Dihydroartemisinin alleviates doxorubicin-induced cardiotoxicity and ferroptosis by activating Nrf2 and regulating autophagy.

Although the use of Doxorubicin (Dox) is extensive in the treatment of malignant tumor, the toxic effects of Dox on the heart can cause myocardial injury. Therefore, it is necessary to find an alternative drug to alleviate the Dox-induced cardiotoxicity. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin, which is an active ingredient of Artemisia annua. The study investigates the effects of DHA on doxorubicin-induced cardiotoxicity and ferroptosis, which are related to the activation of Nrf2 and the regulation of autophagy. Different concentrations of DHA were administered by gavage for 4 weeks in mice. H9c2 cells were pretreated with different concentrations of DHA for 24 h in vitro. The mechanism of DHA treatment was explored through echocardiography, biochemical analysis, real-time quantitative PCR, western blotting analysis, ROS/DHE staining, immunohistochemistry, and immunofluorescence. In vivo, DHA markedly relieved Dox-induced cardiac dysfunction, attenuated oxidative stress, alleviated cardiomyocyte ferroptosis, activated Nrf2, promoted autophagy, and improved the function of lysosomes. In vitro, DHA attenuated oxidative stress and cardiomyocyte ferroptosis, activated Nrf2, promoted clearance of autophagosomes, and reduced lysosomal destruction. The changes of ferroptosis and Nrf2 depend on selective degradation of keap1 and recovery of lysosome. We found for the first time that DHA could protect the heart from the toxic effects of Dox-induced cardiotoxicity. In addition, DHA significantly alleviates Dox-induced ferroptosis through the clearance of autophagosomes, including the selective degradation of keap1 and the recovery of lysosomes.

Dual network composite hydrogels with robust antibacterial and antifouling capabilities for efficient wound healing.

Wound dressings play a critical role in the wound healing process; however, conventional dressings often address singular functions, lacking versatility in meeting diverse wound healing requirements. Herein, dual-network, multifunctional hydrogels (PSA/CS-GA) have been designed and synthesized through a one-pot approach. The in vitro and in vivo experiments demonstrate that the optimized hydrogels have exceptional antifouling properties, potent antibacterial effects and rapid hemostatic capabilities. Notably, in a full-thickness rat wound model, the hydrogel group displays a remarkable wound healing rate exceeding 95% on day 10, surpassing both the control group and the commercial 3M group. Furthermore, the hydrogels exert an anti-inflammatory effect by reducing inflammatory factors interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), enhance the release of the vascular endothelial growth factor (VEGF) to promote blood vessel proliferation, and augment collagen deposition in the wound, thus effectively accelerating wound healing in vivo. These innovative hydrogels present a novel and highly effective approach to wound healing.

Poor serum uric acid control increases risk for developing hypertension: a retrospective cohort study in China.

Background: Serum uric acid (SUA) has been suggested as a contributor of hypertension. However, reports on the relationship between changes in SUA and hypertension are limited. Hence, we aimed to investigate the potential impact of SUA, especially its change over time, on hypertension incidence. Methods: This dynamic cohort included 6052 participants without hypertension at baseline. Participants were categorized into six grades based on whether baseline SUA was high and whether changes in SUA progressed to hyperuricemia or decreased to normal levels. Grades 1 to 6 represented the participants' SUA control from best to worst. Logistic regression and restricted cubic spline (RCS) models were used to explore the association of the grades of SUA control and hypertension incidence. Results: During a median follow-up of 6 years, 2550 (42.1%) participants developed hypertension. After adjusting confounding factors, compared to grade 1 with the best control of SUA, the odds ratios for grades 2 to 6 with worse control were 1.347 (1.109-1.636), 1.138 (0.764-1.693), 1.552 (1.245-1.934), 1.765 (1.170-2.663), and 2.165 (1.566-2.993), respectively. RCS indicated a linear correlation between the risk of hypertension and changes in SUA, and an elevated risk in participants with baseline hyperuricemia. Subgroup analyses showed that grades of SUA control had an interaction with systolic (P = 0.003) and diastolic blood pressure (P < 0.001). Sensitivity analyses further determined the robustness of the result that participants with poor SUA control have a higher risk of developing hypertension. Conclusion: Poor SUA control, an increase in SUA over time, rises the risk of developing hypertension regardless of whether the initial SUA is normal or not. Initial hyperuricemia will exacerbate this risk. Effective SUA control should be an important measure for primary prevention of hypertension.

Prevalence of natural feline coronavirus infection in domestic cats in Fujian, China.

Only few studies have investigated the prevalence of feline coronavirus (FCoV) infection in domestic cats in Fujian, China. This is the first study to report the prevalence rate of FCoV infection in domestic cats in Fujian, China, and to analyse the epidemiological characteristics of FCoV infection in the region. A total of 112 cat faecal samples were collected from animal hospitals and catteries in the Fujian Province. RNA was extracted from faecal material for reverse transcription polymerase chain reaction (RT-PCR). The prevalence rate of FCoV infection was determined, and its epidemiological risk factors were analysed. The overall prevalence of FCoV infection in the cats, was 67.9%. We did not observe a significant association between the age, sex, or breed of the cats included in the study and the prevalence rate of the viral infection. Phylogenetic analysis showed that the four strains from Fujian were all type I FCoV. This is the first study to analyse the prevalence and epidemiological characteristics of FCoV infection in domestic cats in Fujian, China, using faecal samples. The results of this study provide preliminary data regarding the prevalence of FCoV infection in the Fujian Province for epidemiological studies on FCoV in China and worldwide. Future studies should perform systematic and comprehensive epidemiological investigations to determine the prevalence of FCoV infection in the region.

Taxifolin protects against doxorubicin-induced cardiotoxicity and ferroptosis by adjusting microRNA-200a-mediated Nrf2 signaling pathway.

The chemotherapeutic agent doxorubicin (Dox) is commonly used to treat various types of cancer, even though it can cause life-threatening cardiotoxicity. Clinically, there is no particularly effective way to treat Dox-induced cardiotoxicity. Therefore, it is imperative to identify compounds that can effectively alleviate Dox-induced cardiotoxicity. Ferroptosis and oxidative stress play a key role in Dox-induced cardiotoxicity, and the inhibition of ferroptosis and oxidative stress could effectively protect against doxorubicin-induced cardiotoxicity. Taxifolin (TAX) is a flavonoid commonly found in onions and citrus fruits. In the present study, we evaluated the effects of TAX on Dox-induced cardiac injury and dysfunction and aimed to explore the mechanisms underlying these effects. Using a mouse model of Dox-induced cardiotoxicity, we administered 20 mg/kg/day of TAX by gavage for 2 weeks. A week after the first use of TAX, each mouse was administered a 10 mg/kg dose of Dox. TAX was first evaluated for its cardioprotective properties, and the outcomes showed that TAX significantly reduced the damage caused by Dox to the myocardium in terms of structural and functional damage by effectively inhibiting ferroptosis and oxidative stress. In vivo, echocardiography, histopathologic assay, serum biochemical analysis and western blotting was used to find the results that Dox promoted ferroptosis-induced cardiomyocyte death, while TAX reversed these effects. In vitro, we also found that TAX alleviated Dox-induced cardiotoxicity by using ROS/DHE staining assay, Cellular immunofluorescence and western blotting. TAX increasing expression of microRNA-200a (miR-200a) which affects ferroptosis by activating Nrf2 signaling pathway. We believe that TAX inhibits ferroptosis and is a potential phytochemical that prevents Dox-induced cardiotoxicity.

Antibiotic resistance profile of Helicobacter pylori to 14 antibiotics: a multicenter study in Fujian, China.

Background and aim: Efficacy of Helicobacter pylori (H. pylori) eradication is related to the local antimicrobial resistance epidemiology. We aimed to investigate the antibiotic resistance of H. pylori in Fujian, China. Methods: H. pylori-infected patients in four centers were enrolled in the study from Oct 2019 to Jan 2022. The bacteria were isolated, cultured and identified from the biopsy of patients' gastric mucosa samples. Antimicrobial susceptibility testing was performed by a modified broth microdilution method for H. pylori to seven guideline-recommended antibiotics and seven potential choices for H. pylori eradication. Results: A total of 205 H. pylori strains were isolated. The resistance rates of amoxicillin (AMX), amoxicillin and clavulanate potassium (AMC), cefixime (CFM), gentamicin (GEN), tetracycline (TET), doxycycline (DOX), azithromycin (AZM), clarithromycin (CLR), levofloxacin (LVFX), sparfloxacin (SPFX), metronidazole (MTZ), tinidazole (TID), rifampicin (RFP) and furazolidone (FZD) were 11.22%, 12.20%, 7.32%, 12.20%, 4.88%, 4.39%, 44.39%, 43.90%, 30.24%, 21.46%, 40.98%, 45.85%, 5.37% and 10.24%, respectively. The rates of pan-sensitivity, single, double, triple and multiple resistance for seven guideline-recommended antibiotics were 32.68%, 30.24%, 13.17%, 7.76%, and 14.15%, respectively. The main double-resistance patterns were CLR+MTZ (10/205, 5%) and CLR+LVFX (9/205, 4%). The main triple-resistance pattern was CLR+MTZ+ LVFX (15/205, 7%). Conclusions: In Fujian, the prevalence of H. pylori resistance to AZM, CLR, LVFX, SPFX, MTZ, and TID was high, whereas that to AMX, AMC, GEN, CFM, TET, DOX, RFP and FZD was relatively low. CFM and DOX are promising new choices for H. pylori eradication.

3,4-benzo[a]pyrene aggravates myocardial infarction injury by activating NLRP3-related pyroptosis through PINK1/Parkin-mitophagy-mPTP opening axis.

BACKGROUND: Air pollution is an important and interventionable risk factor for cardiovascular disease. Air pollution exposure, even for a short-term exposure, is conspicuously relevant to increased risk of myocardial infarction (MI) mortality and clinical evidence has shown that air pollution particulate matter (PM) induces the aggravation of AMI. 3,4-benzo[a]pyrene (BaP), an extremely toxic polycyclic aromatic hydrocarbon (PAH) and a common component of PM, is listed as one of the main objects of environmental pollution monitoring. Both epidemiological and toxicological studies suggest that BaP exposure may be associated with cardiovascular disease. Since PM is significantly associated with the increased risk of MI mortality, and BaP is an important component of PM associated with cardiovascular disease, we intend to investigate the effect of BaP on MI models. METHODS: The MI mouse model and the oxygen and glucose deprivation (OGD) H9C2 cell model were used to investigate the effect of BaP in MI injury. The involvement of mitophagy and pyroptosis in regulating deterioration of cardiac function and aggravation of MI injury induced by BaP was comprehensively evaluated. RESULTS: Our study shows that BaP exacerbates MI injury in vivo and in vitro, a result based on BaP-induced NLRP3-related pyroptosis. In addition, BaP can inhibit PINK1/Parkin dependent mitophagy through the aryl hydrocarbon receptor (AhR), thus the mitochondrial permeability transition pore (mPTP) was induced to open. CONCLUSION: Our results suggest a role for the BaP from air pollution in MI injury aggravation and reveal that BaP aggravates MI injury by activating NLRP3-related pyroptosis via the PINK1/Parkin-mitophagy-mPTP opening axis.

A method to protect the endometrium for microwave ablation treating types 1-3 uterine fibroids: a preliminary comparative study.

PURPOSE: To investigate the feasibility of percutaneous intrauterine instillation of chilled saline to protect the endometrium during microwave ablation (MWA) treating types 1-3 uterine fibroids. MATERIALS AND METHODS: Twenty-six patients with types 1-3 uterine fibroids were prospectively enrolled in an intrauterine saline instillation group (study group). The same number of patients with types 1-3 uterine fibroids who previously received MWA without endometrial protection were retrospectively included in a control group. Endometrial impairment was evaluated by hysteroscopy and magnetic resonance imaging (MRI). RESULTS: In the study group, hysteroscopy revealed an intact endometrium in 17 patients, congestion and reddening of the endometrium due to heat in 8 patients, and a burnt necrosis with a size < 1 cm on the functional layer of the endometrium in 1 patient. On MRI, in the study group, there were 17 (65.4%), 6 (23.1%), and 3 (11.5%) patients with grades 0, 1, and 2 endometrial impairment, respectively, but no grade 3 endometrial impairment. In the control group, there were 8 (30.8%), 8 (30.8%), 7 (26.9%), and 3 (11.5%) patients with grades 0, 1, 2, and 3 endometrial impairment, respectively. Endometrial impairment in the study group was significantly better than that in the control group (p = 0.006). One patient had puncture tunnel bleeding and no other complications occurred in the study group. CONCLUSION: Intraoperative percutaneous intrauterine instillation of chilled saline may be effective and safe in reducing the thermal damage to the endometrium caused by MWA for treating types 1-3 uterine fibroids.

3,4-benzopyrene aggravates myocardial ischemia-reperfusion injury-induced pyroptosis through inhibition of autophagy-dependent NLRP3 degradation.

Polycyclic aromatic hydrocarbons (PAHs) are produced during combustion of organic matter, such as during cigarette smoking, and they exist widely in the environment. Exposure to 3,4-benzo[a]pyrene (BaP), as the most widely studied PAHs, relates to many cardiovascular diseases. However, the underlying mechanism of its involvement remains largely unclear. In this study, we developed a myocardial ischemia-reperfusion (I/R) injury mouse model and an oxygen and glucose deprivation-reoxygenation H9C2 cell model to evaluate the effect of BaP in I/R injury. After BaP exposure, the expression of autophagy-related proteins, the abundance of NLRP3 inflammasomes, and the degree of pyroptosis were measured. Our results show that BaP aggravates myocardial pyroptosis in a autophagy-dependent manner. In addition, we found that BaP activates the p53-BNIP3 pathway via the aryl hydrocarbon receptor to decrease autophagosome clearance. Our findings present new insights into the mechanisms underlying cardiotoxicity and reveal that the p53-BNIP3 pathway, which is involved in autophagy regulation, is a potential therapeutic target for BaP-induced myocardial I/R injury. Because PAHs are omnipresent in daily life, the toxic effects of these harmful substances should not be underestimated.

The Neutrophil Percentage-to-Albumin Ratio is Associated with All-Cause Mortality in Patients with Atrial Fibrillation: A Retrospective Study.

Objective: The present study aimed to evaluate the relationship between all-cause mortality and the neutrophil percentage-to-albumin ratio (NPAR) in patients with atrial fibrillation (AF). Methods: We obtained clinical information from patients with AF from the Medical Information Mart for Intensive Care-IV version 2.0 (MIMIC-IV) database and the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University (WMU). The clinical endpoints were all-cause death measured at 30-day, 90-day, and one-year intervals. For endpoints associated with the NPAR, logistic regression models were used to calculate odds ratios (OR) with 95% confidence intervals (CI). Receiver operating characteristic (ROC) curves and area under the curve (AUC) were developed to compare the ability of different inflammatory biomarkers to predict 90-day mortality in patients with AF. Results: Higher NPAR was associated with a higher risk of 30-day (OR 2.08, 95% CI 1.58-2.75), 90-day (OR 2.07, 95% CI 1.61-2.67), and one-year mortality (OR 1.60, 95% CI 1.26-2.04) in patients with AF in 2813 patients from MIMIC-IV. The predictive performance of NPAR (AUC = 0.609) for 90-day mortality was better than that of neutrophil-to-lymphocyte ratio (NLR) (AUC = 0.565, P < 0.001), and platelet-to-lymphocyte ratio (PLR) (AUC = 0.528, P < 0.001). When NPAR and sequential organ failure assessment (SOFA) were combined, the AUC increased from 0.609 to 0.674 (P < 0.001). Higher NPAR was associated with a higher risk of 30-day mortality (OR 2.54, 95% CI 1.02-6.30) and 90-day mortality (OR 2.76, 95% CI 1.09-7.01) in 283 patients from WMU. Conclusion: An increased 30-day, 90-day, and one-year mortality risk among patients with AF were linked to a higher NPAR in MIMIC-IV. NPAR was thought to be a good predictor of 90-day all-cause mortality. Higher NPAR was associated with a higher risk of 30-day and 90-day mortality in WMU.

A Matching Strategy To Guide Donor Selection for Ulcerative Colitis in Fecal Microbiota Transplantation: Meta-Analysis and Analytic Hierarchy Process.

Fecal microbiota transplantation (FMT) targeting gut microbiota has recently been applied to the treatment of ulcerative colitis (UC). However, preliminary trials showed that only a subset of patients responded to FMT, and the heterogeneity in donor gut microbiota probably played important roles in patients' responses, implying the significance of matching an appropriate donor to a specified patient. We developed a strategy to build a donor-recipient matching model to guide rational donor selection for UC in FMT. We collected and uniformly reanalyzed 656 fecal 16S rRNA gene sequencing samples (350 from UC patients and 306 from healthy subjects) from 9 studies. Significantly lower α-diversity indexes were observed in UC patients by random effects model. Thirty-four bacterial genera and 34 predicted pathways were identified with significant odds ratios and classification potentials for UC patients. Based on six bacterial indicators, including richness, overall distance, genera, and pathways (beneficial and harmful), the analytic hierarchy process-based donor-recipient matching model was set to rank and select appropriate donors for patients with UC. Finally, the model showed favorable classification powers (>70%) for FMT effectiveness in two previous clinical trials. This study revealed the dysbiosis of fecal bacterial diversity, composition, and predicted pathways of patients with UC by meta-analysis and hereby developed a donor-recipient matching strategy to guide donor selection for UC in FMT. This strategy can also be applied to other diseases associated with gut microbiota. IMPORTANCE Modulation of gut microbiota by FMT from donors has been applied to the treatment of UC and yielded variable effectiveness in clinical trials. One possibility is that this variable effectiveness was related to donor selection, as a patient's response to FMT may rely on the capability of the used donor's microbiota to restore the specific gut disturbances of the patient. However, the biggest issues on the practical level are what should be considered in the selection process and how to set up such a donor-recipient matching model. In this study, we presented a bacterial profile-based donor-recipient matching strategy to guide donor selection for UC in FMT by first meta-analysis of 656 fecal 16S rRNA gene sequencing samples from 9 studies to identify significant indicators and then setting up the model by an analytic hierarchy process. The applicability and accuracy of this model were verified in the data sets from two previous FMT clinical studies. Our data indicate that the donor-recipient matching model built in this study enables researchers to rationally select donors for UC patients in FMT clinical practice, although it needs more samples and prospective trials for validation. The strategy adopted in this study to leverage existing data sets to build donor-recipient matching models for precision FMT is feasible for other diseases associated with gut microbiota.

Regulation of wakefulness by astrocytes in the lateral hypothalamus.

The lateral hypothalamus (LH) is an important brain region mediating sleep-wake behavior. Recent evidence has shown that astrocytes in central nervous system modulate the activity of adjacent neurons and participate in several physiological functions. However, the role of LH astrocytes in sleep-wake regulation remains unclear. Here, using synchronous recording of electroencephalogram/electromyogram in mice and calcium signals in LH astrocytes, we show that the activity of LH astrocytes is significantly increased during non-rapid eye movement (NREM) sleep-to-wake transitions and decreased during Wake-to-NREM sleep transitions. Chemogenetic activation of LH astrocytes potently promotes wakefulness and maintains long-term arousal, while chemogenetic inhibition of LH astrocytes decreases the total amount of wakefulness in mice. Moreover, by combining chemogenetics with fiber photometry, we show that activation of LH astrocytes significantly increases the calcium signals of adjacent neurons, especially among GABAergic neurons. Taken together, our results clearly illustrate that LH astrocytes are a key neural substrate regulating wakefulness and encode this behavior through surrounding GABAergic neurons. Our findings raise the possibility that overactivity of LH astrocytes may be an underlying mechanism of clinical sleep disorders.

Incidence and clinical characteristics of hypertriglyceridemic acute pancreatitis: A retrospective single-center study.

BACKGROUND: The incidence of hypertriglyceridemic acute pancreatitis (HTG-AP) has increased yearly, but updated population-based estimates on the incidence of HTG-AP are lacking. Reducing serum triglyceride (TG) levels quickly is crucial in the early treatment of HTG-AP. Decreased serum TG levels are treated by non-invasive methods, which include anti-lipidemic agents, heparin, low-molecular weight heparin, and insulin, and invasive methods, such as blood purification including hemoperfusion (HP), plasmapheresis, and continuous renal replacement therapy. However, authoritative guidelines have not been established. Early selection of appropriate treatment is important and beneficial in controlling the development of HTG-AP. AIM: To evaluate the effect between patients treated with intravenous insulin (INS) and HP to guide clinical treatment. METHODS: We retrospectively reviewed 371 patients with HTG-AP enrolled in the Department of Fujian Provincial Hospital form April 2012 to March 2021. The inpatient medical and radiologic records were reviewed to determine clinical features, severity, complications, mortality, recurrence rate, and treatment. Multivariate logistic regression analyses were used to analyze risk factors for severe HTG-AP. Propensity score matching was used to compare the clinical outcomes of INS and HP. RESULTS: A total of 371 patients met the HTG-AP criteria. The incidence of HTG-AP was increased by approximately 2.6 times during the 10 years (8.4% in April 2012-March 2013 and 22.3% in April 2020-March 2021). The highest incidence rate of acute pancreatitis was observed for men in the age group of 30-39 years. The amylase level was elevated in 80.1% of patients but was only three times the normal value in 46.9% of patients. The frequency of severe acute pancreatitis (26.9%), organ failure (31.5%), rate of recurrence (32.9%), and mortality (3.0%) of HTG-AP was high. Improved Marshall score, modified computed tomography severity index score, baseline TG, baseline amylase, C-reactive protein (CRP), albumin, aspartate aminotransferase, low-density lipoprotein cholesterol, urea nitrogen, creatinine, calcium, hemoglobin, free triiodothyronine, admission to intensive care unit, and mortality were significantly different between patients with different grades of severity (P < 0.050). Multivariate logistic regression analysis confirmed that high CRP [P = 0.005, odds ratio (OR) = 1.011, 95%CI: 1.003-1.019], low calcium (P = 0.003, OR = 0.016, 95%CI: 0.001-0.239), and low albumin (P = 0.023, OR = 0.821, 95%CI: 0.693-0.973) were risk factors of severe HTG-AP. After propensity score matching adjusted by sex, age, severity of HTG-AP, and baseline TG, the serum TG significantly decreased in patients treated with INS (P < 0.000) and HP (P < 0.000) within 48 h. However, the clearance rate of TG (57.24 ± 33.70% vs 56.38 ± 33.61%, P = 0.927) and length of stay (13.04 ± 7.92 d vs 12.35 ± 6.40 d, P = 0.730) did not differ between the two groups. CONCLUSION: The incidence of HTG-AP exhibited a significant increase, remarkable severity, and recurrent trend. Patients with mild and moderately severe acute pancreatitis can be treated effectively with INS safely and effectively without HP.

Regulation of wakefulness by GABAergic dorsal raphe nucleus-ventral tegmental area pathway.

The dorsal raphe nucleus (DRN) has previously been proved to be involved in the regulation of the sleep-wake behavior. DRN contains several neuron types, such as 5-HTergic and GABAergic neurons. GABAergic neurons, which are the second largest cell subtype in the DRN, participate in a variety of neurophysiological functions. However, their role in sleep-wake regulation and the underlying neural circuitry remains unclear. Herein, we used fiber photometry and synchronous electroencephalogram (EEG)/electromyography (EMG) recording to demonstrate that DRN GABAergic neurons exhibit high activities during wakefulness and low activities during NREM sleep. Short-term optogenetic activation of DRN GABAergic neurons reduced the latency of NREM-to-wake transition and increased the probability of wakefulness, while long-term optogenetic activation of these neurons significantly increased the amount of wakefulness. Chemogenetic activation of DRN GABAergic neurons increased wakefulness for almost 2 h and maintained long-lasting arousal. In addition, inhibition of DRN GABAergic neurons with chemogenetics caused a reduction in the amount of wakefulness. Finally, similar to the effects of activating the soma of DRN GABAergic neurons, optogenetic stimulation of their terminals in the ventral tegmental area (VTA) induced instant arousal and promoted wakefulness. Taken together, our results illustrated that DRN GABAergic neurons are vital to the induction and maintenance of wakefulness, which promote wakefulness through the GABAergic DRN-VTA pathway.

Shexiang Baoxin Pill attenuates myocardial ischemia/reperfusion injury by activating autophagy via modulating the ceRNA-Map3k8 pathway.

BACKGROUND: The pathogenesis of myocardial ischemia/reperfusion is complex, involving multiple regulatory genes and environmental factors, and requiring the simultaneous regulation of multiple targets. Meanwhile, Traditional Chinese Medicine (TCM) has certain advantages in the comprehensive treatment of multi-site, multi-target conditions and overall regulation of this condition. This study explores the effect of the well-known TCM, the Shexiang Baoxin Pill (SBP) on myocardial ischemia/reperfusion injury in mice. MATERIALS AND METHODS: In vivo, 20 mg/kg/day SBP was administered by gavage for 28 days. In vitro, cardiomyocytes were pretreated with 25 µg/ml SBP for 24 h. Evans blue/TTC double-staining was employed to determine the infarct size. Markers of myocardial injury were detected in the serum and cell supernatants. The changes of pyroptosis and autophagy proteins were detected by western blot. Immunofluorescence, immunohistochemistry and PCR were performed to further illustrate the results. RESULTS: SBP significantly reduced the myocardial infarct size, decreased the myocardial injury markers, inhibited cardiomyocyte pyroptosis and oxidative stress, and promoted autophagy in vivo. In vitro, SBP alleviated cardiomyocyte pyroptosis, inhibited oxidative stress, reduced IL-1ß and IL-18 secretion, and unblocked autophagy flux. Myocardial injury is mitigated by SBP via the rapid degradation of autophagosomes, and SBP promotes the accumulation of autophagosomes by downregulating mmu_circ_0005874, Map3k8 and upregulating mmu-miR-543-3p. CONCLUSION: We found for the first time that SBP can inhibit pyroptosis and oxidative stress, and protect from myocardial I/R injury. In addition, it inhibits pyroptosis and improves H/R injury by promoting autophagosome generation and accelerating autophagic flux. SBP interferes with autophagy through the interaction between mmu_circ_0005874/mmu-miR-543-3p/Map3k8.

ZIC2 promotes colorectal cancer growth and metastasis through the TGF-ß signaling pathway.

ZIC2 is involved in the tumor progression of many types of cancers. The role of ZIC2 in the metastasis of colorectal cancer and its mechanism are not yet clear. In this study, we found that high ZIC2 expression was not only associated with poor prognosis, relapse-free survival and advanced metastasis but was also an independent prognostic factor in colorectal cancer patients. Moreover, ZIC2 knockdown inhibited cell proliferation, migration and invasion, while the upregulation of ZIC2 had the opposite effect in vitro. ZIC2 overexpression induced TGF-ß1 expression and increased Smad3 phosphorylation. The carcinogenic effects of elevated ZIC2 expression can be eliminated by interfering with the TGF-ß1 receptor with inhibitors. This further verified the promoting effect of ZIC2 on the TGF-ß signaling pathway. In vivo experiments have also confirmed that ZIC2 can promote liver metastases of colorectal cancer. The results suggest that ZIC2 is associated with poor prognosis and relapse-free survival in colorectal cancer patients. Moreover, ZIC2 promoted colorectal cancer progression and metastasis by activating the TGF-ß signaling pathway. Hence, ZIC2 is expected to be a new therapeutic and prognostic target for colorectal cancer in the future.

RAGE is a potential biomarker implicated in immune infiltrates and cellular senescence in lung adenocarcinoma.

BACKGROUND: Receptor for Advanced Glycation End-products (RAGE) is an oncogene abnormally expressed in various cancers. However, the clinical value of RAGE and the biological role of RAGE in lung cancer have not been fully investigated. METHODS: We compared the RAGE expression using several public databases. The relationship between RAGE expression and clinicopathological variables was assessed. The R software package was used to carry out enrichment analyses of RAGE co-expression and gene set enrichment analysis (GSEA). Additionally, we used the TIMER database to assess the association between immune infiltration and RAGE expression. The correlation between RAGE expression and senescence biomarkers in lung adenocarcinoma was analyzed using the TCGA database. RESULTS: Our findings indicated that the expression of RAGE was downregulated in lung adenocarcinoma, and down-regulation of RAGE was related to poor overall survival and disease-free survival. Functional enrichment analysis indicated that RAGE co-expression genes were mainly associated with neutrophil activation involved in immune response, neutrophil degranulation, and regulation of leukocyte-mediated immunity. Correlation analysis revealed that RAGE expression was closely related to the purity of the tumor and immune infiltration. GSEA indicated that the RAGE-related differential genes were mainly enriched in senescence-related pathways. Besides, the RAGE expression was significantly associated with senescence-related genes. CONCLUSION: Down-regulation of RAGE expression was associated with poor prognosis, as well as defective immune infiltration and cellular senescence in lung adenocarcinoma.

A glutamatergic basal forebrain to midbrain circuit mediates wakefulness and defensive behavior.

Defensive behavior, a group of responses that evolved due to threatening stimuli, is crucial for animal survival in the natural environment. For defensive measures to be timely and successful, a high arousal state and immediate sleep-to-wakefulness transition are required. Recently, the glutamatergic basal forebrain (BF) has been implicated in sleep-wake regulation; however, the associated physiological functions and underlying neural circuits remain unknown. Here, using in vivo fiber photometry, we found that BF glutamatergic neuron is activated by various threatening stimuli, including predator odor, looming threat, sound, and tail suspension. Optogenetic activation of BF glutamatergic neurons induced a series of context-dependent defensive behaviors in mice, including escape, fleeing, avoidance, and hiding. Similar to the effects of activated BF glutamatergic cell body, photoactivation of BF glutamatergic terminals in the ventral tegmental area (VTA) strongly drove defensive behaviors in mice. Using synchronous electroencephalogram (EEG)/electromyogram (EMG) recording, we showed that photoactivation of the glutamatergic BF-VTA pathway produced an immediate transition from sleep to wakefulness and significantly increased wakefulness. Collectively, our results clearly demonstrated that the glutamatergic BF is a key neural substrate involved in wakefulness and defensive behaviors, and encodes these behaviors through glutamatergic BF-VTA pathway. Overexcitation of the glutamatergic BF-VTA pathway may be implicated in clinical psychiatric diseases characterized by exaggerated defensive responses, such as autism spectrum disorders.

Implant placement in the pterygoid region with dynamically navigated surgery: A clinical report.

Implant placement in the pterygoid region is a reliable treatment for posterior maxillary tooth loss. However, the surgery is not widely applied because the implant placement region is hard to access and the direct visual access is limited. This clinical report describes the use of a dynamic navigation system to improve the pterygoid implant placement surgery. Real-time imaging of the surgery area and full-time guidance are provided by the system to alleviate the problem of lack of visibility and to reduce the complexity of placement.

Identification and Validation of Hub Genes Predicting Prognosis of Hepatocellular Carcinoma.

INTRODUCTION: The aim of this study is selecting the hub genes associated with hepatocellular carcinoma (HCC) to construct a Cox regression model for predicting prognosis in HCC patients. METHODS: Using HCC patient data from the ICGC and TCGA databases, screened for 40 core genes highly correlated with histological grade of HCC. Univariate and multivariate Cox regression analyses were performed on the genes highly associated with HCC prognosis, and the model was established. The expression of those genes was measured by immunohistochemistry in 110 HCC patients who underwent the surgery in the First Affiliated Hospital of Wenzhou Medical University. The survival of HCC patients was analyzed by the Kaplan-Meier method. RESULTS: Eight genes (CDC45, CENPA, MCM10, MELK, CDC20, ASF1B, FANCD2, and NCAPH) were correlated with prognosis, and the same result was observed in 110 HCC patients. Using the regression model, the HCC patients in the training set were classified as high- and low-risk groups. The overall survival of patients in the high-risk group was shorter than that in the low-risk group, and the same results were obtained in the verification set. CONCLUSION: This study found that the risk model according to these 8 genes can be used as a predictor of prognosis in HCC. These genes may become alternative biomarkers and therapeutic targets and provide new therapeutic strategies for HCC.