisplatin resistant (CR) human lung adenocarcinoma cells (A549/DDP and H1299/DDP) were established, and the EMT characteristics and invasion and metastasis ability of CR cells were determined by tumor cell-related biological behavior experiments. The role of miR-146b in EMT of CR cells was determined by in vitro functional test. The targeted binding of miR-146b to protein tyrosine phosphatase 1B (PTP1B) was verified by biological information and double luciferin gene reporting experiments. The effect of miR-146b on tumor growth and EMT phenotype in vivo was investigated by establishing the xenotransplantation mouse model. Compared with the control group, H1299/DDP and A549/DDP cells showed the enhanced EMT phenotypes, invasion and migration ability. Besides, miR-146b was lowly expressed in H1299/DDP and A549/DDP cells. More importantly, overexpressed miR-146b could specifically bind to PTP1B, thus inhibiting the EMT process and ultimately reducing CR in H1299/DDP and A549/DDP cells. Finally, overexpressed miR-146b observably inhibited tumor growth in xenograft model mice and inhibited the EMT phenotype of A549/DDP cells in vivo by regulating the expressions of EMT-related proteins. Overexpressed miR-146b could reverse the EMT phenotype of CR lung adenocarcinoma cells by targeting PTP1B, providing new therapeutic directions for CR of lung adenocarcinoma cells.

Knockout of MD1 contributes to sympathetic hyperactivity and exacerbates ventricular arrhythmias following heart failure with preserved ejection fraction via NLRP3 inflammasome activation.

NEW FINDINGS: What is the central question of this study? In this study, we investigated whether MD1 interacted with the sympathetic nerves in ventricular arrhythmia (VA) during heart failure with preserved ejection fraction (HFpEF). What is the main finding and its importance? Mice with HFpEF showed increased susceptibility to VA, adverse electrical remodelling, impaired heart rate variability, enhanced sympathetic hyperactivity, activation of the NLRP3 inflammasome and increased interleukin-1ß release. These changes induced by HFpEF were exacerbated by MD1 deficiency. ABSTRACT: Sympathetic hyperactivity can promote malignant ventricular arrhythmia (VA), and myeloid differentiation 1 (MD1) has been reported to play an important role in obesity-induced VA. However, it is not known whether an interaction of MD1 with sympathetic hyperactivity contributes to the VA induced by heart failure with preserved ejection fraction (HFpEF). The aim of this study was to investigate the potential interaction between MD1 and sympathetic hyperactivity in HFpEF-induced VA and the underlying mechanism. Eight-week-old MD1-knockout (MD1-KO) and wild-type (WT) mice were subjected to a model of HFpEF induced by uninephrectomy, a continuous saline or d-aldosterone infusion and provision of drinking water containing 1.0% sodium chloride for 4 weeks. Echocardiography and haemodynamics were used to verify the model of HFpEF. An isolated electrophysiological study was performed to assess the susceptibility to VA. Four weeks later, the mice with HFpEF showed an increased heart weight to tibia length ratio, decreased left ventricular minimum rates of pressure rise (dP/dtmin ), increased τ, lung weight to tibia length ratio and preserved left ventricular ejection fraction compared with WT mice. The mice with HFpEF exhibited increased susceptibility to VA, as shown by the shortened effective refractory period, prolonged action potential duration (APD), increased APD alternans threshold and higher incidence of VA. Moreover, we also found that mice with HFpEF showed impaired heart rate variability, sympathetic hyperactivity, activation of the NLRP3 inflammasome and increased interleukin-1ß release. These changes induced by HFpEF were exacerbated by MD1 deficiency. We conclude that MD1-KO contributes to sympathetic hyperactivity and facilitates VA in HFpEF via activation of the NLRP3 inflammasome. Treatment targeting MD1 and NLRP3 might decrease the risk of HFpEF-induced VA.

Amelioration of the Lipogenesis, Oxidative Stress and Apoptosis of Hepatocytes by a Novel Proteoglycan from Ganoderma lucidum.

The steatosis and resultant oxidative stress and apoptosis play the important roles in the progression of nonalcoholic fatty liver disease (NAFLD), therefore, searching for the effective drugs against NAFLD has been a hot topic. In this work, we investigated a hyperbranched proteoglycan, namely FYGL extracted from Ganoderma lucidum, inhibiting the palmitic acid (PA)-induced steatosis in HepG2 hepatocytes. FYGL compose of hydrophilic polysaccharide and lipophilic protein. Both moieties conclude the reductive residues, such as glucose and cystine, making FYGL capable of anti-oxidation. Herein, we demonstrated that FYGL can significantly inhibit the steatosis, i.e., decrease the contents of triglycerides (TG) and total cholesterol (TC) in hepatic cells on the mechanism of increasing the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), therefore inhibiting the expressions of sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN), furthermore leading to the carnitine palmitoyl transferase-1 (CPT-1) expression increased against steatosis induced by fatty acids oxidation. Meanwhile, FYGL can alleviate reactive oxygen species (ROS) and malondialdehyde (MDA), promote superoxide dismutase (SOD) and total antioxidant capacity (T-AOC). Moreover, FYGL can prevent the cells from apoptosis by regulating the apoptosis-related protein expressions and alleviating oxidative stress. Notably, FYGL could significantly recover the cells activity and inhibit lactate dehydrogenase (LDH) release which were negatively induced by high concentration PA. These results demonstrated that FYGL has the potential functions to prevent the hepatocytes from lipid accumulation, oxidative stress and apoptosis, therefore against NAFLD.

A proteoglycan extract from Ganoderma Lucidum protects pancreatic beta-cells against STZ-induced apoptosis.

The pancreatic ß-cell death or dysfunction induced by oxidative stress plays an important effect on the development and progression of diabetes mellitus. Based on our previous findings, a natural proteoglycan extracted from Ganoderma Lucidum, named FYGL, could treat T2DM in vivo. In this study, we investigated the effects of FYGL on STZ-induced apoptosis of INS-1 cells and its underlying mechanisms. The results showed that FYGL significantly improved the cell viability and alleviated the apoptosis in STZ-treated INS-1 cells. Moreover, FYGL markedly decreased the intracellular ROS accumulation and NO release, and deactivated NF-κB, JNK, and p38 MAPK signaling pathways in STZ-induced INS-1 cells. Furthermore, FYGL improved the insulin secretion through inhibiting the activation of JNK and improving the expression of Pdx-1 in INS-1 cells damaged by STZ. These results indicated that FYGL could protect pancreatic ß-cells against apoptosis and dysfunction, and be used as a promising pharmacological medicine for diabetes management. Abbreviations: T2DM: type 2 diabetes mellitus; FYGL: Fudan-Yueyang G. lucidum; ROS: reactive oxygen species; NO: reactive oxygen species; NF-κB: nuclear factor kappa beta; JNK: c-jun N-terminal kinase; MAPK: mitogen-activated protein kinase; Pdx-1: Pancreatic duodenal homeobox 1.

Estimation of genetic parameters for reproductive traits in connectedness groups of Duroc, Landrace and Yorkshire pigs in China.

The objective of this study was to estimate group- and breed-specific genetic parameters for reproductive traits in Chinese Duroc, Landrace, and Yorkshire populations. Records for reproductive traits between April 1998 and December 2017 from 92 nucleus pig breeding farms, which were involved in the China Swine Genetic Improvement Program, were analysed. Due to weak genetic connectedness across all farms, connectedness groups consisting of related farms were used. Three, two and four connectedness groups for Duroc, Landrace and Yorkshire were firstly established according to the genetic connectedness rating among farms. For each connectedness group a five-trait animal model was implemented, and via restricted maximum likelihood procedure the genetic parameters were estimated for five reproductive traits i.e., total number born (TNB), number born alive (NBA), litter weight at farrowing (LWF), farrowing interval (FI) and age at first farrowing (AFF). The average of heritabilities among connectedness groups ranged from .01 (for FI in Yorkshire) to .30 (for AFF in Duroc). Estimates of repeatability for litter traits ranged from .14 to .20 and were consistent for each breed, and for FI, the estimates varied from .01 to .11 across breeds and groups. The estimated genetic correlations among litter traits (i.e., TNB, NBA and LWF) were all significantly high (>.56) and similar across breeds. Averaged genetic correlations over three breeds were -.25, -.27, -.18, -.04, -.10, -.02, and .28 for FI-TNB, FI-NBA, FI-LWF, AFF-TNB, AFF-NBA, AFF-LWF and FI-AFF, respectively. The standard errors of the estimates were all very low (<0.01) in most situations. Results from this study suggest that selection based on TNB which is currently used in dam line selection index can improve NBA and LWF simultaneously. However, care should be taken on FI and AFF as they are both greatly influenced by non-genetic factors such as management and measurement.

Altered expression of microRNA-365 is related to the occurrence and development of non-small-cell lung cancer by inhibiting TRIM25 expression.

The purpose of this current study is to elucidate whether altered microRNA-365 (miR-365) has an association with the initiation and development of non-small-cell lung cancer (NSCLC) by targeting TRIM25 expression. The expression of miR-365 and TRIM25 in NSCLC tissues, adjacent normal tissues, and NSCLC cell lines were detected. The relationship between miR-365 expression and TRIM25 with the clinicopathological characteristics of NSCLC was analyzed. The putative binding site between miR-365 and TRIM25 was determined by luciferase activity assay. miR-365 inhibitors and miR-365 mimics were transfected to human NSCLC A549 cells, and the cell viability was detected by cell counting kit-8 assay; flow cytometry was carried out to determine cell cycle and apoptosis rate. Poorly expressed miR-365 and overexpressed TRIM25 was found in NSCLC tissues. TRIM25 was determined as a target gene of miR-365. The miR-365 and TRIM25 expression were related to the clinicopathological features of NSCLC, such as pathological classification, differentiation degree, TNM stage as well as lymph node metastasis. miR-365 suppressed the expression of TRIM25 and elevated the expression of the proapoptotic protein in NSCLC cells. Our study demonstrates that altered expression of miR-365 has a close association with the occurrence and development of NSCLC by inhibiting TRIM25 expression.