Real-world effectiveness of Azvudine versus nirmatrelvir-ritonavir in hospitalized patients with COVID-19: A retrospective cohort study.

Chinese guidelines prioritize the use of Azvudine and nirmatrelvir-ritonavir in COVID-19 patients. Nevertheless, the real-world effectiveness of Azvudine versus nirmatrelvir-ritonavir is still lacking, despite clinical trials showing their effectiveness compared with matched controls. To compare the effectiveness of Azvudine versus nirmatrelvir-ritonavir treatments in real-world clinical practice, we identified 2118 hospitalized COVID-19 patients, with a follow-up of up to 38 days. After exclusions and propensity score matching, we included 281 Azvudine recipients and 281 nirmatrelvir-ritonavir recipients who did not receive oxygen therapy at admission. The lower crude incidence rate of composite disease progression outcome (7.83 vs. 14.83 per 1000 person-days, p = 0.026) and all-cause death (2.05 vs. 5.78 per 1000 person-days, p = 0.052) were observed among Azvudine recipients. Azvudine was associated with lower risks of composite disease progression outcome (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.32-0.94) and all-cause death (HR: 0.40; 95% CI: 0.16-1.04). In subgroup analyses, the results of composite outcome retained significance among patients aged <65 years, those having a history of disease, those with severe COVID-19 at admission, and those receiving antibiotics. These findings suggest that Azvudine treatment showed effectiveness in hospitalized COVID-19 patients compared with nirmatrelvir-ritonavir in terms of composite disease progression outcome.

NLRC5: potential novel non-invasive biomarker for predicting and reflecting the progression of IgA nephritis.

BACKGROUND: The nucleotide oligomerization domain-like receptor subfamily C5 (NLRC5) is primarily expressed in the adaptive and innate immune systems. NLRC5 was recently discovered to regulate immunity and inflammatory responses. Abnormal immune and inflammatory responses are considered critical pathogenesis in IgA nephritis (IgAN). However, the role of NLRC5 in IgAN is unknown. We previously showed that NLRC5 can be detected in patients with IgAN; herein, we further examined the pathophysiological significance of NLRC5 in the serum and renal deposits of patients with IgAN. This study is the first to find that NLRC5 is closely correlated with IgAN. METHODS: IgAN patients (n = 50) who were diagnosed by renal biopsy provided blood and renal biopsy tissue, and age-matched healthy control subjects (blood donators n = 22; tissue donators n = 5) were included. Renal biopsies were diagnosed, and blood biochemical parameters were tested. Serum creatinine, urea, proteinuria, haematuria, albumin, and immunoglobulin A levels were recorded. Serum NLRC5 concentrations were detected by enzyme-linked immunosorbent assay, and tissue NLRC5 expression in kidney tissue was detected by immunohistochemical analysis. ROC curve analysis was used to evaluate the diagnostic value of the serum NLRC5 concentration in IgAN. RESULTS: Serum NLRC5 concentration was significantly decreased in the IgAN group compared to that in the healthy control group (P < 0.0001), especially in S1 (Oxford classification) patients (P < 0.0001). Furthermore, serum NLRC5 concentration had a negative correlation with Lee's grade (r = 0.3526, P = 0.0060) and proteinuria levels (r = 0.4571, P = 0.0004). Tissue NLRC5 expression was significantly increased in the IgAN group compared to that in the healthy control group (P < 0.0001); a more significant increase was identified in the S1 group (P < 0.05) and had a positive correlation with Lee's grade (r = 0.497, P < 0.0001). We proposed a cut-off value of 1415 pg/ml for serum NLRC5 concentration, which was able to predict IgAN with 77.27% sensitivity and 87.5% specificity. CONCLUSIONS: Serum NLRC5 concentrations in IgAN are significantly decreased, and tissue NLRC5 expression is significantly increased in IgAN renal tissue, which is consistent with pathological severity. This finding suggests that NLRC5 could potentially be a diagnostic index and represents a prognostic factor in IgAN patients.

Intrinsic renal cells induce lymphocytosis of Th22 cells from IgA nephropathy patients through B7-CTLA-4 and CCL-CCR pathways.

IgA nephropathy (IgAN), the most common glomerulonephritis, has an unclear pathogenesis. The role of Th22 cells, which are intimately related to proteinuria and progression in IgAN, in mediating infection-related IgAN is unclear. This study aimed to characterize the association between intrinsic renal cells (tubular epithelial cells and mesangial cells) and Th22 cells in immune regulation of infection-related IgAN and to elucidate the impact of Th22 lymphocytosis; the proinflammatory cytokines IL-1, IL-6, and TNF-α; and CCL chemokines on kidney fibrosis. Hemolytic streptococcus infection induced an increase in IL-1, IL-6, and TNF-α, resulting in Th22 cell differentiation from T lymphocytes obtained from patients with IgAN, and the CCL20-CCR6, CCL22-CCR4, and/or CCL27-CCR10 axes facilitated Th22 cell chemotaxis. The increased amount of Th22 cells caused an increase in TGF-ß1 levels, and anti-CD80, anti-CD86, and CTLA-4Ig treatment reduced TGF-ß1 levels by inhibiting Th22 lymphocytosis and secretion of cytokines and chemokines, thus potentially relieving kidney fibrosis. Our data suggest that Th22 cells might be recruited into the kidneys via the CCL20-CCR6, CCL22-CCR4, and/or CCL27-CCR10 axes by mesangial cells and tubular epithelial cells in infection-related IgAN. Th22 cell overrepresentation was attributed to stimulation of the B7-CTLA-4Ig antigen-presenting pathway and IL-1, IL-6, and TNF-α.

Neferine reduces cisplatin-induced nephrotoxicity by enhancing autophagy via the AMPK/mTOR signaling pathway.

Cisplatin is one of the most effective chemotherapeutic agents; however, its clinical use is limited by serious side effects of which nephrotoxicity is the most important. Nephrotoxicity induced by cisplatin is closely associated with autophagy reduction and caspase activation. In this study, we investigated whether neferine, an autophagy inducer, had a protective effect against cisplatin-induced nephrotoxicity. In an in vitro cisplatin-induced nephrotoxicity model, we determined that neferine was able to induce autophagy and that pretreatment with neferine not only attenuated cisplatin-induced cell apoptosis but further activated cell autophagy. This pro-survival effect was abolished by the autophagic flux inhibitor chloroquine. Furthermore, neferine pretreatment activated the AMPK/mTOR pathway; however, pharmacological inhibition of AMPK abolished neferine-mediated autophagy and nephroprotection against cisplatin-induced apoptosis. Collectively, our findings suggest for the first time the possible protective mechanism of neferine, which is crucial for its further development as a potential therapeutic agent for cisplatin-induced nephrotoxicity.

Ganoderic acid A attenuated hepatic impairment by down-regulating the intracellular JAK2-STAT3 signaling pathway in induced mushroom poisoning.

BACKGROUND: Mushroom poisoning is one of the most prominent public health problems. However, there is no special antidote so far. In the present study, we verified that Ganoderma lucidum may be an effective approach for treatment of acute mushroom poisoning. METHODS: A retrospective study was performed within the past 20 years, we compiled information on the treatment of α-Amatoxin mushroom poisoning with Ganoderma lucidum by evaluating the mortality rate and liver function before and after treatment. Moreover, we explore the potential underlying mechanism of Ganoderma lucidum in the treatment of α-amanita poisoning in both in vivo animal experiments and in vitro cell experiments. RESULTS: In our study, a total of 556 cases of mushroom poisoning were integrated over the past 20 years, the primary outcome was in-hospital mortality. Specificity, descriptive data of ALT, AST, BA and STB were evaluated for the effectiveness of protection to acute liver damage. From 1994 to 2002, there were 55 cases of mushroom poisoning in which 372 individuals were poisoned, 129 individuals died, with a mortality of 35%. Since 2002, after being treated with Ganoderma lucidum, surprisingly, the mortality decreased to 0%, and all the 184 patients were cured, the hepatic impairment improved significantly within 10 days. Based on a multivariate logistic regression analyses, after adjusting for age, gender and baseline clinical indicators, it was found that Ganoderma lucidum treatment was effective in reducing the morbidity (OR = 0.58), and Ganoderma lucidum treatment also showed an improvement in liver enzymes and in shortening the length of hospitalization significantly. Meanwhile, the main components of Ganoderma lucidum, Ganoderic acid A could significantly improve the survival rate and liver function in α-Amatoxin poisoned mice and may effectively inhibit the JAK2-STAT3 pathway, which could contribute to the detoxification in poisoned patients. CONCLUSION: Ganoderma lucidum is very effective in treating mushroom poisoning by α-amanita and is worth promoting.

[A cross-sectional study of restless legs syndrome in maintenance hemodialysis patients].

OBJECTIVE: To explore the incidence and possible risk factors of restless legs syndrome (RLS) in the maintenance hemodialysis patients. METHODS: A total of 375 maintenance hemodialysis patients were enrolled in this study from September 1 to 30 in 2012. The diagnosis and assessment of severity were based on the International Restless Leg Syndrome Study Group (IRLSSG) standard. The relevant laboratory parameters and dialysis indicators were collected, such as hemoglobin, serum ferritin, parathyroid hormone, blood flow and dialysis mode. The clinical data were analyzed by multivariate logistic regression method. RESULTS: The incidence of RLS was 13.3% with the severity score of 18.69 ± 0.95. The logistic regression analysis showed that anuria (OR 0.292, 95%CI 0.114-0.750) and ß2 microglobulin (OR 1.023, 95%CI 1.003-1.044) were the risk factors for RLS in the maintenance hemodialysis patients, while hemoglobin, serum iron and parathyroid hormone were not correlated with RLS. CONCLUSIONS: The incidence of RLS is high in the maintenance hemodialysis patients. The risk factors of RLS are anuria and ß2 microglobulin. Therefore, the preservation of residual renal function and the improvement of dialysis adequacy, especially the removal of the middle molecular weight toxins, may reduce the occurrence of RLS and improve the quality of life in the hemodialysis patients.

Interleukin-22 exacerbates angiotensin II-induced hypertensive renal injury.

Hypertensive renal injury (HRI) is a main cause of end-stage renal diseases, and CD4+ T cells and the secreted inflammatory cytokines contribute to the progress of HRI. However, the exact mechanisms remain unidentified in HRI, and there is still a shortage of effective treatments. Here, we aim to explore the role of interleukin-22 (IL-22) and its underlying mechanism in HRI. Serum IL-22 level and peripheral Th22 cells frequency in patients with HRI were detected by ELISA and flow cytometry respectively. Angiotension II (Ang II) was infused subcutaneously to C57BL/6 mice for 28 days. Hypertensive mice were treated with recombinant IL-22 (rIL-22), anti-IL-22 antibody, or JAK2/STAT3 pathway blocker AG-490 respectively. Blood pressure (BP), urinary albumin/creatinine ratio (UACR), serum creatinine (Scr) and renal histopathology were measured; renal Th22 cells proportion were evaluated; inflammatory factors were evaluated by ELISA; JAK2/STAT3 pathway and fibrosis related factors expression in kidney were detected by Western blot. Serum IL-22 and Th22 cells proportion in kidney of mice were elevated after Ang II infusion. Compared to Ang II-infused mice, treatment with rIL-22 resulted in further increased UACR, Scr, renal pathological damage, inflammation and renal fibrosis, accompanied by elevated BP and JAK2/STAT3 pathway activation. Conversely, anti-IL-22 antibody reduced inflammation, renal fibrosis and BP in Ang II treated mice. AG490 could compromised the above effects of rIL-22. Taken together, recombinant IL-22 may aggravate hypertensive renal damage mediated by Ang II in mice, which may be through promoting JAK2/STAT3 pathway activation. Anti-IL-22 antibody exerts the opposite effects. These data suggest the IL-22 signaling maybe a novel therapeutic target for the treatment of hypertensive renal injury.

Irbesartan may relieve renal injury by suppressing Th22 cells chemotaxis and infiltration in Ang II-induced hypertension.

Angiotensin II (Ang II) as an important pathogenic factor, has been implicated in the pathogenesis of hypertension and associated renal injury, and inhibition of Ang II can reduce renal inflammation and exert renal protective effects. In the present study, we determine the infiltration of Th22 cells in kidney and serum IL-22 level in hypertensive renal injury, and explore the effects and mechanisms of a widely used angiotensin II type 1 receptor blocker irbesartan on Th22 cells infiltration and related renal injury. Hypertension was induced by administering 1.5 mg/kg Ang II subcutaneously daily in C57BL/6 mice for 28 days. The mice were additionally treated by irbesartan or amlodipine. Renal Th22 lymphocytes frequency was evaluated through flow cytometry, serum IL-22 was detected by ELISA, and renal histopathological changes were also detected. The levels of renal chemokines (CCL20, CCL22, CCL27) and serum proinflammatory factors (IL-1ß, IL-6, TNF-α) were measured by ELISA. Renal expression of alpha-smooth muscle actin (α-SMA), Fibronectin (FN) and collagen I (Col I) were evaluated by western blot. Chemotaxis assay and co-culture assay were conducted to clarify the effect of irbesartan on Th22 cells chemotaxis and differentiation in vitro. Our results showed in Ang II-infused hypertension mice, irbesartan suppressed renal Th22 cells accumulation as well as CCL20, CCL22, CCL27 expression. Serum IL-22, IL-1ß, IL-6 and TNF-α concentrations wasere also reduced, in addition to inhibited renal expression of α-SMA, FN and Col I. Irbesartan treatment lowered blood pressure, urinary protein and renal pathological damage. In vitro, irbesartan could abrogate the Th22 cells chemotaxis and differentiation, compared to control and amlodipine groups. Our study reveals a new pharmacological mechanism that irbesartan ameliorates inflammation and fibrosis in hypertensive renal injury induced by Ang II, maybe through inhibiting Th22 cells chemotaxis and infiltration, which provides a new theoretical basis and therapeutic target for hypertensive renal injury.

Streptococcus may aggravate inflammatory damage in chronic nephritis via the chemotaxis of Th22 cells.

BACKGROUND: Infection can induce and aggravate chronic kidney disease (CKD), and the chemotaxis of Th22 cells may aggravate CKD. However, the mechanism underlying group A Streptococcus (GAS) infections in CKD through the chemotaxis of Th22 cells remains unknown. METHODS: The experiment was divided into a normal control group, an IgAN model group, a GAS-treated normal group, a GAS-treated IgAN group and an anti-CCL intervention group. An IgA nephropathy model was established, and after the success of the IgA nephropathy model was confirmed, Streptococcus haemolyticus A was inoculated intranasally and compared with treatment with anti-CCL to detect changes in Th22 cells, related chemotaxis factors and kidney pathology before and after intervention. RESULTS: An immunoglobulin A nephropathy model was successfully established. Streptococcus was successfully inoculated into the nasal cavity of the normal group and the IgA nephropathy infection control group. After intervention, pulmonary inflammatory cell infiltration was more obvious in the IgA nephropathy group than in the normal control group after Streptococcus infection. Th22 cells were detected more frequently in IgA nephropathy; after streptococcal infection, the percentage of Th22 cells in the IgAN group was higher than that in the normal group but decreased significantly when chemotaxis was blocked, the expression of CCL27, CCR10 and IL-22 declined simultaneously, and improvements in pathological changes were observed. CONCLUSION: Streptococcus may cause the chemotaxis of Th22 cells to kidney tissue, leading to or aggravating nephritis injury.

Hydrogen-rich saline protects rat from oxygen glucose deprivation and reperusion-induced apoptosis through VDAC1 via Bcl-2.

BACKGROUND: Hydrogen is received as an inert gas that thought to be non-functional in vivo previously. Recently, emerging evidences showed that in ischemia/reperfusion (IR) condition, hydrogen reduced cellular reactive oxygen species (ROS) production and ameliorated cell apoptosis. However, the underlying mechanism of hydrogen on IR-induced apoptosis remains elusive. Here we tried to unravel the mode of action of hydrogen with rat adrenal medulla cell line PC-12 in vitro. METHODS: The mitochondrial functions before and after oxygen glucose deprivation and reperfusion (OGD/RP) were determined with corresponding dyes. The expression of Bcl-2, Bax, VDAC1, cytochrome c and caspase 9 was detected using qRT-PCR and Western Blotting method. Then Bcl-2 inhibitor, AB-199, was applied to investigate the role of Bcl-2 in OGD/RP-induced cell apoptosis. Finally, we manipulated the expression of VDAC1 with plasmids transfection to understand the effects of VDAC1 on Bcl-2-mediated anti-apoptosis in OGD/RP. RESULTS: In this study, we demonstrated that hydrogen-rich saline (HRS) reduced OGD/RP-mediated neuronal loss by stimulating the expression of Bcl-2, which suppressed the activity of VDAC1. Consequently, HRS maintained the mitochondrial functions, restrained the release of cytochrome c and caspase 9 activation, resulting in ameliorated cell viability. CONCLUSIONS: HRS ameliorated OGD/RP-induced PC-12 cell apoptosis and provided a novel treatment option for ischemia.

Cordyceps sinensis may inhibit Th22 cell chemotaxis to improve kidney function in lgA nephropathy.

IgA nephropathy is the most common form of primary glomerulonephritis and an important cause of kidney failure. Cordyceps sinensis (CS) is a parasitic fungus that has a long history of use in Chinese medicine for the treatment of nephritis. Interleukin (IL)-22-producing helper T cells (Th22 cells) have been reported to be involved in lgA nephropathy. Th22 cells link the immune response to tissue inflammation. To elucidate the possible efficacy and mechanisms by which CS counteracts nephritis, we established an IgA nephropathy model in 6-week-old female BALB/c mice. The mice were randomly separated into 3 groups, the normal control, IgA nephropathy and CS (5 mg/kg/d) treatment groups. The Th22 cell frequencies and the relative pathological and cytokine changes were measured with flow cytometry, whereas the serum chemokine ligand 27 (CCL27) and IL-22 concentrations were detected with ELISA. The Th22 cell frequency decreased after 1 month of CS therapy. Additionally, mesangial cell proliferation decreased. Moreover, the chemokine receptor type 10 (CCR10), CCL27 and IL-22 expression levels were significantly reduced. In conclusion, CS may modulate the chemotaxis of Th22 cells to suppress inflammatory responses in IgA nephropathy.

Peripheral kynurenine/tryptophan ratio is not a reliable marker of systemic indoleamine 2,3-dioxygenase: A lesson drawn from patients on hemodialysis.

Indoleamine 2,3-dioxygenase (IDO) has emerged as a pivotal enzyme for mediating immune tolerance. Because IDO metabolizes tryptophan into kynurenine, the plasma kynurenine/tryptophan (Kyn/Trp) ratio has been widely used as a marker of systemic IDO. Here, we evaluated the clinical value of using the plasma Kyn/Trp ratio to estimate cell-mediated immune responses to tuberculin skin testing and risk of new bacterial infection. We also compared the Kyn/Trp ratio to a novel IDO marker, the IDO median fluorescence index (MFI) of peripheral blood mononuclear cells, which was determined by flow cytometry. In 228 patients from two hemodialysis centers, the two IDO markers were higher in patients than in healthy controls but were not correlated with each other. In vitro experiments demonstrated that peripheral blood mononuclear cells could not metabolize tryptophan into kynurenine, indicating that the increased Kyn/Trp ratio was IDO-independent. Skin induration diameters of tuberculin skin testing were correlated with the IDO MFI (negatively), but not the Kyn/Trp ratio. Further, in a 24-month prospective cohort, the Kyn/Trp ratio was not correlated with clinical infection. Alternatively, patients with a higher IDO MFI had a lower accumulative infection-free survival rate. Using a Cox proportional hazard model, it was also revealed that a higher IDO MFI was significantly associated with new bacterial infection. Taken together, these results indicate that the Kyn/Trp ratio is not a reliable circulating IDO marker in hemodialysis patients. However, the IDO MFI reflects an immunocompromised state and thus might be a potential clinical marker of bacterial infection.

Losartan and Dexamethasone may inhibit chemotaxis to reduce the infiltration of Th22 cells in IgA nephropathy.

Angiotensin II is considered a major profibrotic factor that is involved in tissue remodeling processes, as the inhibition of Angiotensin II can halt renal inflammatory processes. Dexamethasone, an important anti-inflammatory and immunosuppressive agent, has been widely used to treat renal disease for decades. In this study, we explored the frequency of Th22 cells in a mouse model of IgA nephropathy and compared the possible effects of Losartan and Dexamethasone on Th22 cells. The experiments were performed using 6-week-old BALB/c female mice in an established IgA nephropathy model. The mice were randomly separated into 4 groups, which were administered Losartan (30mg/kg/d) or Dexamethasone (10mg/kg/d) and subjected to IgA nephropathy or the normal control treatment for 1month. The frequency of Th22 cells was measured via flow cytometry, and the relative pathological changes in renal morphology were measured with different pathological staining methods. Immunohistochemistry was performed to verify the expression of CCR10 and CCL27, which is specialized receptor on Th22 cells and its corresponding chemokine, respectively. The concentrations of CCL27 and IL-22 in renal tissue homogenates and sera were detected using ELISAs. Losartan and Dexamethasone differentially decreased the frequency of Th22 cells after 1month, and mesangial cell proliferation was also improved. Moreover, the expression of CCR10, CCL27 and IL-22 was reduced by treatment with either drug. However, significant differences between Losartan and Dexamethasone were not observed. Based on these findings, Losartan and Dexamethasone may suppress inflammatory responses by inhibiting the chemotaxis of Th22 cells in IgA nephropathy.

Differentiation and recruitment of IL-22-producing helper T cells in lgA nephropathy.

IL-22-producing helper T cells (Th22 cells) have been reported to be involved in lgA nephropathy. However, the mechanisms underlying the differentiation and immune regulation of Th22 cells in lgA nephropathy remain unknown. To elucidate the mechanisms by which Th22 cells differentiate and are recruited into the kidney in lgA nephropathy, the distribution of Th22 cells in both the kidney and blood was determined. Additionally, the impacts of proinflammatory cytokines and antigen presentation in the kidney on Th22 cell differentiation were explored. Specifically, the chemoattractant activities of chemokines produced by the kidney for Th22 cells were investigated. Th22 cells were significantly higher both in the kidney and in the blood in lgA nephropathy mice. IL-1ß, IL-6, IL-21 and/or TNF-a promoted Th22 cells differentiation from CD4+ T cells. It was observed that kidneys undergoing lgA nephropathy expressed CCL20, CCL22 and CCL27, and kidney supernatants were chemotactic for Th22 cells. This activity was partially blocked by anti-CCL20, anti-CCL22, and anti-CCL27 antibodies, which also potentially improved renal lesions simultaneously. The overrepresentation of Th22 cells in lgAN may be attributable to the actions of kidney chemokines and cytokines. Our data suggest a collaborative loop between the kidney and Th22 cells in lgA nephropathy.

A modified HPLC method improves the simultaneous determination of plasma kynurenine and tryptophan concentrations in patients following maintenance hemodialysis.

The ratio between plasma kynurenine (Kyn) and tryptophan (Trp) serves as a marker of indoleamine 2,3-dioxygenase, a critical immunomodulatory molecule. Simultaneous detection of the two markers may be performed using high-pressure liquid chromatography (HPLC). However, for uremic patients, the conventional detection method may be affected by a range of accumulated toxins. The current study aimed to establish a method for the simultaneous measurement of Kyn and Trp in patients following maintenance hemodialysis via HPLC-ultraviolet detection. The procedure involved the use of a SinoChrom ODS-BP C18 column (4.6×150 mm; inner diameter, 4.5 µm) and a mobile phase of 15 mmol/l sodium acetate acetic acid solution (containing 5% acetonitrile, pH 4.8). The modified method was verified using plasma samples from 10 healthy controls and 91 maintenance hemodialysis patients. The results demonstrated that the modified method was successful in simultaneously detecting the concentrations of Trp and Kyn in the healthy controls and maintenance hemodialysis patients. The method is simple, fast, accurate and suitable for clinical and research purposes in maintenance hemodialysis patients.