Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity.

The inflammasome adaptor ASC contributes to innate immunity through the activation of caspase-1. Here we found that signaling pathways dependent on the kinases Syk and Jnk were required for the activation of caspase-1 via the ASC-dependent inflammasomes NLRP3 and AIM2. Inhibition of Syk or Jnk abolished the formation of ASC specks without affecting the interaction of ASC with NLRP3. ASC was phosphorylated during inflammasome activation in a Syk- and Jnk-dependent manner, which suggested that Syk and Jnk are upstream of ASC phosphorylation. Moreover, phosphorylation of Tyr144 in mouse ASC was critical for speck formation and caspase-1 activation. Our results suggest that phosphorylation of ASC controls inflammasome activity through the formation of ASC specks.

Melatonin attenuates diabetic cardiomyopathy by increasing autophagy of cardiomyocytes via regulation of VEGF-B/GRP78/PERK signaling pathway.

AIMS: Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, and the potential strategies for treating DCM are insufficient. Melatonin (Mel) has been shown to attenuate DCM, however, the underlying mechanism remains unclear. The role of vascular endothelial growth factor-B (VEGF-B) in DCM is little known. In present study, we aimed to investigate whether Mel alleviated DCM via regulation of VEGF-B and explored its underlying mechanisms. METHODS AND RESULTS: We found that Mel significantly alleviated cardiac dysfunction and improved autophagy of cardiomyocytes in type 1 diabetes mellitus (T1DM) induced cardiomyopathy mice. VEGF-B was highly expressed in DCM mice in comparison with normal mice, and its expression was markedly reduced after Mel treatment. Mel treatment diminished the interaction of VEGF-B and Glucose-regulated protein 78 (GRP78) and reduced the interaction of GRP78 and protein kinase RNA -like ER kinase (PERK). Furthermore, Mel increased phosphorylation of PERK and eIF2α, then up-regulated the expression of ATF4. VEGF-B-/- mice imitated the effect of Mel on wild type diabetic mice. Interestingly, injection with Recombinant adeno-associated virus serotype 9 (AAV9)-VEGF-B or administration of GSK2656157 (GSK), an inhibitor of phosphorylated PERK abolished the protective effect of Mel on DCM. Furthermore, rapamycin, an autophagy agonist displayed similar effect with Mel treatment; while 3-Methyladenine (3-MA), an autophagy inhibitor neutralized the effect of Mel on high glucose-treated neonatal rat ventricular myocytes. CONCLUSIONS: These results demonstrated that Mel attenuated DCM via increasing autophagy of cardiomyocytes, and this cardio-protective effect of Mel was dependent on VEGF-B/GRP78/PERK signaling pathway.

Cocaine and amphetamine-regulated transcript improves myocardial ischemia-reperfusion injury through PI3K/AKT signalling pathway.

Myocardial ischemia-reperfusion injury (MIRI) is a common clinic scenario that occurs in the context of reperfusion therapy for acute myocardial infarction. It has been shown that cocaine and amphetamine-regulated transcript (CART) can ameliorate cerebral ischemia-reperfusion (I/R) injury, but the effect of CART on MIRI has not been studied yet. Here, we revealed that CART protected the heart during I/R process by inhibiting apoptosis and excessive autophagy, indicating that CART would be a potential drug candidate for the treatment of MIRI. Further analysis showed that CART upregulated the activation of phospho-AKT, leading to downregulation of lactate dehydrogenase (LDH) release, apoptosis, oxidative stress and excessive autophagy after I/R, which was inhibited by PI3K inhibitor, LY294002. Collectively, CART attenuated MIRI through inhibition of cardiomyocytes apoptosis and excessive autophagy, and the protective effect was dependent on PI3K/AKT signalling pathway.

Observation of the clinical features of dupilumab-associated facial erythema.

Introduction: Dupilumab is the first biologic agent used to clinically treat moderate and severe atopic dermatitis (AD) and is currently the only biologic agent used for this condition. Many studies have reported that moderate-to-severe AD was significantly improved after dupilumab injection, although head/neck dermatitis occurred with itching, flushing, and scaling. Moreover, because all the symptoms occur after dupilumab treatment, they are called "dupilumab facial redness (DFR)". Aim: To retrospectively analyse the clinical characteristics and treatment of facial erythema in patients with atopic dermatitis treated with dupilumab. Material and methods: The clinical data of patients with moderate-to-severe atopic dermatitis treated with dupilumab (600 mg for the first time, 300 mg every 2 weeks thereafter) in the department of dermatology from July 2020 to May 2022 were obtained. We described their characteristics and analysed their symptomatic treatment measures and efficacy. Results: Twenty-one patients with DFR were included. Most clinical manifestations were erythema and pruritus, which differed from the symptoms of typical moderate-to-severe AD. After treatment, drug withdrawal, and dressing change, the symptoms of 17 patients were effectively controlled or completely improved, while these of 4 did not improve. Conclusions: Although the mechanism of DFR is still unclear, symptomatic treatment is partially effective, and medication discontinuation and switching to Janus kinase inhibitors are acceptable for some patients.

Real-world study of the effectiveness of BBIBP-CorV (Sinopharm) COVID-19 vaccine in the Kingdom of Morocco.

BACKGROUND: The Kingdom of Morocco approved BBIBP-CorV (Sinopharm) COVID-19 vaccine for emergency use on 22 January 2021 in a two-dose, three-to-four-week interval schedule. We conducted a retrospective cohort study to determine real-world BBIBP-CorV vaccine effectiveness (VE) against serious or critical hospitalization of individuals RT-PCR-positive for SARS-CoV-2 during the first five months of BBIBP-CorV use in Morocco. METHODS: The study was conducted among adults 18-99 years old who were tested by RT-PCR for SARS-CoV-2 infection between 1 February and 30 June 2021. RT-PCR results were individually linked with outcomes from the COVID-19 severe or critical hospitalization dataset and with vaccination histories from the national vaccination registration system. Individuals with partial vaccination (< 2 weeks after dose two) or in receipt of any other COVID-19 vaccine were excluded. Unadjusted and adjusted VE estimates against hospitalization for serious or critical illness were made by comparing two-dose vaccinated and unvaccinated individuals in logistic regression models, calculated as (1-odds ratio) * 100%. RESULTS: There were 348,190 individuals able to be matched across the three databases. Among these, 140,892 were fully vaccinated, 206,149 were unvaccinated, and 1,149 received homologous BBIBP-CorV booster doses. Unadjusted, full-series, unboosted BBIBP-CorV VE against hospitalization for serious or critical illness was 90.2% (95%CI: 87.8-92.0%). Full-series, unboosted VE, adjusted for age, sex, and calendar day of RT-PCR test, was 88.5% (95%CI: 85.8-90.7%). Calendar day- and sex-adjusted VE was 96.4% (95%CI: 94.6-97.6%) for individuals < 60 years, and was 53.3% (95%CI: 39.6-63.9%) for individuals 60 years and older. There were no serious or critical illnesses among BBIBP-CorV-boosted individuals. CONCLUSIONS: Effectiveness of Sinopharm's BBIBP-CorV was consistent with phase III clinical trial results. Two doses of BBIBP-CorV was highly protective against COVID-19-associated serious or critical hospitalization in working-age adults under real-world conditions and moderately effective in older adults. Booster dose vaccination was associated with complete protection, regardless of age, although only a small proportion of subjects received booster doses.

Corin plays a protective role via upregulating MAPK and downregulating eNOS in diabetic nephropathy endothelial dysfunction.

Diabetic nephropathy (DN) is one of the leading causes of mortality in diabetic patients, but its pathogenesis is unclear. We aimed to study the role of the pro-ANP convertase Corin in the pathogenesis of DN. Corin and ANP expression in DN rat kidneys and high-glucose-treated HK-2 cells was analyzed by real-time PCR, western blotting, and immunohistochemical staining. The effect of Corin-siRNA or ANP-siRNA HK-2 cells on EA.hy926 cell migration was determined by scratch-wound healing assay. The expression of mitogen-activated protein kinase (MAPK) and endothelial NO synthase (eNOS) in EA.hy926 cells treated with conditioned medium from Corin-siRNA- or ANP-siRNA-transfected HK-2 cells was determined by western blotting. We found a significant reduction in Corin and ANP expression in DN rat kidneys. These results were recapitulated in HK-2 cells treated with high glucose. EA.hy926 cells treated with conditioned medium from Corin-deficient HK-2 cells had inhibited migration, increased MAPK activity, and decreased eNOS activity. Similar effects were observed with ANP-siRNA transfection. Finally, adding ANP to the Corin-deficient HK-2 conditioned medium rescued the above defects, indicating that Corin mediates its effects through ANP. In conclusion, Corin plays a renoprotective role through pro-ANP processing, and defects in Corin cause endothelial dysfunction through MAPK and eNOS signaling in DN.

[Advances in formation and regulation of ASC-speck in inflammasome activation - A review].

Under the effects of a series of microbial infection and endogenous or exogenous stimuli, inflammasomes are assembled as multiple protein complexes in the cytoplasm, which mainly contain pattern recognition receptors (PRRs), apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1. The inflammasomes are the platform for caspase-1 activation and subsequent proinflammatory cytokines secretion, and caspase-1 dependent cell death as well. As a key adaptor protein, ASC concatenates PRRs and pro-caspase-1 in the cytoplasm. During inflammasome activation, ASC molecules assemble into large molecule dimers, which is called ASC-speck. The formation of ASC-speck is critical for caspase-1 activation, and ASC-speck becomes a target for the therapy and prevention of inflammatory diseases. In this review, advances in molecular mechanism of ASC-speck formation and the regulation systems for ASC-speck are summarized from the aspects of phosphorylation, ubiquitination and iron channels etc. Finally, the research prospects in this field are discussed.

Corin is down-regulated and exerts cardioprotective action via activating pro-atrial natriuretic peptide pathway in diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DCM), a fatal cardiovascular complication of diabetes mellitus, often leads to progressive heart failure, however its pathogenesis remains unclear. Corin, a cardiac serine protease, is responsible for converting pro-atrial natriuretic peptide (pro-ANP) to biologically active atrial natriuretic peptide (ANP). It has been well established that corin deficiency is associated with the progression of hypertension, cardiac hypertrophy and heart failure. However, because the involvement of corin-mediated pro-ANP processing in DCM has not been clarified, this study aims to investigate the role of corin in the pathogenesis of DCM. METHODS: Diabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (STZ 65 mg/kg) to Sprague-Dawley rats (180-220 g). DCM was confirmed by monitoring continuously transthoracic echocardiography every 4 weeks and hemodynamic measurements at 20 weeks. Myocardial disorder and fibrosis were detected by HE staining and Masson's trichrome staining. The mRNA and protein levels of corin and ANP in rat hearts and cardiomyocytes were determined by quantitative real-time PCR, western blotting and immunohistochemical staining, respectively. H9c2 cardiomyoblasts proliferation was detected by MTT colorimetric assay and viable cell counting with trypan blue. The effect of Corin-siRNA H9c2 cardiomyoblasts on EA.hy926 cells migration was measured by the wound healing scratch assay. RESULTS: The corin and ANP expression in mRNA and protein levels was decreased in DCM rat hearts. Corin and ANP levels of neonatal rat cardiomyocytes and H9c2 cardiomyoblasts treated with high glucose were significantly lower than that of normal glucose treated. Precisely, corin and ANP levels decreased in DCM rats at 12, 16, 20 and 33 weeks; neonatal cardiomyocytes and H9c2 cardiomyoblasts treated with high glucose at 36, 48 and 60 h demonstrated significant reduction in corin and ANP levels. Corin-siRNA H9c2 cardiomyoblasts showed decreased proliferation. Culture supernatants of Corin-siRNA H9c2 cardiomyoblasts prevented endothelial cell line EA.hy926 migration in the wound healing scratch assay. Furthermore, iso-lectin expression in arteriole and capillary endothelium was down-regulated in DCM rats. CONCLUSIONS: Our results indicate that corin plays an important role in cardioprotection by activating pro-atrial natriuretic peptide pathway in DCM. Corin deficiency leads to endothelial dysfunction and vascular remodeling.

Elevated Plasma P-Selectin Autoantibodies in Primary Sjögren Syndrome Patients with Thrombocytopenia.

BACKGROUND Primary Sjögren's syndrome (pSS) is one of the most common chronic systemic autoimmune diseases, and thrombocytopenia is one of the hematological manifestations of pSS. When platelet and endothelial cells are activated, P-selectin is expressed on the cell surface. This study aimed to investigate the role of P-selectin autoantibodies in the pathogenesis of thrombocytopenia in pSS. MATERIAL AND METHODS P-selectin autoantibodies were measured by enzyme-linked immunosorbent assay (ELISA) in 38 pSS patients without thrombocytopenia and 32 pSS patients with thrombocytopenia, 32 idiopathic thrombocytopenic purpura (ITP) patients, and 35 healthy controls. RESULTS The plasma P-selectin autoantibodies (A490) in ITP patients and pSS patients with/without thrombocytopenia were significantly higher than those in healthy controls, but there were no significant differences between ITP patients and pSS patients with thrombocytopenia. The positive rate of P-selectin autoantibodies in pSS patients with thrombocytopenia was significantly higher than that in ITP patients. The platelet count was lower in P-selectin autoantibodies-positive patients, while among pSS patients with thrombocytopenia, the platelet count was lower in P-selectin autoantibodies-positive patients than in P-selectin autoantibodies-negative patients. In ITP patients and pSS patients with thrombocytopenia, the platelet count was lower in P-selectin autoantibodies-positive patients. CONCLUSIONS Elevated plasma P-selectin autoantibodies may play a role in the pathogenesis of thrombocytopenia in pSS patients.

Optimal method for short-term or long-term islet preservation: comparison of islet culture, cold preservation and cryopreservation.

Islet preservation plays an important role for the success of islet transplantation. To determine the optimal method for islet preservation, we compared the outcomes of islet culture, cold preservation, and cryopreservation in this study. Isolated rat islets were divided into three groups: 37 °C group (conventional culture at 37 °C in RPMI-1640 medium), 4 °C group (cold preservation at 4 °C in University of Wisconsin (UW) solution), and -80 °C group (cryopreservation at -80 °C with dimethyl sulfoxide (DMSO)). Recovery rate, Calcein-AM/PI double staining, insulin release, mRNA level of hypoxia-inducible factor-1α (HIF-1α), and protein level of Bax in islets were examined after short-term (1 day) or long-term (7 days) preservation. After either short-term or long-term preservation, 4 °C group showed higher recovery rate of the islets number, lower percentage of PI positive area, better insulin release ability, and lower expression levels of HIF-1α and Bax in comparison to the 37 or -80 °C group. Meanwhile, islets in 37 °C group showed better function, and down-regulation of HIF-1α and Bax than those in -80 °C group on day 1; however, worse function of islets, up-regulated HIF-1α and Bax in 37 °C group were observed in comparison to -80 °C group on day 7. These results suggest that cold preservation at 4 °C in UW solution is the optimal method in comparison to the conventional culture at 37 °C or cryopreservation at -80 °C for short-term or long-term islet preservation. Furthermore, the potential mechanism may relate to, at least in part, apoptosis induced by the HIF-1α.

YOD1 protects against MRSA sepsis-induced DIC through Lys33-linked deubiquitination of NLRP3.

Disseminated intravascular coagulation (DIC) is considered to be the most common and lethal complication of sepsis. NLR-family pyrin domain-containing-3 (NLRP3) inflammasome plays an important role in host defense against microbial pathogens, and its deregulation may cause coagulation cascade and should be strictly managed. Here, we identified the deubiquitinase YOD1, which played a vital role in regulating coagulation in a NLRP3 inflammasome-dependent manner in sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA). YOD1 interacted with NLRP3 to remove K33-linked ubiquitination of NLRP3 based on its deubiquitinating enzyme activity and specifically inhibited expression of NLRP3 as well as activation of NLRP3 inflammasome. Deficiency of YOD1 expression enhanced NLRP3 inflammasome activation and coagulation both in vitro and in vivo. In addition, pharmacological inhibition of the NLRP3 effectively improved coagulation and alleviated organ injury in Yod1-/- mice infected with MRSA. Thus, our study reported that YOD1 is a key regulator of coagulation during MRSA infection, and provided YOD1 as a potential therapeutic target for the treatment of NLRP3 inflammasome-related diseases, especially MRSA sepsis-induced DIC.

Critical roles of ASC inflammasomes in caspase-1 activation and host innate resistance to Streptococcus pneumoniae infection.

Streptococcus pneumoniae is a Gram-positive, extracellular bacterium that is responsible for significant mortality and morbidity worldwide. Pneumolysin (PLY), a cytolysin produced by all clinical isolates of the pneumococcus, is one of the most important virulence factors of this pathogen. We have previously reported that PLY is an essential factor for activation of caspase-1 and consequent secretion of IL-1ß and IL-18 in macrophages infected with S. pneumoniae. However, the host molecular factors involved in caspase-1 activation are still unclear. To further elucidate the mechanism of caspase-1 activation in macrophages infected with S. pneumoniae, we examined the involvement of inflammasomes in inducing this cellular response. Our study revealed that apoptosis-associated specklike protein containing a caspase recruitment domain (ASC), an adaptor protein for inflammasome receptors such as nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2), is essentially required for the induction of caspase-1 activation by S. pneumoniae. Caspase-1 activation was partially impaired in NLRP3(-/-) macrophages, whereas knockdown and knockout of AIM2 resulted in a clear decrease in caspase-1 activation in response to S. pneumoniae. These results suggest that ASC inflammasomes, including AIM2 and NLRP3, are critical for caspase-1 activation induced by S. pneumoniae. Furthermore, ASC(-/-) mice were more susceptible than wild-type mice to S. pneumoniae, with impaired secretion of IL-1ß and IL-18 into the bronchoalveolar lavage after intranasal infection, suggesting that ASC inflammasomes contribute to the protection of host from infection with PLY-producing S. pneumoniae.

Critical role of TRPC6 channels in the development of human renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common tumor arising from the cells in the lining of tubules in the kidney. Some members of the Ca2+-permeable transient receptor potential canonical (TRPC) family of channel proteins have demonstrated a role in the proliferation of some types of cancer cells. In this study, we investigated the role of TRPC6 in the development of human RCC. RT-PCR and Western blotting were used to investigate TRPC6 expression in 1932 and ACHN cells. Immunohistochemical techniques were applied to study TRPC6 expression in 60 cases of RCC primary tissue samples and 10 cases of corresponding normal renal tissues. To inhibit TRPC6 activity or expression, RNA interference was used. The effects of TRPC6 channels on RCC cell viability and cell cycle progression were investigated by MTT and flow cytometry. TRPC6 was expressed in 1932 and ACHN cells. TRPC6 protein was detected in 73.3% of RCC samples, and there was a significant difference compared with the normal renal samples (30%) (p<0.05). Moreover the level of TRPC6 expression was associated with RCC Fuhrman grade (p<0.01). Blockade of TRPC6 channels in ACHN cells suppressed basal cell proliferation and partially inhibited HGF-induced cell proliferation. Furthermore, inhibition of TRPC6 channels expression prolonged the transition through G2/M phase in ACHN cells. In summary, expression of TRPC6 is markedly increased in RCC specimens and associated with RCC histological grade. TRPC6 plays an important role in ACHN cells proliferation.

The diagnostic value of lipoprotein-associated phospholipase A2 in early diabetic nephropathy.

OBJECTIVE: The aim of this study was to investigate diagnosis of lipoprotein-associated phospholipase A2 (Lp-PLA2) in early diabetic nephropathy (DN). METHODS: A total of 342 type 2 diabetes mellitus (T2DM) patients hospitalized in department of metabolism and nephrology in our hospital from January 2019 to December 2019 were randomly selected. Patients were divided into three groups via urine albumin level: diabetes mellitus (DM) group, simple diabetes group (114 patients, urinary albumin creatinine ratio (UACR) < 30 mg/g); DN1 group, early DN group (114 patients, UACR: 30-300 mg/g); DN2 group: clinical DN group (114 patients, UACR > 300mg/g). Eighty healthy adults were examined at the same time. Lp-PLA2, fasting blood glucose (FBG), creatinine (Cr), triglyceride (TG), total cholesterol (TCHOL), high-density lipoprotein (HDL), low-density lipoprotein (LDL), haemoglobin A1c (HbA1c), blood urea nitrogen/creatinine (BUN/Cr), estimated glomerular filtration rate (eGFR), 24-h urine protein, albumin and creatinine of all subjects were detected and compared. Pearson's correlation analysis and multiple ordered logistic regression were used to investigate the correlation between serum Lp-PLA2 level and DN. The possibility of Lp-PLA2 in the diagnosis of early DN was studied by using the subject working curve. RESULTS: Lp-PLA2 level in DN1 and DN2 groups was significantly higher than that in DM group, with statistical difference (p < .05). With the progression of DN, the level of Lp-PLA2 gradually increased p < .05. Lp-PLA2 was positively correlated with FBG, TG, LDL and HbA1c (R = 0.637, p < .01; R = 0.314, p = .01; R = 0.213, p = .01; R = 0.661, p ≤ .01), was negatively correlated with HDL (r = -0.230, p < .01). The results showed that Lp-PLA2 was an independent factor in the evaluation of early DN. The area under the curve for the evaluation of serum Lp-PLA2 level in early DN was 0.841, the optimal critical value was 155.9 ng/mL, the sensitivity was 88% and the specificity was 76.2%. CONCLUSIONS: Lp-PLA2 is an independent factor for the evaluation of early DN, and can be used as an important potential specific indicator for the diagnosis of early DN, meanwhile monitoring the progression of DN.

ALK-JNK signaling promotes NLRP3 inflammasome activation and pyroptosis via NEK7 during Streptococcus pneumoniae infection.

Streptococcus pneumoniae (S. pneumoniae), a clinically important pathogen worldwide, causes serious invasive diseases, such as pneumonia, otitis media, and meningitis. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome, an important component of the innate immune system, plays a key role in defense against pathogen infection; however the specific activation mechanism induced by S. pneumoniae infection is not fully understood. Here, primary mouse macrophages were selected as the in vitro cell model, and the effect of kinases on S. pneumoniae infection-induced NLRP3 inflammasome activation was investigated in vivo and in vitro using the western blot/RT-PCR/Co-IP/immunofluorescence staining/ELISA with or without kinase inhibitor or siRNA pretreatment. In this study, we found that the formation of the NEK7-NLRP3 complex significantly increased during S. pneumoniae infection and that anaplastic lymphoma kinase (ALK) and Jun N-terminal kinase (JNK) were phosphorylated rapidly. ALK and JNK inhibitors significantly reduced the ability of bacterial killing, the gene expression of NLRP3 inflammasome, the formation of apoptosis-associated speck-like protein containing caspase-recruitment domain (ASC) specks and the NEK7-NLRP3 complex, which in turn decreased the activation level of NLRP3 inflammasome-associated molecules and the maturation of interleukin-1ß (IL-1ß). In addition, ALK regulated the phosphorylation of JNK. Interestingly, the ALK/JNK/NEK7-NLRP3 signaling pathway is also involved in regulating pyroptosis and IL-1ß secretion triggered by S. pneumoniae infection. In conclusion, our data suggest, for the first time, that the ALK/JNK/NEK7-NLRP3 signaling pathway may play an important role in NLRP3 inflammasome activation and pyroptosis and consequently regulate the host immune response upon S. pneumoniae infection.

Melanin nanoparticles alleviate sepsis-induced myocardial injury by suppressing ferroptosis and inflammation.

Myocardial injury as one of the severe complications leads to the increasing morbidity and mortality in patients with sepsis. Recent studies reported that reactive oxygen species (ROS)-mediated ferroptosis plays a critical role in the development of heart diseases. Therefore, we hypothesized that anti-ferroptosis agent might be a novel potential therapeutic strategy for sepsis-induced cardiac injury. Herein, we demonstrated that a small biocompatible and MRI-visible melanin nanoparticles (MMPP) improves myocardial function by inhibiting ROS-related ferroptosis signaling pathway. In LPS-induced murine sepsis model, after a single dose intravenously injection of MMPP treatment, MMPP markedly alleviated the myocardial injury including cardiac function and heart structure disorder through suppressing iron-accumulation induced ferroptosis. In vitro, MMPP inhibited cardiomyocyte death by attenuating oxidative stress, inflammation and maintaining mitochondrial homeostasis. Collectively, our findings demonstrated that MMPP protected heart against sepsis-induced myocardial injury via inhibiting ferroptosis and inflammation, which might be a novel therapeutic approach in future.

GSDME-dependent pyroptosis signaling pathway in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the serious chronic microvascular complications of diabetes, and leads to the increased morbidity and mortality in diabetic patients. Gasdermin E (GSDME)-dependent pyroptosis signaling pathway plays important roles in a variety of physiological and pathological processes. However, its role and mechanism in DN are still unclear. In this study, we established a rat DN model by intraperitoneal injection of streptozotocin (STZ) successfully. Structural and functional disorders in the kidney were exhibited on the 12th week after STZ injection; the expressions of caspase-3 and GSDME at protein level in renal cortex were significantly up-regulated. At the 20th week, GSDME-N increased significantly, accompanied by the upregulation of caspase-1 in renal cortex and the release of mature IL-1ß (mIL-1ß) in serum. Furthermore, we found the protein levels of GSDME, caspase-3, caspase-1 and IL-1ß were all increased in HK2 and HBZY-1 cells under high-glucose conditions. We also found that the expression of GSDME-N significantly decreased when caspase-3 was knockdown. In contrast, knockdown of GSDME has no effect on caspase-3. Interestingly, either caspase-3, caspase-1 or GSDME knockdown reduced the release of mIL-1ß. Finally, injection of adeno-associated virus (AAV) 9-shGSDME into the rat kidney reduced kidney damage and renal cell pyroptosis in comparison with wild-type diabetic rats. These results indicated that the activation of caspase-1 induced IL-1ß maturation, and the activation of caspase-3 mediated cleavage of GSDME responsible for the formation of plasma membrane pore, followed by cytoplasmic release of mIL-1ß. Overall, we identified a pro-pyroptosis role for GSDME in DN, which does provide an important basis for clinical therapeutic studies.

Involvement of absent in melanoma 2 in inflammasome activation in macrophages infected with Listeria monocytogenes.

Listeria monocytogenes invades the cytoplasm of macrophages and induces the activation of caspase-1 and the subsequent maturation of IL-1beta and IL-18. Although apoptosis-associated speck-like protein containing a caspase-activating and recruitment domain (ASC), an adaptor protein of nucleotide-binding oligomerization domain (Nod)-like receptors, has been shown to play an essential role in inducing this cellular response to L. monocytogenes, the mechanism has not been fully elucidated. In this study, we demonstrate the role of absent in melanoma 2 (AIM2), a recently described receptor of cytosolic DNA, in the activation of caspase-1 upon infection with L. monocytogenes. Secretion of IL-1beta and IL-18 from Nod-like receptor family, pyrin domain containing 3 (NLRP3) and Nod-like receptor family, caspase-activating and recruitment domain containing 4 (NLRC4) knockout macrophages in response to L. monocytogenes was only slightly decreased compared with the levels secreted from wild-type macrophages, whereas secretion from ASC knockout macrophages was completely impaired, suggesting that receptors other than NLRP3 and NLRC4 also take part in inflammasome activation in an ASC-dependent manner. To identify such receptors, the abilities of several receptor candidates (NLRP2, NLRP6, NLRP12, and AIM2) to induce the secretion of IL-1beta in response to L. monocytogenes were compared using the inflammasome system reconstructed in HEK293 cells. Among these receptor candidates, AIM2 conferred the highest responsiveness to the bacterium on HEK293 cells. Knockdown of AIM2 significantly decreased the secretion of IL-1beta and IL-18 from L. monocytogenes-infected macrophages. These results suggest that AIM2, in cooperation with NLRP3 and NLRC4, plays an important role in the activation of caspase-1 during L. monocytogenes infection.

Erythrodermic Psoriasis in a Patient with Plaque Psoriasis Who Presented with Symptoms of Niacin Deficiency: A Special Case Report.

Psoriasis is relatively common in clinical practice, whereas niacin deficiency is relatively rare. We describe the clinical case of a patient with plaque psoriasis for over 20 years who also had a concomitant latent tuberculosis infection. After secukinumab and anti-tuberculosis treatment for 1 year, the psoriatic rash mostly resolved, but atypical symptoms of niacin deficiency suddenly appeared. The patient's symptoms rapidly subsided after experimental treatment with niacin. After 2 weeks, the patient suddenly developed an erythroderma-like rash, manifesting as large areas of erythema and plaque psoriasis throughout the body. The patient was admitted to the hospital and treated with an anti-inflammatory, biologic adalimumab, tripterygium glycoside, and sodium thiosulfate. The patient was discharged after a week. This case suggests the need for caution and to look out for the emergence of new symptoms when treating patients with moderate-to-severe plaque psoriasis, especially with biologics.

Metformin Attenuates Cardiac Hypertrophy Via the HIF-1α/PPAR-γ Signaling Pathway in High-Fat Diet Rats.

Coronary artery disease (CAD) and cardiac hypertrophy (CH) are two main causes of ischemic heart disease. Acute CAD may lead to left ventricular hypertrophy (LVH). Long-term and sustained CH is harmful and can gradually develop into cardiac insufficiency and heart failure. It is known that metformin (Met) can alleviate CH; however, the molecular mechanism is not fully understood. Herein, we used high-fat diet (HFD) rats and H9c2 cells to induce CH and clarify the potential mechanism of Met on CH. We found that Met treatment significantly decreased the cardiomyocyte size, reduced lactate dehydrogenase (LDH) release, and downregulated the expressions of hypertrophy markers ANP, VEGF-A, and GLUT1 either in vivo or in vitro. Meanwhile, the protein levels of HIF-1α and PPAR-γ were both decreased after Met treatment, and administrations of their agonists, deferoxamine (DFO) or rosiglitazone (Ros), markedly abolished the protective effect of Met on CH. In addition, DFO treatment upregulated the expression of PPAR-γ, whereas Ros treatment did not affect the expression of HIF-1α. In conclusion, Met attenuates CH via the HIF-1α/PPAR-γ signaling pathway.