POZ/BTB and AT hook containing zinc finger 1 (PATZ1) suppresses differentiation and regulates metabolism in human embryonic stem cells.

Human embryonic stem cells (hESCs) can proliferate infinitely (self-renewal) and give rise to almost all types of somatic cells (pluripotency). Hence, understanding the molecular mechanism of pluripotency regulation is important for applications of hESCs in regenerative medicine. Here we report that PATZ1 is a key factor that regulates pluripotency and metabolism in hESCs. We found that depletion of PATZ1 is associated with rapid downregulation of master pluripotency genes and prominent deceleration of cell growth. We also revealed that PATZ1 regulates hESC pluripotency though binding the regulatory regions of OCT4 and NANOG. In addition, we demonstrated PATZ1 is a key node in the OCT4/NANOG transcriptional network. We further revealed that PATZ1 is essential for cell growth in hESCs. Importantly, we discovered that depletion of PATZ1 drives hESCs to exploit glycolysis which energetically compensates for the mitochondrial dysfunction. Overall, our study establishes the fundamental role of PATZ1 in regulating pluripotency in hESCs. Moreover, PATZ1 is essential for maintaining a steady metabolic homeostasis to refine the stemness of hESCs.

Risk exploration and prediction model construction for linezolid-resistant Enterococcus faecalis based on big data in a province in southern China.

BACKGROUND: Enterococcus faecalis is a common cause of healthcare-associated infections. Its resistance to linezolid, the antibiotic of last resort for vancomycin-resistant enterococci, has become a growing threat in healthcare settings. METHODS: We analyzed the data of E. faecalis isolates from 26 medical institutions between 2018 and 2020 and performed univariate and multivariate logistic regression analyses to determine the independent predictors for linezolid-resistant E. faecalis (LREFs). Then, we used the artificial neural network (ANN) and logistic regression (LR) to build a prediction model for linezolid resistance and performed a performance evaluation and comparison. RESULTS: Of 12,089 E. faecalis strains, 755 (6.25%) were resistant to linezolid. Among vancomycin-resistant E. faecalis, the linezolid-resistant rate was 24.44%, higher than that of vancomycin-susceptible E. faecalis (p < 0.0001). Univariate and multivariate regression analyses showed that gender, age, specimen type, length of stay before culture, season, region, GDP (gross domestic product), number of beds, and hospital level were predictors of linezolid resistance. Both the ANN and LR models constructed in the study performed well in predicting linezolid resistance in E. faecalis, with AUCs of 0.754 and 0.741 in the validation set, respectively. However, synthetic minority oversampling technique (SMOTE) did not improve the prediction ability of the models. CONCLUSION: E. faecalis linezolid-resistant rates varied by specimen site, geographic region, GDP level, facility level, and the number of beds. At the same time, community-acquired E. faecalis with linezolid resistance should be monitored closely. We can use the prediction model to guide clinical medication and take timely prevention and control measures.

Comparison of ANN and LR models for predicting Carbapenem-resistant Klebsiella pneumoniae isolates from a southern province of China's RNSS data.

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a serious threat to public health due to its limited treatment options and high mortality rate. This study aims to identify the risk factors of Carbapenem resistant in Patients with Klebsiella pneumoniae isolates and develop CRKP prediction models using logistic regression (LR) and artificial neural network (ANN) methods. METHODS: We retrospectively analyzed the data of 49,774 patients with Klebsiella pneumoniae isolates from a regional nosocomial infection surveillance system (RNSS) between 2018 and 2021. We performed logistic regression analyses to determine the independent predictors for CRKP. We then built and evaluated LR and ANN models based on these predictors using calibration curves, ROC curves, and decision curve analysis (DCA). We also applied the Synthetic Minority Over-Sampling Technique (SMOTE) to balance the data of CRKP and non-CRKP groups. RESULTS: The LR model showed good discrimination and calibration in both training and validation sets, with areas under the ROC curve (AUROC) of 0.824 and 0.825, respectively. The DCA indicated that the LR model had clinical usefulness for decision making. The ANN model outperformed the LR model both in the training set and validation set. The SMOTE technique improved the performance of both models for CRKP detection in training set, but not in validation set. CONCLUSIONS: We developed and validated LR and ANN models for predicting CRKP based on RNSS data. Both models were feasible and reliable for CRKP inference, and could potentially assist clinicians in selecting appropriate empirical antibiotics and reducing unnecessary medical resource utilization.

Peroxiredoxin 1 aggravates acute kidney injury by promoting inflammation through Mincle/Syk/NF-κB signaling.

Damage-associated molecular patterns (DAMPs) are a cause of acute kidney injury (AKI). Our knowledge of these DAMPs remains incomplete. Here, we report serum peroxiredoxin 1 (Prdx1) as a novel DAMP for AKI. Lipopolysaccharide (LPS) and kidney ischemia/reperfusion injury instigated AKI with concurrent increases in serum Prdx1 and reductions of Prdx1 expression in kidney tubular epithelial cells. Genetic knockout of Prdx1 or use of a Prdx1-neutralizing antibody protected mice from AKI and this protection was impaired by introduction of recombinant Prdx1 (rPrdx1). Mechanistically, lipopolysaccharide increased serum and kidney proinflammatory cytokines, macrophage infiltration, and the content of M1 macrophages. All these events were suppressed in Prdx1-/- mice and renewed upon introduction of rPrdx1. In primary peritoneal macrophages, rPrdx1 induced M1 polarization, activated macrophage-inducible C-type lectin (Mincle) signaling, and enhanced proinflammatory cytokine production. Prdx1 interacted with Mincle to initiate acute kidney inflammation. Of note, rPrdx1 upregulated Mincle and the spleen tyrosine kinase Syk system in the primary peritoneal macrophages, while knockdown of Mincle abolished the increase in activated Syk. Additionally, rPrdx1 treatment enhanced the downstream events of Syk, including transcription factor NF-κB signaling pathways. Furthermore, serum Prdx1 was found to be increased in patients with AKI; the increase of which was associated with kidney function decline and inflammatory biomarkers in patient serum. Thus, kidney-derived serum Prdx1 contributes to AKI at least in part by activating Mincle signaling and downstream pathways.

Corrigendum: Protective effects of Mefunidone on ischemia-reperfusion injury/folic acid-induced acute kidney injury.

[This corrects the article DOI: 10.3389/fphar.2022.1043945.].

High Expression of COA6 Is Related to Unfavorable Prognosis and Enhanced Oxidative Phosphorylation in Lung Adenocarcinoma.

Mitochondrial metabolism plays an important role in the occurrence and development of cancers. Cytochrome C oxidase assembly factor six (COA6) is essential in mitochondrial metabolism. However, the role of COA6 in lung adenocarcinoma (LUAD) remains unknown. Here we report that the expression of COA6 mRNA and protein were upregulated in LUAD tissues compared with lung normal tissues. We found that COA6 had high sensitivity and specificity to distinguish LUAD tissues from normal lung tissues shown by a receiver operating characteristic (ROC) curve. In addition, our univariate and multivariate Cox regression analysis indicated that COA6 was an independent unfavorable prognostic factor for LUAD patients. Furthermore, our survival analysis and nomogram showed that a high expression of COA6 mRNA was related to the short overall survival (OS) of LUAD patients. Notably, our weighted correlation network analysis (WGCNA) and functional enrichment analysis revealed that COA6 may participate in the development of LUAD by affecting mitochondrial oxidative phosphorylation (OXPHOS). Importantly, we demonstrated that depletion of COA6 could decrease the mitochondrial membrane potential (MMP), nicotinamide adenine dinucleotide (NAD) + hydrogen (H) (NADH), and adenosine triphosphate (ATP) production in LUAD cells (A549 and H1975), hence inhibiting the proliferation of these cells in vitro. Together, our study strongly suggests that COA6 is significantly associated with the prognosis and OXPHOS in LUAD. Hence, COA6 is highly likely a novel prognostic biomarker and therapeutic target of LUAD.

Unruptured brain arteriovenous malformations causing seizures localize to one common brain network.

Seizures are a frequent symptom of unruptured brain arteriovenous malformations (bAVMs). However, the brain regions responsible for these seizures remain unclear. To identify the brain regions causally involved in bAVM-related seizures, we retrospectively reviewed 220 patients with unruptured bAVMs. Using voxel-based lesion-symptom mapping (VLSM) analyses, we tested whether individual brain regions were associated with unruptured bAVM-related seizures. The result revealed that unruptured bAVMs causing seizures are anatomically heterogeneous at the voxel level. Subsequently, lesion network mapping (LNM) analyses was performed to determine whether bAVMs causing seizures belonged to a distributed brain network. LNM analyses indicated that these lesions were located in a functional network characterized by connectivity to the left caudate and precuneus. Moreover, the discrimination performance of the identified seizure network was evaluated in discovery set by calculating the individualized network damage score and was tested in validation set. Based on the calculated network damage scores, patients were divided into low-, medium-, and high-risk groups. The prevalence of seizures significantly differed among the three risk categories in both discovery (p = .003) and validation set (p = .004). Finally, we calculated the percentage of voxels in the canonical resting-state networks that overlapped with the seizure-susceptible brain regions to investigate the involvement of resting-state networks. With an involvement percentage over 50%, the frontoparietal control (82.9%), limbic function (76.7%), and default mode network (69.3%) were considered to be impacted in bAVM-related seizures. Our study identified the seizure-susceptible brain regions for unruptured bAVMs, which could be a plausible neuroimaging biomarker in predicting possible seizures.

Protective effects of mefunidone on ischemia-reperfusion injury/Folic acid-induced acute kidney injury.

Renal ischemia-reperfusion injury (IRI) is one of the most common causes of acute kidney injury (AKI). It poses a significant threat to public health, and effective therapeutic drugs are lacking. Mefunidone (MFD) is a new pyridinone drug that exerts a significant protective effect on diabetic nephropathy and the unilateral ureteral obstruction (UUO) model in our previous study. However, the effects of mefunidone on ischemia-reperfusion injury-induced acute kidney injury remain unknown. In this study, we investigated the protective effect of mefunidone against ischemia-reperfusion injury-induced acute kidney injury and explored the underlying mechanism. These results revealed that mefunidone exerted a protective effect against ischemia-reperfusion injury-induced acute kidney injury. In an ischemia-reperfusion injury-induced acute kidney injury model, treatment with mefunidone significantly protected the kidney by relieving kidney tubular injury, suppressing oxidative stress, and inhibiting kidney tubular epithelial cell apoptosis. Furthermore, we found that mefunidone reduced mitochondrial damage, regulated mitochondrial-related Bax/bcl2/cleaved-caspase3 apoptotic protein expression, and protected mitochondrial electron transport chain complexes III and V levels both in vivo and in vitro, along with a protective effect on mitochondrial membrane potential in vitro. Given that folic acid (FA)-induced acute kidney injury is a classic model, we used this model to further validate the efficacy of mefunidone in acute kidney injury and obtained the same conclusion. Based on the above results, we conclude that mefunidone has potential protective and therapeutic effects in both ischemia-reperfusion injury- and folic acid-induced acute kidney injury.

NR2F2 Regulates Cell Proliferation and Immunomodulation in Whartons' Jelly Stem Cells.

(1) Background: Wharton's Jelly stem cells (WJ-MSCs) are multipotent mesenchymal stem cells that can proliferate rapidly and have low immunogenicity. Therefore, WJ-MSCs have gained considerable attention in the fields of immunomodulation and disease treatment and have entered clinical trials for the treatment of various diseases. Therefore, it is crucial to study the underlying mechanisms of WJ-MSCs proliferation, immune regulation, and disease treatment. Nuclear Receptor Subfamily 2 Group F Member 2 (NR2F2) is a transcription factor that is involved in the regulation of many different genes. However, it remains unknown how NR2F2 regulates stem cell identity in WJ-MSCs. (2) Methods: We used RNAi technology to knock down NR2F2 in WJ-MSCs, and studied the regulatory role of NR2F2 in WJ-MSCs by MTT, flow cytometry, RNA-seq, and other methods. We also utilized a co-culture system in which NR2F2-depleted WJ-MSCs with MH7A and HCT116/HepG2 were used to investigate the role of NR2F2 in immunomodulation and the inhibition of cancer cell growth. (3) Results: NR2F2 knockdown resulted in decreased expressions of Cyclin D1 and CDK4, slower cell proliferation, and increased expressions of IL6 and IL8. Furthermore, Cyclin D1, CDK4, and inflammatory factors were increased in human rheumatoid fibroblast-like synoviocyte line MH7A if co-cultured with NR2F2 depleted WJ-MSCs. In addition, we observed increased p53, decreased BCL-2, and increased cell apoptosis in liver cancer cell line HepG2 if co-cultured with NR2F2-depleted WJ-MSCs. (4) Conclusions: NR2F2 not only plays an important role in the cell cycle and immune regulation of WJ-MSCs but also has potential effects on the WJ-MSCs treatment of related diseases.

Fluorofenidone Inhibits UUO/IRI-Induced Renal Fibrosis by Reducing Mitochondrial Damage.

Objective: Mitochondrial damage contributes to extracellular matrix (ECM) deposition and renal fibrosis. In this study, we aimed (1) to investigate whether fluorofenidone (AKF-PD) can attenuate mitochondrial damage in two renal fibrosis models: unilateral ureteral obstruction (UUO) and renal ischemia-reperfusion injury (IRI), and (2) to explore the underlying mechanism. Method: Mitochondrial damage and renal lesions were analyzed in the UUO and IRI models. Mitochondrial energy metabolism, mitochondrial biogenesis, and oxidative stress were measured to assess the effect of AKF-PD on mitochondrial damage and to explore the underlying mechanism. In addition, HK-2 cells were stimulated with TGF-ß with and without AKF-PD. The mitochondrial morphology, mtROS, ATP contents, and redox-related proteins were then examined. Results: In both UUO and IRI models, AKF-PD relieved renal fibrosis, maintained mitochondrial structure, and increased mitochondrial DNA copy numbers. The protection was associated with (1) sustaining mitochondrial energy metabolism, evident by elevations of tricarboxylic acid (TCA) cycle enzymes and mitochondrial respiratory chain complexes; (2) improving mitochondrial biogenesis with increases of TFAM, NRF1, PGC-1α, and SIRT1; and (3) reducing mitochondrial oxidative stress likely via regulating SOD2, SIRT3, and NOX4 expressions. In HK-2 cells treated with TGF-ß, AKF-PD protected mitochondria along with improving mitochondrial morphology, enhancing ATP production, reducing mtROS, and regulating SOD2, SIRT3, and NOX4 expression. Conclusion: We demonstrate that AKF-PD inhibited renal fibrosis at least in part via protecting mitochondria from damages developed in the UUO and IRI models. The mitochondrial protection was associated with sustaining mitochondrial energy metabolism, improving mitochondrial biogenesis, and reducing mitochondrial oxidative stress. This research verified the protective effect of AKF-PD on mitochondria in the UUO and IRI models and elaborated the underlying mechanism.

Mefunidone Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice.

Idiopathic pulmonary fibrosis (IPF) is one of the most common and devastating interstitial lung diseases with poor prognosis. Currently, few effective drugs are available for IPF. Hence, we sought to explore the role of mefunidone (MFD), a newly synthesized drug developed by our team, in lung fibrosis. In this study, MFD was found to attenuate bleomycin (BLM) -induced lung fibrosis and inflammation in mice according to Ashcroft and alveolitis scoring. The protein contents and total cell counts in bronchoalveolar lavage fluids of BLM-treated mice were also lowered by MFD. Moreover, the elevation of TGF-ß/Smad2 and phosphorylation of MAPK pathways was repressed by MFD. Additionally, MFD attenuated the swelling and vacuolization of mitochondria, lowered the ratio of apoptotic cells, restored the mitochondrial membrane potential, and reversed the expression of cleaved-caspase 3, Bcl-2 and Bax. Meanwhile, the level of epithelial marker, E-cadherin, was restored by MFD, while the levels of mesenchymal markers such as Snail and vimentin were down-regulated by MFD. Besides, MFD inhibited the expression of fibronectin and α-smooth muscle actin in TGF-ß treated normal human lung fibroblasts. Thus, our findings suggested that MFD could ameliorate lung fibrosis, cell apoptosis and EMT potentially via suppression of TGF-ß/Smad2 and MAPK pathways.

A Retrospective Cohort Study on the Clinical Course of Patients With Moderate-Type COVID-19.

Background: A large number of people contracted moderate-type COVID-19 around the world. However, to our knowledge no studies have covered the clinical course of patients with moderate-type COVID-19. This study describes the clinical course of moderate-type patients with COVID-19 from Wuhan City and Yiyang City, and explores factors relevant to the length of hospitalization and symptoms relief. Methods: The study analyzed the clinical course of 107 moderate-type patients with COVID-19 from the outbreak area (Wuhan) and the imported area (Yiyang), and used automatic linear modeling and multivariate linear regression analysis to explore the factors relevant to the length of hospitalization and symptoms relief. Furthermore, we created a scoring system to value the length of hospitalization and symptoms relief. Results: Lymphopenia, elevated C-reactive protein, increased LDH, bilateral lung GGO (ground glass opacity), and lung consolidation were more likely to appear in ordinary inpatients with moderate-type COVID-19 from Wuhan (P < 0.05), compared to infected medical staff from Wuhan and ordinary inpatients with moderate-type COVID-19 from Yiyang. Meanwhile, the length of hospitalization and symptoms relief was longer in ordinary patients with moderate-type COVID-19 from Wuhan (P < 0.05). Onset of symptoms to admission, ESR, leucocytes count, and bilateral lung GGO were linearly related to the length of hospitalization (P < 0.05); onset of symptoms to admission, leucocytes count, bilateral lung GGO, and lung consolidation were linearly related to the length of symptoms relief (P < 0.05). By using the scoring system, we found that the time of hospitalization and symptoms relief lengthened as the scores increased. Conclusions: This study described the clinical course of patients with moderate-type COVID-19, and found that ordinary patients with moderate-type COVID-19 in outbreak areas were more serious and needed stronger treatment and longer treatment time. Onset of symptoms to admission, ESR, leucocytes count, and bilateral lung GGO can be effective predictors of the length of hospitalization. And onset of symptoms to admission, leucocytes count, bilateral lung GGO, and lung consolidation can be effective predictors of the amount of time until symptoms relief. Most importantly, we have created a scoring system, which could contribute to the diagnosis and treatment of COVID-19.

PATZ1 (MAZR) Co-occupies Genomic Sites With p53 and Inhibits Liver Cancer Cell Proliferation via Regulating p27.

Liver cancer is the third most common cause of cancer death in the world. POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1/MAZR) is a transcription factor associated with various cancers. However, the role of PATZ1 in cancer progression remains controversial largely due to lack of genome-wide studies. Here we report that PATZ1 regulates cell proliferation by directly regulating CDKN1B (p27) in hepatocellular carcinoma cells. Our PATZ1 ChIP-seq and gene expression microarray analyses revealed that PATZ1 is strongly related to cancer signatures and cellular proliferation. We further discovered that PATZ1 depletion led to an increased rate of colony formation, elevated Ki-67 expression and greater S phase entry. Importantly, the increased cancer cell proliferation was accompanied with suppressed expression of the cyclin-dependent kinase inhibitor CDKN1B. Consistently, we found that PATZ1 binds to the genomic loci flanking the transcriptional start site of CDKN1B and positively regulates its transcription. Notably, we demonstrated that PATZ1 is a p53 partner and p53 is essential for CDKN1B regulation. In conclusion, our study provides novel mechanistic insights into the inhibitory role of PATZ1 in liver cancer progression, thereby yielding a promising therapeutic intervention to alleviate tumor burden.

Urinary coenzyme Q10 as a diagnostic biomarker and predictor of remission in a patient with ADCK4-associated Glomerulopathy: a case report.

BACKGROUND: AarF domain-containing kinase 4 (ADCK4)-associated glomerulopathy is a mitochondrial nephropathy caused by mutations in the ADCK4 gene, which disrupt coenzyme Q10 biosynthesis. CASE PRESENTATION: We report the case of a 25-year-old female patient with ADCK4-associated glomerulopathy presenting with proteinuria (and with no additional systemic symptoms). A known missense substitution c.737G > A (p.S246N) and a novel frameshift c.577-600del (p.193-200del) mutation were found. We followed the patient for 24 months during supplementation with coenzyme Q10 (20 mg/kg/d - 30 mg/kg/d) and describe the clinical course. In addition, we measured serum and urine coenzyme Q10 levels before and after coenzyme Q10 supplementation and compared them with those of healthy control subjects. The patient's urinary coenzyme Q10 to creatinine ratio was higher than that of healthy controls before coenzyme Q10 supplementation, but decreased consistently with proteinuria after coenzyme Q10 supplementation. CONCLUSIONS: Although the use of urinary coenzyme Q10 as a diagnostic biomarker and predictor of clinical remission in patients with ADCK4-associated glomerulopathy should be confirmed by larger studies, we recommend measuring urinary coenzyme Q10 in patients with isolated proteinuria of unknown cause, since it may provide a diagnostic clue to mitochondrial nephropathy.

Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice.

Diabetic kidney disease (DKD) is a major cause of end stage renal diseases worldwide. Despite successive interventions for delaying the progression of DKD, current treatments cannot reverse the pathological progression. Mefunidone (MFD) is a new compound with potent antifibrotic properties, but the effect of MFD on DKD remains unknown. Therefore, we investigated the protective effects of MFD in both models of the db/db type 2 diabetes (T2D) and streptozotocin (STZ)-induced type 1 diabetes (T1D) models. Compared with the model group, MFD treatment significantly reduced pathological changes observed by PAS staining, PASM staining, and Masson staining in vivo. To further elucidate the potential mechanisms, we discovered MFD treatment notably restored podocyte function, alleviated inflammation, abated ROS generation, inhibited the TGF-ß1/SAMD2/3 pathway, suppressed the phosphorylation levels of MAPKs (ERK1/2, JNK, and P38), and reduced epithelial-to-mesenchymal transition(EMT). In conclusion, these findings demonstrate the effectiveness of MFD in diabetic nephropathy and elucidate its possible mechanism.

Fluorofenidone attenuates renal fibrosis by inhibiting the mtROS-NLRP3 pathway in a murine model of folic acid nephropathy.

Fluorofenidone (AKF-PD) is a novel pyridone agent that reduces the deposition of extracellular matrix (ECM) in various models of renal fibrosis. However, there are no reports on the effect of AKF-PD in preventing fibrosis in the folic acid nephropathy model. Besides, the mechanisms of action of AKF-PD in preventing renal fibrosis are not fully understood. In the study, we observed that AKF-PD reduced folate-induced kidney injury, ameliorated the deterioration of renal function, and suppressed the deposition of ECM by decreasing the expression of collagen I, collagen III, transforming growth factor-ß (TGF-ß), fibronectin (FN), and alpha smooth muscle actin (α-SMA) in the folic acid nephropathy model. Additionally, AKF-PD suppressed the activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the production of caspase-1 and IL-1ß, and alleviated mitochondrial oxidative damage by promoting mitochondrial energy metabolism and reducing the expression of NADPH oxidase 4 (NOX4). The results of in vitro experiments demonstrated that AKF-PD suppressed NLRP3 inflammasome activation in activated peritoneal-derived macrophages (PDMs) and renal tubular epithelial cells (RTECs). AKF-PD increased the intracellular ATP content and decreased the expression of NOX4, while preventing the excessive production of mitochondrial reactive oxygen species (mtROS) in activated PDMs. In conclusion, this study demonstrated that AKF-PD inhibited renal fibrosis by suppressing the mtROS-NLRP3 pathway in the folic acid nephropathy model. These findings provide new evidence in support of the clinical use of AKF-PD in the treatment of diseases related to renal fibrosis.

Blood Pressure Variability and Outcomes in End-Stage Renal Disease Patients on Dialysis: A Systematic Review and Meta-Analysis.

OBJECTIVE: Previous studies have suggested that blood pressure variability (BPV) is associated with an increased risk of mortality and cardiovascular events in patients on dialysis. However, the results are inconsistent. A comprehensive literature review was conducted to analyze the association between BPV and outcomes in patients on dialysis. METHODS: Articles in Embase, Medline, and Web of Science from the date of inception through January 1, 2020, were identified. The outcomes were all-cause and cardiovascular mortality and cardiovascular events. The risk of bias was assessed using the Newcastle-Ottawa scale tool. Random effects models were used to pool the overall effect sizes. Two reviewers extracted the data independently. Meta-regression and subgroup analyses were performed to explore potential heterogeneity. RESULTS: Fifteen eligible studies were included, and all enrolled hemodialysis recipients only. The overall risk of bias for the included studies was low. A 1-SD increase in systolic BPV was associated with higher risks of all-cause mortality (HR = 1.18; 95% CI 1.11-1.26, I2 = 53.8%), cardiovascular mortality (HR = 1.23; 95% CI 1.10-1.37, I2 = 57.2%), and cardiovascular events (HR = 1.27; 95% CI 1.07-1.51, I2 = 69.3%). Likewise, a 1-SD increase in diastolic BPV was associated with higher HR for all-cause and cardiovascular mortality (HR = 1.14; 95% CI 1.05-1.23, I2 = 0.0%, and HR = 1.14; 95% CI 0.94-1.38, I2 = 0.0%, respectively). CONCLUSIONS: A greater BPV is associated with higher risks of cardiovascular and mortality outcomes in patients on hemodialysis. Further research is required to determine whether BPV may be useful either as a marker enabling individualized treatment of cardiovascular risk or as a treatment target in its own right.

COVID-19 in a patient with long-term use of glucocorticoids: A study of a familial cluster.

Clusters of patients with novel coronavirus disease 2019 (COVID-19) have been successively reported globally. Studies show clear person-to-person transmission. The average incubation period is 2-14 days, and mostly 3-7 days. However, in some patients, this period may be longer. Here, we report a familial cluster of COVID-19 where a 47-year-old woman with long-term use of glucocorticoids did not develop any symptoms within the 14-day quarantine period but was confirmed with COVID-19 by tested positive of antibody on day 40 after she left Wuhan. Almost at the same time, her father and sister were diagnosed with COVID-19. The results suggest that the long-term use of glucocorticoids might cause atypical infections, a long incubation period, and extra transmission of COVID-19.

Fluorofenidone Alleviates Renal Fibrosis by Inhibiting Necroptosis Through RIPK3/MLKL Pathway.

Cell death and sterile inflammation are major mechanisms of renal fibrosis, which eventually develop into end-stage renal disease. "Necroptosis" is a type of caspase-independent regulated cell death, and sterile inflammatory response caused by tissue injury is strongly related to necrosis. Fluorofenidone (AKF-PD) is a novel compound shown to ameliorate renal fibrosis and associated inflammation. We investigated whether AKF-PD could alleviate renal fibrosis by inhibiting necroptosis. Unilateral ureteral obstruction (UUO) was used to induce renal tubulointerstitial fibrosis in C57BL/6J mice. AKF-PD (500 mg/kg) or necrostatin-1 (Nec-1; 1.65 mg/kg) was administered simultaneously for 3 and 7 days. Obstructed kidneys and serum were harvested after euthanasia. AKF-PD and Nec-1 ameliorated renal tubular damage, inflammatory-cell infiltration, and collagen deposition, and the expression of proinflammatory factors (interlukin-1ß, tumor necrosis factor [TNF]-α) and chemokines (monocyte chemoattractant protein-1) decreased. AKF-PD or Nec-1 treatment protected renal tubular epithelial cells from necrosis and reduced the release of lactate dehydrogenase in serum. Simultaneously, production of receptor-interacting protein kinase (RIPK)3 and mixed lineage kinase domain-like protein (MLKL) was also reduced 3 and 7 days after UUO. AKF-PD and Nec-1 significantly decreased the percentage of cell necrosis, inhibiting the phosphorylation of MLKL and RIPK3 in TNF-α- and Z-VAD-stimulated human proximal tubular epithelial (HK-2) cells. In conclusion, AKF-PD and Nec-1 have effective anti-inflammatory and antifibrotic activity in UUO-induced renal tubulointerstitial fibrosis, potentially mediated by the RIPK3/MLKL pathway.

Fluorofenidone protects against acute kidney injury.

Cisplatin (CP) is one of the most effective chemotherapeutics in the treatment of human cancers. However, the beneficial effects of CP are limited by the toxic effects, especially nephrotoxicity. Fluorofenidone (AKFPD) is a promising multifunctional antifibrosis pyridinone drug discovered by our group. But there is no evidence of its protective effects against acute kidney injury (AKI). Therefore, we investigated the protective effects of AKFPD on CP-induced AKI in vivo and in vitro. Compared with the model group, treatment with AKFPD effectively ameliorated kidney damages. In order to elucidate the mechanisms, we discovered that AKFPD treatment notably alleviated generation of reactive oxygen species, reduced the phosphorylation levels of MAPKs (ERK1 and 2, JNKs, and p38), suppressed inflammatory response, inhibited apoptosis, and abated the expression of CP transporters (organic cation transporter 2 and copper transport protein 1) compared with the model group. Moreover, because renal ischemia reperfusion injury (IRI)-induced AKI and LPS-induced AKI are the major models representative of renal transplantation-correlated AKI and sepsis-related AKI, which are also the main causes of AKI, we have also proved the effectiveness of AKFPD on these models. In conclusion, these findings suggest that AKFPD is a potent drug for CP-, IRI-, and LPS-caused AKI and elucidate the underlying mechanism.-Jiang, Y., Quan, J., Chen, Y., Liao, X., Dai, Q., Lu, R., Yu, Y., Hu, G., Li, Q., Meng, J., Xie, Y., Peng, Z., Tao, L. Fluorofenidone protects against acute kidney injury.