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The human myocardium contains robust cells that constantly beat from birth to death without being replaced, even when exposed to various environmental stresses. Myocardial robustness is thought to depend primarily on the strength of the reducing power to protect the heart from oxidative stress. Myocardial antioxidant systems are controlled by redox reactions, primarily via the redox reaction of Cys sulfhydryl groups, such as found in thioredoxin and glutathione. However, the specific molecular entities that regulate myocardial reducing power have long been debated. Recently, reactive sulfide species, with excellent electron transfer ability, consisting of a series of multiple sulfur atoms, i.e., Cys persulfide and Cys polysulfides, have been found to play an essential role in maintaining mitochondrial quality and function, as well as myocardial robustness. This review presents the latest findings on the molecular mechanisms underlying mitochondrial energy metabolism and the maintenance of quality control by reactive sulfide species and provides a new insight for the prevention of chronic heart failure.

Novel coronavirus infection disease 2019 (COVID-19) is an emerging infectious disease that has been rampant worldwide since its onset was confirmed in Wuhan, China in 2019. An effective therapy has not yet been established, and there is an urgent need to establish a breakthrough therapeutic strategy for the prevention and treatment of COVID-19 aggravation. The main route of infection is that the Spike protein (S protein) on the surface of SARS-CoV-2 binds to its recognition receptor, angiotensin converting enzyme (ACE) 2, on the host cell surface. Then, SARS-CoV-2 invades the cell via endocytosis-dependent pathway. Although the major symptom of COVID-19 is lung inflammation, ACE2 is expressed not only in the lungs but also in various tissues including heart and digestive organs. We focused on the molecular mechanism underlying the development of heart failure, a pathology involved in COVID-19 aggravation risk factors and COVID-19 squeals. We revealed that cardiac ACE2 receptors were upregulated by exposure to various environmental stresses reported as COVID-19 aggravation risk factors, and the formation of membrane protein complex between TRPC3 and NADPH oxidase (Nox) 2 that participates in myocardial remodeling underlies pathological ACE2 upregulation. Furthermore, we utilized the already approved drugs that inhibit TRPC3-Nox2 protein complex formation, and identified that clomipramine, a tricyclic antidepressant, has the best potency to suppress ACE2 internalization induced by S protein exposure. This review introduces the mechanism of pathological ACE2 receptor upregulation through TRPC3-Nox2 complex formation in the heart, and the identification of a breakthrough drug candidate using in vitro pseudo-infection screening system.

Myocardial damage caused by the newly emerged coronavirus (SARS-CoV-2) infection is one of the key determinants of COVID-19 severity and mortality. SARS-CoV-2 entry to host cells is initiated by binding with its receptor, angiotensin-converting enzyme (ACE) 2, and the ACE2 abundance is thought to reflect the susceptibility to infection. Here, we report that ibudilast, which we previously identified as a potent inhibitor of protein complex between transient receptor potential canonical (TRPC) 3 and NADPH oxidase (Nox) 2, attenuates the SARS-CoV-2 spike glycoprotein pseudovirus-evoked contractile and metabolic dysfunctions of neonatal rat cardiomyocytes (NRCMs). Epidemiologically reported risk factors of severe COVID-19, including cigarette sidestream smoke (CSS) and anti-cancer drug treatment, commonly upregulate ACE2 expression level, and these were suppressed by inhibiting TRPC3-Nox2 complex formation. Exposure of NRCMs to SARS-CoV-2 pseudovirus, as well as CSS and doxorubicin (Dox), induces ATP release through pannexin-1 hemi-channels, and this ATP release potentiates pseudovirus entry to NRCMs and human iPS cell-derived cardiomyocytes (hiPS-CMs). As the pseudovirus entry followed by production of reactive oxygen species was attenuated by inhibiting TRPC3-Nox2 complex in hiPS-CMs, we suggest that TRPC3-Nox2 complex formation triggered by panexin1-mediated ATP release participates in exacerbation of myocardial damage by amplifying ACE2-dependent SARS-CoV-2 entry.

Our hospital in the western part of Yokohama City managed adult bronchial asthma patients via a coordinated care system with primary care clinics. The aim of the system is to provide effective daily and emergency medical care.The study comprised 288 adult stable asthmatics (201 women) who were examined at Yokohama City Seibu Hospital between Jan 2009 and May 2018 and who were being managed under our coordinated care system at one of 80 primary clinics or hospitals.Of the 288 patients enrolled, 188 continued, 37 ended under management, and 63 dropped out from this system. The drop-out rate was highest at visit 1 (9%). The main reasons for end of cooperation under management were readjustment of asthma treatment and treatment for other diseases. The reasons for dropping out were low adherence, older age, and mild symptoms. There was a significant tendency in the frequency of patients who continued, ended under management, or dropped out (xOur coordinated care system managed 188 asthmatic patients (65.2%) properly. Patients with low adherence tended to drop out from the system at visit 1.

G protein-coupled receptors (GPCRs) play pivotal roles in converting physicochemical stimuli due to environmental changes to intracellular responses. After ligand stimulation, many GPCRs are desensitized and then recycled or degraded through phosphorylation and β-arrestin-dependent internalization, an important process to maintain protein quality control of GPCRs. However, it is unknown how GPCRs with low β-arrestin sensitivity are controlled. Here we unmasked a β-arrestin-independent GPCR internalization, named Redox-dependent Alternative Internalization (REDAI), focusing on β-arrestin-resistant purinergic P2Y

We started robot-assisted minimally invasive esophagectomy (RAMIE) in 2012 using da Vinci S. After the reimbursement in the national insurance system in 2018, RAMIE has been indicated as an institutional standard surgery simply depending on the da Vinci availability. Our early series of 45 RAMIEs showed significantly less postoperative morbidity (p = 0.03) mainly due to less pulmonary complication (p = 0.006) compared to conventional minimally invasive esophagectomy using propensity score matching (Ann Surg Oncol. 2020). This study aims to retrospectively evaluate the feasibility of RAMIE and to demonstrate our standardized RAMIE with updated data. Our surgical technique is as follows. A patient is placed in a prone position with both lung ventilation with 8-10 mmHg artificial pneumothorax. In the upper mediastinum, the thoracic duct is usually preserved unless there is tumor invasion. Then, the tracheoesophageal arteries flowing into the visceral sheath over the recurrent laryngeal nerve (RLN) are divided first and RLN is isolated laterally. Then, the lymphatic tissue is dissected from the trachea. This procedure is identical on both sides of RLN nodal dissection. By January 2022, 89 RAMIEs (S: 6 cases and Xi: 83 cases) were performed. Thoracic operation time was 348 min and console time was 296 min. Intraoperative blood loss was 80 g and the number of harvested thoracic nodes is 23. There was no conversion from RAMIE to MIE nor to open procedure. Overall severe postoperative morbidity (Clavien-Dindo Grade 3 or higher) was 17% (15/89) and clinically relevant postoperative recurrent laryngeal nerve palsy (Clavien-Dindo Grade 2 or higher) was 10% (9/89). There was no postoperative mortality. RAMIE was safe and feasible.

Inflammatory bowel disease is becoming a global health challenge, with substantial variations in incidence and death rates between Eastern and Western countries.To investigate the burden and trends of inflammatory bowel disease in five Asian countries, the US, and the UK.Cross-sectional study.Global Burden of Disease Study 2019.Inflammatory bowel disease.Incidence, death, and age-standardized rates of inflammatory bowel disease.The age-standardized incidence and death rates of inflammatory bowel disease gradually decreased worldwide from 1990 to 2019. The age-standardized incidence rate in the US decreased from 1990 to 2000, and then increased gradually from 2000 to 2019, the rates in the UK, Mongolia, and China increased gradually from 1990 to 2019, while the rate in the Democratic People's Republic of Korea decreased from 1990 to 1995, and increased gradually from 1990 to 2019. The age-standardized death rate in the Republic of Korea exhibited a rising trend until 1995, fell significantly up to 2015, and then stabilized from 2015 to 2019. The age-standardized death rate in the US showed a rising trend until 2007, and then decreased gradually from 2007 to 2019, while the rate in the UK showed a rising trend until 2010 and decreased from 2010 to 2019. The age-standardized death rates in China, Mongolia, the Democratic People's Republic of Korea, and Japan decreased gradually from 1990 to 2019. The age-standardized incidence and death rates in the US and UK in the last decade were higher than those in the five Asian countries. The peak age-standardized incidence rates in the seven countries were among people aged 20 to 60 years. The age-standardized death rates in all seven countries exhibited rising trends with increasing age, with older individuals, particularly those aged ≥70 years, accounting for most deaths.Data from different countries with different quality and accuracy.There have been large variations in the burdens and trends of inflammatory bowel disease between five Asian countries, the US, and UK during the past three decades. These findings may help policymakers to make better public decisions and allocate appropriate resources. See Video Abstract at http://links.lww.com/DCR/B996.

Interleukin (IL)-19 is a cytokine of the IL-10 family. There are many reports on the involvement of IL-19 in several human diseases. There also are many reports elucidating the role of IL-19 using mouse disease models. Most reports use C57BL/6 mice, whereas few reports use BALB/c mice, in terms of the mouse disease model that the researchers used in the present study. To date, research on the role of IL-19 is diversified, yet some basic mechanisms are still unclear. In this study, we administered lipopolysaccharide (LPS), polyI:C, and CpG to BALB/c mice, measured more than 20 cytokines in the blood and compared them with that of the wild-type and IL-19-deficient (IL-19 KO) mice. LPS is associated with bacterial infection, polyI:C is associated with viral infection, and CpG is associated with both bacterial and viral infections. Among the cytokines measured, the results of experiments using LPS revealed that the production of some cytokines was suppressed in IL-19 KO mice. Interestingly, the experiments using polyI:C revealed that production of some cytokines was enhanced in IL-19 KO mice. However, the experiments using CpG have shown that the production of only one cytokine was enhanced in IL-19 KO mice. These results revealed that cytokine production in the blood was regulated by IL-19, and the type of regulation was dependent on the administered stimulant.

Although conventional oxygen therapy (COT) is widely used, hypoxemia frequently occurs in gastrointestinal endoscopy with conscious sedation and can lead to life-threatening consequences. High flow nasal oxygen (HFNO) has been applied to improve oxygenation in clinical entities. However, its efficacy to prevent hypoxemia in gastrointestinal endoscopy with conscious sedation has not been evaluated.We searched databases to identify randomized controlled trials that compared the efficacy of HFNO with COT in gastrointestinal endoscopy with conscious sedation. The primary outcome was hypoxemia. Meta-analyses with trial sequential analysis were performed using a random-effects model.Eight trials with 3212 patients were included. Compared with COT, HFNO significantly reduced the risk of hypoxemia (eight trials; 3212 patients; risk ratio 0.30; 95% confidence interval [CI] 0.13-0.70). Trial sequential analysis showed that the cumulative Z curve did not cross the monitoring or futility boundaries, nor reach the required information size line, indicating that more trials are needed to reach a definitive conclusion. Subgroup analyses indicated the superiority of HFNO over COT with respect to hypoxemia in patients at low risk and high risk. HFNO further improved the lowest oxygen saturation (four trials; 459 patients; mean difference 2.30, 95% CI 0.84-3.77).Compared with COT, HFNO can reduce the risk of hypoxemia and improve the lowest oxygen saturation in gastrointestinal endoscopy with conscious sedation. However, the results should be interpreted with caution due to substantial heterogeneity and limited evidence. Further studies are needed to verify the preliminary findings.

After ligand stimulation, many G protein–coupled receptors (GPCRs) undergo β-arrestin–dependent desensitization, during which they are internalized and either degraded or recycled to the plasma membrane. Some GPCRs are not subject to this type of desensitization because they lack the residues required to interact with β-arrestins. We identified a mechanism of redox-dependent alternative internalization (REDAI) that promotes the internalization and degradation of the purinergic P2Y

Fil: Numaga-Tomita, Takuro. National Institutes of Natural Sciences. National Institute for Physiological Sciences; Japón Fil: Numaga-Tomita, Takuro. National Institutes of Natural Sciences. Exploratory Research Center on Life and Living Systems; Japón Fil: Numaga-Tomita, Takuro. The Graduate University for Advanced Studies. School of Life Science. SOKENDAI; Japón Fil: Numaga-Tomita, Takuro. Shinshu University School of Medicine; Japón Fil: Shimauchi, Tsukasa. National Institutes of Natural Sciences. National Institute for Physiological Sciences; Japón Fil: Shimauchi, Tsukasa. National Institutes of Natural Sciences. Exploratory Research Center on Life and Living Systems; Japón Fil: Shimauchi, Tsukasa. Kyushu University. Graduate School of Pharmaceutical Sciences; Japón Fil: Shimauchi, Tsukasa. Kyushu University. Graduate School of Medical Sciences; Japón Fil: Kato, Yuri. Kyushu University. Graduate School of Pharmaceutical Sciences; Japón Fil: Nishiyama, Kazuhiro. Kyushu University. Graduate School of Pharmaceutical Sciences; Japón Fil: Nishimura, Akiyuki. National Institutes of Natural Sciences. National Institute for Physiological Sciences; Japón Fil: Nishimura, Akiyuki. National Institutes of Natural Sciences. Exploratory Research Center on Life and Living Systems; Japón Fil: Nishimura, Akiyuki. The Graduate University for Advanced Studies. School of Life Science. SOKENDAI; Japón Fil: Sakata, Kosuke. Kyushu University. Graduate School of Pharmaceutical Sciences; Japón Fil: Inada, Hiroyuki. National Institutes of Natural Sciences. National Institute for Physiological Sciences; Japón Fil: Kita, Satomi. Fukuoka University. Faculty of Medicine; Japón Fil: Kita, Satomi. Tokushima Bunri University. Faculty of Pharmaceutical Sciences; Japón Fil: Iwamoto, Takahiro. Fukuoka University. Faculty of Medicine; Japón Fil: Nabekura, Junichi. National Institutes of Natural Sciences. National Institute for Physiological Sciences; Japón Fil: Birnbaumer, Lutz. Research Triangle Park. National Institutes of Health. National Institute of Environmental Health Sciences; Estados Unidos Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina Fil: Mori, Yasuo. Kyoto University. Graduate School of Engineering; Japón Fil: Nishida, Motohiro. National Institutes of Natural Sciences. National Institute for Physiological Sciences; Japón Fil: Nishida, Motohiro. National Institutes of Natural Sciences. Exploratory Research Center on Life and Living Systems; Japón Fil: Nishida, Motohiro. The Graduate University for Advanced Studies. School of Life Science. SOKENDAI; Japón Fil: Nishida, Motohiro. Kyushu University. Graduate School of Pharmaceutical Sciences; Japón Abstract: Background and Purpose: Capillary arterialization, characterized by the coverage of pre-existing or nascent capillary vessels with vascular smooth muscle cells (VSMCs), is critical for the development of collateral arterioles to improve post-ischaemic blood flow. We previously demonstrated that the inhibition of transient receptor potential 6 subfamily C, member 6 (TRPC6) channels facilitate contractile differentiation of VSMCs under ischaemic stress. We here investigated whether TRPC6 inhibition promotes post-ischaemic blood flow recovery through capillary arterialization in vivo. Experimental Approach: Mice were subjected to hindlimb ischaemia by ligating left femoral artery. The recovery rate of peripheral blood flow was calculated by the ratio of ischaemic left leg to non-ischaemic right one. The number and diameter of blood vessels were analysed by immunohistochemistry. Expression and phosphorylation levels of TRPC6 proteins were determined by western blotting and immunohistochemistry. Key Results: Although the post-ischaemic blood flow recovery is reportedly dependent on endothelium-dependent relaxing factors, systemic TRPC6 deletion significantly promoted blood flow recovery under the condition that nitric oxide or prostacyclin production were inhibited, accompanying capillary arterialization. Cilostazol, a clinically approved drug for peripheral arterial disease, facilitates blood flow recovery by inactivating TRPC6 via phosphorylation at Thr69 in VSMCs. Furthermore, inhibition of TRPC6 channel activity by pyrazole-2 (Pyr2; BTP2; YM-58483) promoted post-ischaemic blood flow recovery in Apolipoprotein E-knockout mice. Conclusion and Implications: Suppression of TRPC6 channel activity in VSMCs could be a new strategy for the improvement of post-ischaemic peripheral blood circulation.

Nonalcoholic steatohepatitis (NASH) is a disease that progresses from nonalcoholic fatty liver (NAFL) and which is characterized by inflammation and fibrosis. The purinergic P2Y6 receptor (P2Y6R) is a pro-inflammatory Gq/G12 family protein-coupled receptor and reportedly contributes to intestinal inflammation and cardiovascular fibrosis, but its role in liver pathogenesis is unknown. Human genomics data analysis revealed that the liver P2Y6R mRNA expression level is increased during the progression from NAFL to NASH, which positively correlates with inductions of C-C motif chemokine 2 (CCL2) and collagen type I α1 chain (Col1a1) mRNAs. Therefore, we examined the impact of P2Y6R functional deficiency in mice crossed with a NASH model using a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Feeding CDAHFD for 6 weeks markedly increased P2Y6R expression level in mouse liver, which was positively correlated with CCL2 mRNA induction. Unexpectedly, the CDAHFD treatment for 6 weeks increased liver weights with severe steatosis in both wild-type (WT) and P2Y6R knockout (KO) mice, while the disease marker levels such as serum AST and liver CCL2 mRNA in CDAHFD-treated P2Y6R KO mice were rather aggravated compared with those of CDAHFD-treated WT mice. Thus, P2Y6R may not contribute to the progression of liver injury, despite increased expression in NASH liver.

The burdens and trends of gastric cancer are poorly understood, especially in high-prevalence countries. Based on the Global Burden of Disease Study 2019, we analyzed the incidence, death, and possible risk factors of gastric cancer in five Asian countries, in relation to year, age, sex, and sociodemographic index. The annual percentage change was calculated to estimate the trends in age-standardized incidence rate (ASIR) and age-standardized death rate (ASDR). The highest ASIR per 100,000 person-years in 2019 was in Mongolia [44 (95% uncertainty interval (UI), 34 to 55)], while the lowest was in the Democratic People’s Republic of Korea (DPRK) [23 (95% UI, 19 to 29)]. The highest ASDR per 100,000 person-years was in Mongolia [46 (95% UI, 37 to 57)], while the lowest was in Japan [14 (95% UI, 12 to 15)]. Despite the increase in the absolute number of cases and deaths from 1990 to 2019, the ASIRs and ASDRs in all five countries decreased with time and improved sociodemographic index but increased with age. Smoking and a high-sodium diet were two possible risk factors for gastric cancer. In 2019, the proportion of age-standardized disability-adjusted life-years attributable to smoking was highest in Japan [23% (95% UI, 19 to 28%)], and the proportions attributable to a high-sodium diet were highest in China [8.8% (95% UI, 0.21 to 33%)], DPRK, and the Republic of Korea. There are substantial variations in the incidence and death of gastric cancer in the five studied Asian countries. This study may be crucial in helping policymakers to make better decisions and allocate appropriate resources.

Baroreflex control of cardiac contraction (positive inotropy) through sympathetic nerve activation is important for cardiocirculatory homeostasis. Transient receptor potential canonical subfamily (TRPC) channels are responsible for α

Vascular smooth muscle cells (VSMCs) play a pivotal role in the stability and tonic regulation of vascular homeostasis. VSMCs can switch back and forth between highly proliferative (synthetic) and fully differentiated (contractile) phenotypes in response to changes in the vessel environment. Abnormal phenotypic switching of VSMCs is a distinctive characteristic of vascular disorders, including atherosclerosis, pulmonary hypertension, stroke, and peripheral artery disease; however, how the control of VSMC phenotypic switching is dysregulated under pathological conditions remains obscure. Canonical transient receptor potential (TRPC) channels have attracted attention as a key regulator of pathological phenotype switching in VSMCs. Several TRPC subfamily member proteins-especially TRPC1 and TRPC6-are upregulated in pathological VSMCs, and pharmacological inhibition of TRPC channel activity has been reported to improve hypertensive vascular remodeling in rodents. This review summarizes the current understanding of the role of TRPC channels in cardiovascular plasticity, including our recent finding that TRPC6 participates in aberrant VSMC phenotype switching under ischemic conditions, and discusses the therapeutic potential of TRPC channels.

Definitive chemoradiotherapy (dCRT) is the major treatment for esophageal squamous cell carcinoma (ESCC), and prediction of the response to dCRT is important so as not to miss an opportunity to cure an ESCC. Nevertheless, few validated markers are available. Here, we aimed to identify a highly reproducible marker using multi-layer omics analysis. 117 ESCC samples from 67 responders and 50 non-responders were divided into screening, validation, and re-validation sets. In the screening cohort (n = 41), somatic mutations in 114 genes showed no association with dCRT response. Genome-wide DNA methylation analysis using Infinium HumanMethylation450 BeadChip array identified four genic regions significantly associated with dCRT response. Among them, FGF5 methylation was validated to be associated with dCRT response (n = 34; P = 0.001), and further re-validated (n = 42; P = 0.020) by bisulfite-pyrosequencing. The sensitivity and specificity in the combined validation and re-validation sets (n = 76) were 45% and 90%, respectively, by using the cut-off value established in the screening set, and FGF5 methylation had predictive power independent from clinicopathological parameters. In ESCC cell lines, FGF5 promoter methylation repressed its expression. FGF5 expression was induced by cisplatin (CDDP) treatment in three unmethylated cell lines, but not in two methylated cell lines. Exogenous FGF5 overexpression in a cell line with its methylation conferred resistance to CDDP. In non-cancerous esophageal tissues, FGF5 was not expressed, and its methylation was present in a small fraction of cells. These results showed that FGF5 methylation is a validated marker for ESCC sensitivity to dCRT.

Background and purpose Doxorubicin is a highly effective anticancer agent but eventually induces cardiotoxicity associated with increased production of ROS. We previously reported that a pathological protein interaction between TRPC3 channels and NADPH oxidase 2 (Nox2) contributed to doxorubicin-induced cardiac atrophy in mice. Here we have investigated the effects of ibudilast, a drug already approved for clinical use and known to block doxorubicin-induced cytotoxicity, on the TRPC3-Nox2 complex. We specifically sought evidence that this drug attenuated doxorubicin-induced systemic tissue wasting in mice. Experimental approach We used the RAW264.7 macrophage cell line to screen 1,271 clinically approved chemical compounds, evaluating functional interactions between TRPC3 channels and Nox2, by measuring Nox2 protein stability and ROS production, with and without exposure to doxorubicin. In male C57BL/6 mice, samples of cardiac and gastrocnemius muscle were taken and analysed with morphometric, immunohistochemical, RT-PCR and western blot methods. In the passive smoking model, cells were exposed to DMEM containing cigarette sidestream smoke. Key results Ibudilast, an anti-asthmatic drug, attenuated ROS-mediated muscle toxicity induced by doxorubicin treatment or passive smoking, by inhibiting the functional interactions between TRPC3 channels and Nox2, without reducing TRPC3 channel activity. Conclusions and implications These results indicate a common mechanism underlying induction of systemic tissue wasting by doxorubicin. They also suggest that ibudilast could be repurposed to prevent muscle toxicity caused by anticancer drugs or passive smoking.

Myocardial atrophy, characterized by the decreases in size and contractility of cardiomyocytes, is caused by severe malnutrition and/or mechanical unloading. Extracellular adenosine 5′-triphosphate (ATP), known as a danger signal, is recognized to negatively regulate cell volume. However, it is obscure whether extracellular ATP contributes to cardiomyocyte atrophy. Here, we report that ATP induces atrophy of neonatal rat cardiomyocytes (NRCMs) without cell death through P2Y2 receptors. ATP led to overproduction of reactive oxygen species (ROS) through increased amount of NADPH oxidase (Nox) 2 proteins, due to increased physical interaction between Nox2 and canonical transient receptor potential 3 (TRPC3). This ATP-mediated formation of TRPC3-Nox2 complex was also pathophysiologically involved in nutritional deficiency-induced NRCM atrophy. Strikingly, knockdown of either TRPC3 or Nox2 suppressed nutritional deficiency-induced ATP release, as well as ROS production and NRCM atrophy. Taken together, we propose that TRPC3-Nox2 axis, activated by extracellular ATP, is the key component that mediates nutritional deficiency-induced cardiomyocyte atrophy.

Myocardial damage caused by the newly emerged coronavirus (SARS-CoV-2) infection is one of key determinants of COVID-19 severity and mortality. SARS-CoV-2 entry to host cells are initiated by binding with its receptor, angiotensin converting enzyme (ACE) 2, and the ACE2 abundance is thought to reflect the susceptibility to infection. Here, we found that clomipramine, a tricyclic antidepressant, potently inhibits SARS-CoV-2 infection and metabolic disorder in human iPS-derived cardiomyocytes. Among 13 approved drugs that we have previously identified as potential inhibitor of doxorubicin-induced cardiotoxicity, clomipramine showed the best potency to inhibit SARS-CoV-2 spike glycoprotein pseudovirus-stimulated ACE2 internalization. Indeed, SARS-CoV-2 infection to human iPS-derived cardiomyocytes (iPS-CMs) and TMPRSS2-expressing VeroE6 cells were dramatically suppressed even after treatment with clomipramine. Furthermore, the combined use of clomipramine and remdesivir was revealed to synergistically suppress SARS-CoV-2 infection. Our results will provide the potentiality of clomipramine for the breakthrough treatment of severe COVID-19.

Background The American Joint Committee on Cancer (AJCC) 8th tumor-node-metastasis (TNM) classification for colorectal cancer (CRC) has limited ability to predict prognosis. Methods We included 45 379 eligible stage I-III CRC patients from the Surveillance, Epidemiology, and End Results Program. Patients were randomly assigned individually to a training (n = 31 772) or an internal validation cohort (n = 13 607). External validation was performed in 10 902 additional patients. Patients were divided according to T and N stage permutations. Survival analyses were conducted by a Cox proportional hazard model and Kaplan-Meier analysis, with T1N0 as the reference. Area under receiver operating characteristic curve and Akaike information criteria were applied for prognostic discrimination and model fitting, respectively. Clinical benefits were further assessed by decision curve analyses. Results We created a modified TNM (mTNM) classification: stages I (T1-2N0-1a); IIA (T1N1b, T2N1b, T3N0); IIB (T1-2N2a-2b, T3N1a-1b, T4aN0); IIC (T3N2a, T4aN1a-2a, T4bN0); IIIA (T3N2b, T4bN1a); IIIB (T4aN2b, T4bN1b); and IIIC (T4bN2a-2b). In the internal validation cohort, compared with the AJCC 8th TNM classification, the mTNM classification showed superior prognostic discrimination (area under receiver operating characteristic curve = 0.675 vs 0.667, respectively; 2-sided P Conclusions The mTNM classification provides better prognostic discrimination than AJCC 8th TNM classification, with good applicability in various populations and settings, to help better stratify stage I-III CRC patients into prognostic groups.

Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y6 receptor (P2Y6R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y6R prevents or promotes heart failure. We demonstrate that inhibition of P2Y6R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y6R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y6R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y6R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y6R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y6R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y6R exacerbates pressure overload-induced heart failure in mice, although P2Y6R in cardiomyocytes contributes to the progression of cardiac fibrosis.

Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y6 receptor (P2Y6R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y6R prevents or promotes heart failure. We demonstrate that inhibition of P2Y6R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y6R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y6R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y6R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y6R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y6R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y6R exacerbates pressure overload-induced heart failure in mice, although P2Y6R in cardiomyocytes contributes to the progression of cardiac fibrosis.