The prevalence and genotypes of Cryptosporidium spp. in bar-headed goose (Anser indicus) in China.

Cryptosporidium spp. is an important foodborne and waterborne pathogen in humans and animals, causing diarrhoea in humans and respiratory and gastrointestinal diseases in birds. However, reports of Cryptosporidium infection in bar-headed goose are limited. To determine the infection rate and species/genotypes of Cryptosporidium in bar-headed goose in China, a total of 358 fecal samples were collected from 3 regions. Nested PCR was used to amplify Cryptosporidium SSU rRNA regions from the fecal extracted-DNA samples. The total infection rate of Cryptosporidium in bar-headed in China was 3.9 % (14/358), with 4.2 % (5/120) in Aba (Ngawa) Tibetan and Qiang Autonomous Prefect, Sichuan province, 7.6 % (9/119) in Maqu county, Gansu province, and 0.0 % (0/119) in Caohai, Wei ning county, Guizhou province. The differences in prevalence rate by region were statistically significant. All positive samples were identified as Cryptosporidium goose genotype I (n = 14). This is the first systematic investigation of the epidemiological status and dominant species/genotypes of Cryptosporidium in bar-headed goose in China, thereby enhancing our understanding of the epidemiology of Cryptosporidium infection in wild migratory birds.

Comorbidity increases the risk of pulmonary tuberculosis: a nested case-control study using multi-source big data.

BACKGROUND: Some medical conditions may increase the risk of developing pulmonary tuberculosis (PTB); however, no systematic study on PTB-associated comorbidities and comorbidity clusters has been undertaken. METHODS: A nested case-control study was conducted from 2013 to 2017 using multi-source big data. We defined cases as patients with incident PTB, and we matched each case with four event-free controls using propensity score matching (PSM). Comorbidities diagnosed prior to PTB were defined with the International Classification of Diseases-10 (ICD-10). The longitudinal relationships between multimorbidity burden and PTB were analyzed using a generalized estimating equation. The associations between PTB and 30 comorbidities were examined using conditional logistic regression, and the comorbidity clusters were identified using network analysis. RESULTS: A total of 4265 cases and 17,060 controls were enrolled during the study period. A total of 849 (19.91%) cases and 1141 (6.69%) controls were multimorbid before the index date. Having 1, 2, and ≥ 3 comorbidities was associated with an increased risk of PTB (aOR 2.85-5.16). Fourteen out of thirty comorbidities were significantly associated with PTB (aOR 1.28-7.27), and the associations differed by sex and age. Network analysis identified three major clusters, mainly in the respiratory, circulatory, and endocrine/metabolic systems, in PTB cases. CONCLUSIONS: Certain comorbidities involving multiple systems may significantly increase the risk of PTB. Enhanced awareness and surveillance of comorbidity are warranted to ensure early prevention and timely control of PTB.

Diagnostic value of computed tomography and magnetic resonance imaging in ovarian malignant mesothelioma.

OBJECTIVE: To investigate the diagnostic value of computed tomography (CT) and magnetic resonance imaging (MRI) in ovarian malignant mesothelioma (OMM). METHODS: The clinical and imaging data of 10 pathologically-confirmed OMM patients were analyzed retrospectively. RESULT: (1) The patients were 27 years to 70 years old, with an average age of 57.2 ± 15.4 years. Seven patients reported abdominal distension and pain, 1 reported lower abdominal discomfort and decreased appetite, and 2 patients had no symptoms. (2) Two cases of localized OMM with incomplete semi-annular "capsule" observed around the localized OMM tumors were reported while 8 cases had diffuse OMM in which the tumor parenchyma showed isointense or slightly hypointense on T1WI, inhomogeneous hyperintense on T2WI, and obviously hyperintense on DWI, with obvious inhomogeneous enhancement after enhancement. Diffuse OMM was not mainly composed of ovarian masses and was mainly characterized by mild ovarian enlargement, nodular and irregular thickening of the peritoneum, cloudy omentum, unclear fat gap, and reticular or irregular thickening, which can fuse into a "cake-shape". (3) All 10 patients underwent surgery, while 9 patients underwent systemic chemotherapy or immunotherapy after surgery. All patients with localized OMM survived. Out of the 8 diffuse-type patients, 5 died, 1 was lost to follow-up, and 2 survived. CONCLUSION: OMM has certain clinical and imaging characteristics. There is no liquefaction, calcification, or partition in the tumor. The ovarian enlargement in the diffuse lesion is not significant. The diffuse thickening of the peritoneum and omentum with early appearance of mural nodules and ascites in the upper abdomen, help the diagnosis of OMM.

CT target scanning in the diagnosis of solid pseudopapillary tumor of the pancreas.

OBJECTIVE: To discuss the value of computed tomography (CT) iterative reconstruction technique combined with target scanning in the diagnosis of solid pseudopapillary tumor of the pancreas (SPTP). METHODS: The clinical information and CT examination data of 27 patients with SPTP were retrospectively analyzed, and the general condition and CT performance of the patients were observed. The CT image reconstruction algorithm of all patients used iterative reconstruction technique combined with the application of target scanning technique. RESULTS: A total of 27 patients were included in this study, including 6 males and 21 females, aged 14-72 years with a mean age of 39.6 ± 13.6 years. SPTP was more common in young and middle-aged females, with a low level of tumor markers, dominated by cystic-solid tumors. The combination of CT iterative reconstruction technology and targeted scanning revealed the following: the capsule of SPTP was clear and complete, where calcifications were visible, solid components were progressively enhanced, and rare pancreatic and bile duct dilation was seen. Tumors were cystic-solid in 18 of 27 patients with SPTP, of which the solid components showed isodensity or slightly low-density, with calcifications. The solid components and cyst walls were mildly enhanced during the arterial phase, and were progressively enhanced during the parenchymal phase, portal vein phase, and delayed phase, with their enhancement degree lower than that of normal pancreatic parenchyma, and pancreatic and bile duct dilation was rare. There were no statistical differences in tumor location, morphology, growth pattern, integrity of capsule, cystic or solid, calcifications, and enhancement features between the male group and the female group (P > 0.05). CONCLUSION: The iterative reconstruction combined with target scanning clearly displayed the CT features of tumors, helping the diagnosis and clinical treatment of the disease.

A novel fluorescent probe based on naphthimide for H2S identification and application.

In view of the superior chemical activity of selenoether bond (-Se-) and the excellent optical properties of naphthimide, a novel fluorescent probe (NapSe) with near-rectangular structure, which contains double naphthimide fluorophores linked by selenoether bond, is designed for specific fluorescence detection of hydrogen sulfide (H2S). NapSe has excellent optical properties: super large Stokes Shift (190 nm) and good stability in a wide pH range. The selectivity of NapSe fluorescence detection of H2S is high, and displays excellent "turn-on" phenomenon and strong anti-interference. And the fluorescence intensity increased obviously, reaching 42 times. The time response of probe NapSe is very rapid (3 min) compared with other fluorescence probes that respond to H2S. It shows high sensitivity by calculating the detection limit (LOD) as low as 5.4 µM. Notably, the identification of H2S by probe NapSe has been successfully applied to the detection of test paper and the detection of exogenous and endogenous fluorescence imaging of MCF-7 breast cancer cells.

Circ_0003356 suppresses gastric cancer growth through targeting the miR-668-3p/SOCS3 axis.

BACKGROUND: Circular RNAs (circRNAs) have attracted extensive attention as therapeutic targets in gastric cancer (GC). Circ_0003356 is known to be downregulated in GC tissues, but its cellular function and mechanisms remain undefined. AIM: To investigate the role of circ_0003356 in GC at the molecular and cellular level. METHODS: Circ_0003356, miR-668-3p, and SOCS3 expression were assessed via quantitative real time-polymerase chain reaction (qRT-PCR). Wound healing, EdU, CCK-8, flow cytometry and transwell assays were used to analyze the migration, proliferation, viability, apoptosis and invasion of GC cells. The subcellular localization of circ_0003356 was monitored using fluorescence in situ hybridization. The interaction of circ_0003356 with miR-668-3p was confirmed using RIP-qRT-PCR, RNA pull-down, and dual luciferase reporter assays. We observed protein levels of genes via western blot. We injected AGS cells into the upper back of mice and performed immunohistochemistry staining for examining E-cadherin, N-cadherin, Ki67, and SOCS3 expressions. TUNEL staining was performed for the assessment of apoptosis in mouse tumor tissues. RESULTS: Circ_0003356 and SOCS3 expression was downregulated in GC cells, whilst miR-668-3p was upregulated. Exogenous circ_0003356 expression and miR-668-3p silencing suppressed the migration, viability, proliferation, epithelial to mesenchy-mal transition (EMT) and invasion of GC cells and enhanced apoptosis. Circ_0003356 overexpression impaired tumor growth in xenograft mice. Targeting of miR-668-3p by circ_0003356 was confirmed through binding assays and SOCS3 was identified as a downstream target of miR-668-3p. The impacts of circ_0003356 on cell proliferation, apoptosis, migration, invasion and EMT were reversed by miR-668-3p up-regulation or SOCS3 down-regulation in GC cells. CONCLUSION: Circ_0003356 impaired GC development through its interaction with the miR-668-3p/SOCS3 axis.

Ligamentum teres hepatis as a graft for portal and/or superior mesenteric vein reconstruction: From bench to bedside.

BACKGROUND: Pancreaticoduodenectomy combined with portal vein (PV) and/or superior mesenteric vein (SMV) resection in patients with pancreaticobiliary malignancy has become a common surgical procedure. There are various grafts currently used for PV and/or SMV reconstruction, but each of these grafts have certain limitations. Therefore, it is necessary to explore novel grafts that have an extensive resource pool, are low cost with good clinical application, and are without immune response rejection or additional damage to patients. AIM: To observe the anatomical and histological characteristics of the ligamentum teres hepatis (LTH) and evaluate PV/SMV reconstruction using an autologous LTH graft in pancreaticobiliary malignancy patients. METHODS: In 107 patients, the post-dilated length and diameter in resected LTH specimens were measured. The general structure of the LTH specimens was observed by hematoxylin and eosin (HE) staining. Collagen fibers (CFs), elastic fibers (EFs), and smooth muscle (SM) were visualized by Verhoeff-Van Gieson staining, and the expression of CD34, factor VIII-related antigen (FVIIIAg), endothelial nitric oxide synthase (eNOS), and tissue type plasminogen activator (t-PA) were detected using immunohistochemistry in LTH and PV (control) endothelial cells. PV and/or SMV reconstruction using the autologous LTH was conducted in 26 patients with pancreaticobiliary malignancies, and the outcomes were retrospectively analyzed. RESULTS: The post-dilated length of LTH was 9.67 ± 1.43 cm, and the diameter at a pressure of 30 cm H2O was 12.82 ± 1.32 mm at the cranial end and 7.06 ± 1.88 mm at the caudal end. Residual cavities with smooth tunica intima covered by endothelial cells were found in HE-stained LTH specimens. The relative amounts of EFs, CFs and SM in the LTH were similar to those in the PV [EF (%): 11.23 ± 3.40 vs 11.57 ± 2.80, P = 0.62; CF (%): 33.51 ± 7.71 vs 32.11 ± 4.82, P = 0.33; SM (%): 15.61 ± 5.26 vs 16.74 ± 4.83, P = 0.32]. CD34, FVIIIAg, eNOS, and t-PA were expressed in both LTH and PV endothelial cells. The PV and/or SMV reconstructions were successfully completed in all patients. The overall morbidity and mortality rates were 38.46% and 7.69%, respectively. There were no graft-related complications. The postoperative vein stenosis rates at 2 wk, 1 mo, 3 mo and 1 year were 7.69%, 11.54%, 15.38% and 19.23%, respectively. In all 5 patients affected, the degree of vascular stenosis was less than half of the reconstructed vein lumen diameter (mild stenosis), and the vessels remained patent. CONCLUSION: The anatomical and histological characteristics of LTH were similar to the PV and SMV. As such, the LTH can be used as an autologous graft for PV and/or SMV reconstruction in pancreaticobiliary malignancy patients who require PV and/or SMV resection.

Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA.

Proper defense against microbial infection depends on the controlled activation of the immune system. This is particularly important for the RIG-I-like receptors (RLRs), which recognize viral dsRNA and initiate antiviral innate immune responses with the potential of triggering systemic inflammation and immunopathology. Here, we show that stress granules (SGs), molecular condensates that form in response to various stresses including viral dsRNA, play key roles in the controlled activation of RLR signaling. Without the SG nucleators G3BP1/2 and UBAP2L, dsRNA triggers excessive inflammation and immune-mediated apoptosis. In addition to exogenous dsRNA, host-derived dsRNA generated in response to ADAR1 deficiency is also controlled by SG biology. Intriguingly, SGs can function beyond immune control by suppressing viral replication independently of the RLR pathway. These observations thus highlight the multi-functional nature of SGs as cellular "shock absorbers" that converge on protecting cell homeostasis by dampening both toxic immune response and viral replication.

A central amygdala input to the dorsal vagal complex controls gastric motility in mice under restraint stress.

Background/aims: Psychological and physiological stress can cause gastrointestinal motility disorders. Acupuncture has a benign regulatory effect on gastrointestinal motility. However, the mechanisms underlying these processes remain unclear. Methods: Herein, we established a gastric motility disorder (GMD) model in the context of restraint stress (RS) and irregular feeding. The activity of emotional center-central amygdala (CeA) GABAergic neurons and gastrointestinal center-dorsal vagal complex (DVC) neurons were recorded by electrophysiology. Virus tracing and patch clamp analysis of the anatomical and functional connection between the CeAGABA → dorsal vagal complex pathways were performed. Optogenetics inhibiting or activating CeAGABA neurons or the CeAGABA → dorsal vagal complex pathway were used to detect changes in gastric function. Results: We found that restraint stress induced delayed gastric emptying and decreased gastric motility and food intake. Simultaneously, restraint stress activated CeA GABAergic neurons, inhibiting dorsal vagal complex neurons, with electroacupuncture (EA) reversing this phenomenon. In addition, we identified an inhibitory pathway in which CeA GABAergic neurons project into the dorsal vagal complex. Furthermore, the use of optogenetic approaches inhibited CeAGABA neurons and the CeAGABA → dorsal vagal complex pathway in gastric motility disorder mice, which enhanced gastric movement and gastric emptying, whereas activation of the CeAGABA and CeAGABA → dorsal vagal complex pathway mimicked the symptoms of weakened gastric movement and delayed gastric emptying in naïve mice. Conclusion: Our findings indicate that the CeAGABA → dorsal vagal complex pathway may be involved in regulating gastric dysmotility under restraint stress conditions, and partially reveals the mechanism of electroacupuncture.

Comparison of microstructure, mechanical property, and degradation rate of Mg-1Li-1Ca and Mg-4Li-1Ca alloys.

Mg-1 wt.% Li-1 wt.% Ca (LX11) and Mg-4 wt.% Li-1 wt.% Ca (LX41) alloys share the same hexagonal closed-packed crystalline structure. However, the differences in microstructure, mechanical properties, and degradation rates between the two alloys are not well understood. Hereby, the above three aspects of LX11 and LX41 alloys were studied via optical microscopy, tensile tests, and electrochemical polarization and electrochemical impedance spectroscopy, together with hydrogen evolution. The concentration of the released Mg2+, Ca2+, and Li+ ions was analyzed using a flame atomic absorption spectrophotometer. Results demonstrated that the LX11 alloy was composed of finer α-Mg grains, fewer twins, and smaller volume fractions of the intermetallic phases Mg2Ca than the LX41 alloy. The increasing Li concentration generated a weak decrease in the yield strength of the Mg-Li-Ca alloys, a remarkable increase in elongation to failure, and a stable ultimate tensile strength. The LX11 alloy had better corrosion resistance than the LX41 alloy. The release rate of the cations (Mg2+, Ca2+, and Li+) varied significantly with time. The release rate of metallic ions in Hank's solution cannot reflect the true corrosion rate of Mg-Li-Ca alloys due to the formation of the precipitated corrosion products and their difference in solubility. The dealloying corrosion mechanism of the Mg2Ca phase in Mg-Li-Ca alloys was proposed.

A neural circuit for gastric motility disorders driven by gastric dilation in mice.

Introduction: Symptoms of gastric motility disorders are common clinical manifestations of functional gastrointestinal disorders (FGIDs), and are triggered and exacerbated by stress, but the neural pathways underpinning them remain unclear. Methods: We set-up a mouse model by gastric dilation (GD) in which the gastric dynamics were assessed by installing strain gauges on the surface of the stomach. The neural pathway associated with gastric motility disorders was investigated by behavioral tests, electrophysiology, neural circuit tracing, and optogenetics and chemogenetics involving projections of the corticotropin-releasing hormone (CRH) from the paraventricular nucleus of the hypothalamus (PVN) to acetylcholine (ChAT) neurons in the dorsal motor nucleus of the vagus (DMV). Results: We found that GD induced gastric motility disorders were accompanied by activation of PVN CRH neurons, which could be alleviated by strategies that inhibits the activity of PVN CRH neurons. In addition, we identified a neural pathway in which PVN CRH neurons project into DMV ChAT neurons, modulated activity of the PVN CRH →DMV ChAT pathway to alleviate gastric motility disorders induced by GD. Discussion: These findings indicate that the PVN CRH →DMV ChAT pathway may mediate at least some aspects of GD related gastric motility, and provide new insights into the mechanisms by which somatic stimulation modulates the physiological functions of internal organs and systems.

Identification and characterization of circular RNAs as novel putative biomarkers to predict anti-PD-1 monotherapy response in metastatic melanoma patients - Knowledge from two independent international studies.

Melanoma is the most aggressive skin malignancy with high morbidity. Anti-programmed cell death protein 1 (PD-1) monotherapy has been applied in metastatic melanoma. However, still most of the patients do not respond to anti-PD-1 and the availability of the present approved biomarkers therefore is limited. Here we combined the transcriptomic and clinical data of 163 advanced melanoma patients receiving anti-PD-1 from NIH Melanoma Genome Sequencing Project (phs000452, 122 patients) as the training and internal validation cohort, and Melanoma Institute Australia cohort (PRJEB23709, 41 patients) as the external validation cohort, respectively. Circular RNAs (circRNAs) are an evolutionarily conserved novel class of noncoding endogenous RNAs (ncRNAs) found in the eukaryotic transcriptome and were used based on RNAseq data for our analyses. 74,243 circular RNAs (circRNAs) were identified with NCLscan and CIRCexplorer2. Thereof, 70 circRNAs significantly associated with progression-free survival and overall survival. Further, a prognostic circRNAs signature consisting of HSA_CIRCpedia_1497, HSA_CIRCpedia_12559, HSA_CIRCpedia_43640, HSA_CIRCpedia_43070, and HSA_CIRCpedia_21660 could be determined with LASSO regression. This signature was a prognostic factor of overall survival and progression-free survival among the analyzed advanced melanoma patients. The concordance indexes (C-index of OStraining: 0.61, C-index of PFStraining: 0.68) also confirmed its credibility and accuracy. First enrichment analysis indicated that immune response and pathways related to tumor immune microenvironment were enriched. In conclusion, we succeeded to construct and validate novel prognostic circRNAs signature for advanced melanoma patients treated with anti-PD-1 immunotherapy.

Up-regulation of microglial chemokine CXCL12 in anterior cingulate cortex mediates neuropathic pain in diabetic mice.

Diabetic patients frequently experience neuropathic pain, which currently lacks effective treatments. The mechanisms underlying diabetic neuropathic pain remain unclear. The anterior cingulate cortex (ACC) is well-known to participate in the processing and transformation of pain information derived from internal and external sensory stimulation. Accumulating evidence shows that dysfunction of microglia in the central nervous system contributes to many diseases, including chronic pain and neurodegenerative diseases. In this study, we investigated the role of microglial chemokine CXCL12 and its neuronal receptor CXCR4 in diabetic pain development in a mouse diabetic model established by injection of streptozotocin (STZ). Pain sensitization was assessed by the left hindpaw pain threshold in von Frey filament test. Iba1+ microglia in ACC was examined using combined immunohistochemistry and three-dimensional reconstruction. The activity of glutamatergic neurons in ACC (ACCGlu) was detected by whole-cell recording in ACC slices from STZ mice, in vivo multi-tetrode electrophysiological and fiber photometric recordings. We showed that microglia in ACC was significantly activated and microglial CXCL12 expression was up-regulated at the 7-th week post-injection, resulting in hyperactivity of ACCGlu and pain sensitization. Pharmacological inhibition of microglia or blockade of CXCR4 in ACC by infusing minocycline or AMD3100 significantly alleviated diabetic pain through preventing ACCGlu hyperactivity in STZ mice. In addition, inhibition of microglia by infusing minocycline markedly decreased STZ-induced upregulation of microglial CXCL12. Together, this study demonstrated that microglia-mediated ACCGlu hyperactivity drives the development of diabetic pain via the CXCL12/CXCR4 signaling, thus revealing viable therapeutic targets for the treatment of diabetic pain.

Mitofusin-2 mediates cannabidiol-induced neuroprotection against cerebral ischemia in rats.

Cannabidiol (CBD) reportedly exerts protective effects against many psychiatric disorders and neurodegenerative diseases, but the mechanisms are poorly understood. In this study, we explored the molecular mechanism of CBD against cerebral ischemia. HT-22 cells or primary cortical neurons were subjected to oxygen-glucose deprivation insult followed by reoxygenation (OGD/R). In both HT-22 cells and primary cortical neurons, CBD pretreatment (0.1, 0.3, 1 µM) dose-dependently attenuated OGD/R-induced cell death and mitochondrial dysfunction, ameliorated OGD/R-induced endoplasmic reticulum (ER) stress, and increased the mitofusin-2 (MFN2) protein level in HT-22 cells and primary cortical neurons. Knockdown of MFN2 abolished the protective effects of CBD. CBD pretreatment also suppressed OGD/R-induced binding of Parkin to MFN2 and subsequent ubiquitination of MFN2. Overexpression of Parkin blocked the effects of CBD in reducing MFN2 ubiquitination and reduced cell viability, whereas overexpressing MFN2 abolished Parkin's detrimental effects. In vivo experiments were conducted on male rats subjected to middle cerebral artery occlusion (MCAO) insult, and administration of CBD (2.5, 5 mg · kg-1, i.p.) dose-dependently reduced the infarct volume and ER stress in the brains. Moreover, the level of MFN2 within the ischemic penumbra of rats was increased by CBD treatment, while the binding of Parkin to MFN2 and the ubiquitination of MFN2 was decreased. Finally, short hairpin RNA against MFN2 reversed CBD's protective effects. Together, these results demonstrate that CBD protects brain neurons against cerebral ischemia by reducing MFN2 degradation via disrupting Parkin's binding to MFN2, indicating that MFN2 is a potential target for the treatment of cerebral ischemia.

Flexural Strengthening of Large-Scale RC Beams with Nonprestressed and Prestressed CFRP Using Different Anchorages.

Externally bonded carbon-fiber-reinforced polymer (CFRP) technology can be used by different methods based on the anchorage device, CFRP type, and prestressing/nonprestressing. However, a direct comparison between the strengthening efficacies of different methods is still lacking. Seven large-scale RC beams were tested in this study to investigate the influences of the anchorage method, CFRP type, prestress, and prestressing system on the flexural strengthening efficacy of RC beams. The test results showed that the ultimate load increased by 38.3%, whereas the cracking and yielding loads were slightly affected when the anchorage method was enhanced from CFRP U-wraps to wedge-clamp anchors. The CFRP plate and CFRP sheet could provide a rather close flexural strengthening efficacy under the same CFRP strengthening amount. Compared to the nonprestressed CFRP plate, the prestressed CFRP plate was highly superior in improving the flexural behavior of RC beams. The cracking, yielding, and ultimate loads of the prestressed CFRP-strengthened specimens were 57.1%, 22.9%, and 5.9%, respectively, higher than those of the nonprestressed CFRP-strengthened specimen with an effective anchorage. The two types of prestressing systems based on the adhesive-friction anchor and wedge-clamp anchor were proven to be effective for flexural strengthening of RC beams with prestressed CFRP plates, and they could provide almost the same strengthening effect.

[Effects of aerobic exercise on Nrf2/GPX4/Ferroptosis pathway in myocardial injury in high-fat diet mice].

Objective: To illuminate the protective effects of pathway in inhibiting ferroptosis by glutathione peroxidase 4 (GPX4) activated by nuclear factor erythroid 2-related factor 2 (Nrf2) during aerobic exercise against myocardial injury in high-fat diet mice. Methods: Forty 5-week-old SPF C57BL/6 male mice were randomly divided into the control group (NC), the exercise group (NE), the high fat group (HC) and the high fat diet with exercise group (HE, began at the same time). There were 10 mice in each group. The mice in the high fat diet group were fed with 60% Kcal SPF high fat model diet. Aerobic exercise was performed using increasing load platform exercise, 5 days /week, 60 min/d, the speed started from 13m/min, and increased by 1m/min every two weeks. Myocardium and blood samples were collected after 14 weeks. Structural changes of myocardial tissues were observed by HE staining. Western blot was used to detect the expressions of Nrf2/GPX4/Ferroptosis related proteins in myocardium. Myocardial peroxide concentration and antioxidant enzyme activity were measured by spectrophotometry. Myocardial mitochondrial 8-hydroxy-2 deoxyguanosine (8-OHdG) and serum insulin were measured by ELISA. Results: Compared with the NC group, there was more lipid accumulation in the myocardial fiber space in the HC group, and the levels of FBG and FINS were increased significantly, while ISI was decreased significantly (P＜0.01). Compared with the HC group, the lipid concentration was decreased in the HE group, and the activities of total antioxidant capacity (T-AOC), total superoxide dismutase (T-SOD) and glutathione (GSH) were increased significantly, while the levels of mitochondrial 8-OHdG and myocardial iron content were decreased (P＜0.01). The expression levels of Ferroportin1 (FPN1), ferritin heavy chain 1 (FTH1), GPX4, glucose transporter (GLUT1) and Nrf2 in the HE group were significantly higher than those in the HC group (P＜0.01). Conclusion: The expression of GPX4 was enhanced by more Nrf2 transposition into the nuclear during aerobic exercise, which inhibited the occurrence of myocardial ferroptosis. The activities of antioxidant enzymes were promoted and inhibited the peroxidation damage of myocardial mitochondria.

Discovery of novel 2,3-dihydro-1H-inden-1-ones as dual PDE4/AChE inhibitors with more potency against neuroinflammation for the treatment of Alzheimer's disease.

Recently, the discovery of multifunctional molecules that target different factors in the treatment of dementia is a significant research area. Both PDE4 and AChE inhibitors display improvement in cognitive and memory function. In this study, twenty-eight novel 2,3-dihydro-1H-inden-1-ones were designed, synthesized, and evaluated as catechol ether-based dual PDE4/AChE inhibitors to treat Alzheimer's disease (AD). Among these compounds, 12C bearing a 2-(piperidin-1-yl)ethoxy group at the 6-position of indanone ring displayed satisfactory inhibitory activities and selectivity against AChE (IC50 = 0.28 µM) and PDE4D (IC50 = 1.88 µM). Compared with donepezil, 12C revealed a comparable neuroprotective effect. Moreover, 12C exhibited comparable AChE inhibitory activity with donepezil in the hippocampus of AD model mice. Interestingly, 12C displayed more potent anti-neuroinflammation than the donepezil and drug combination (donepezil + rolipram) groups. These results suggest that 12C is a promising multifunctional agent for the treatment of AD.