Immunoregulatory effects of Huaier (Trametes robiniophila Murr) and relevant clinical applications.

Huaier (Trametes robiniophila Murr) is a medicinal fungus of traditional Chinese medicine with more than 1000 years of history of clinical application. Its remarkable anticancer activities has led to its application in treating diverse malignancies. In recent years, the immunomodulatory effects of Huaier have been uncovered and proved to be beneficial in a plethora of immune-related diseases including cancer, nephropathy, asthma, etc. In this review, we comprehensively summarized the active components of Huaier, its regulatory activities on multifaceted aspects of the immune system, its application in various clinical settings as well as toxicologic evidence. Based on currently available literature, Huaier possesses broad-spectrum regulatory activities on various components of the innate and adaptive immune system, including macrophages, dendritic cells, natural killer cells, T and B lymphocytes, etc. Versatile immunologic reactions are under the regulation of Huaier from expression of damage-associated molecular patterns, immune cell activation and maturation to cell proliferation, differentiation, antibody production, expression of cytokines and chemokines and terminal intracellular signal transduction. Moreover, some modulatory activities of Huaier might be context-dependent, typically promoting the restoration toward normal physiological status. With excellent efficacy and minimal side effects, we foresee more extensive application of Huaier for treating immune-related disorders.

The probiotic Lactobacillus casei Zhang-mediated correction of gut dysbiosis ameliorates peritoneal fibrosis by suppressing macrophage-related inflammation via the butyrate/PPAR-γ/NF-κB pathway.

Peritoneal fibrosis is a complication of long-term peritoneal dialysis (PD) that restricts its clinical application for the treatment of end-stage renal disease. Lactobacillus casei Zhang (LCZ), a probiotic strain isolated from traditional fermented koumiss, exhibits health benefits such as anti-inflammatory and antioxidative effects, improvement of insulin resistance and mitigation of renal injury. However, whether LCZ can prevent peritoneal fibrosis remains unknown. Here, we assessed the effects of LCZ in a mouse model of PD-induced peritoneal fibrosis. Our results showed that the administration of LCZ significantly ameliorated peritoneal fibrosis in experimental mice. Macrophage infiltration, inflammatory M1 polarization and inflammatory cytokines in peritoneal dialysis effluents were effectively reduced by LCZ. Meanwhile, LCZ corrected gut dysbiosis and enriched beneficial bacteria that produce short-chain fatty acids, specifically Dubosiella, Lachnospiraceae, Parvibacter, and Butyricicoccus. Correspondingly, the local butyrate level in peritoneal dialysis effluents was significantly elevated by LCZ. Mechanistically, we found activation of PPARγ and inhibition of the NF-κB pathway in LCZ-treated mice, an observation that was replicated in a butyrate-treated macrophage cell line. In conclusion, our study suggests that LCZ is beneficial for preventing PD-induced peritoneal fibrosis through modulating the gut microbiota, enhancing butyrate production, activating PPARγ, and suppressing NF-κB-mediated inflammation.

Identification of Major Risk Factors and Non-linear Effects to the Development of Left Ventricular Hypertrophy in Chronic Kidney Disease by Constructing and Validation of Nomograms.

Background: Left ventricular hypertrophy (LVH) is a common cardiovascular complication among chronic kidney disease (CKD) patients. The present study aimed to identify major independent risk factors and determine their contribution and relationship to LVH development. Methods: Clinical and echocardiographic data of 2002 pre-dialytic CKD patients were retrospectively collected. Independent risk factors for LVH were identified using univariable and multivariable logistic regression. Nomograms together with restricted cubic splines method were employed to explore the effect size and possible non-linear relationship with regard to LVH. A simplified predictive model was constructed and its predictive ability was validated to demonstrate to which extent the identified risk factors accounted for LVH risk. Results: Multivariable logistic regression identified age, body mass index (BMI), systolic blood pressure (SBP), eGFR and hemoglobin as independent influencing factors for LVH. Nomogram revealed BMI, SBP and hemoglobin concentration as the most important risk factors. Impaired renal function only showed obvious risk for LVH when eGFR declined below 30 ml/min/1.73 m2. Significant threshold effects existed for blood pressure and obesity that the risks for LVH doubled when SBP exceeded 160 mmHg or BMI exceeded 30 kg/m2. The predictive model constructed performed well on both the training and validation cohort using calibration curve, ROC curve and AUC value, with AUC above 0.80 for both the training cohort and the validation cohort. Conclusions: With the help of nomogram model, we identified five independent factors that explain a large proportion of LVH risk in CKD patients. Among them, major contribution to LVH development was resulted from comorbidities and complications of CKD (hypertension, anemia, obesity) rather than eGFR reduction per se. Non-linear relationship and threshold relationship between eGFR, blood pressure, obesity and LVH risk were also identified.

Shrunken Pore Syndrome Is Associated with Renal Function Decline in Female Patients with Kidney Diseases.

Background: Shrunken pore syndrome (SPS) represents selective impairment of kidney filtration of low-molecular-weight molecules between 1 and 30 kDa and has been related to outcomes including morbidity, mortality, and cardiovascular events. However, the prevalence and kidney outcomes of SPS have not been investigated in patients with IgA nephropathy (IgAN) and membranous nephropathy (MN). Methods: We retrospectively collected information of 536 patients including 414 with IgAN and 122 with MN. SPS was mainly defined by cystatin C-based eGFR < 70% of creatinine-based eGFR using the CAPA-LM equation pairs, while CKD-EPI equations were also employed in sensitivity analyses. Prevalence rate of SPS and its association with end-stage renal disease (ESRD) or severe eGFR decline (≥50% eGFR reduction or doubling of baseline creatinine) were investigated. Results: 44% (8%) patients were identified as possessing SPS using the CAPA-LM definition. ESRD happened in 24 patients during the average follow-up period of 27.7 months. Despite dramatic increase of incidence rate of ESRD for SPS, significant hazard ratio (HR) only existed in IgAN patients after multivariable adjustment (HR: 8.35, 95% CI: 2.10~33.26), but lost significance in sensitivity analyses. 36 patients were determined as having experienced severe eGFR decline after excluding transient creatinine fluctuation. SPS was associated with severe eGFR decline by Kaplan-Meier survival analyses in the overall population as well as the IgAN, MN, male, and female subpopulations, which remained significant in multivariable adjustments in all groups except IgAN. However, only in female patients the association between SPS and eGFR decline remained significant in all the sensitivity analyses. Conclusions: SPS was independently associated with eGFR decline in female patients with IgAN and MN.

The probiotic L. casei Zhang slows the progression of acute and chronic kidney disease.

The relationship between gut microbial dysbiosis and acute or chronic kidney disease (CKD) is still unclear. Here, we show that oral administration of the probiotic Lactobacillus casei Zhang (L. casei Zhang) corrected bilateral renal ischemia-reperfusion (I/R)-induced gut microbial dysbiosis, alleviated kidney injury, and delayed its progression to CKD in mice. L. casei Zhang elevated the levels of short-chain fatty acids (SCFAs) and nicotinamide in the serum and kidney, resulting in reduced renal inflammation and damage to renal tubular epithelial cells. We also performed a 1-year phase 1 placebo-controlled study of oral L. casei Zhang use (Chinese clinical trial registry, ChiCTR-INR-17013952), which was well tolerated and slowed the decline of kidney function in individuals with stage 3-5 CKD. These results show that oral administration of L. casei Zhang, by altering SCFAs and nicotinamide metabolism, is a potential therapy to mitigate kidney injury and slow the progression of renal decline.

A Spatiotemporal Analysis of Schistosomiasis in Hunan Province, China.

Based on annual parasitological data recently collected at county and village levels, this article presents a multiscale spatiotemporal analysis of transmission risk of schistosomiasis japonica in Hunan Province during 2001 to 2015 in a geographic information system environment. The study shows that the incidence and prevalence rate of human Schistosoma japonicum infection in Hunan Province decreased after 2001. A spatial autocorrelation analysis reveals the existence of spatial clusters of human Schistosoma japonicum infection and a growing tendency of spatial clustering over time. The identification of high-risk areas (hot spots) helps find areas of priority for future implementation of control strategies. The research demonstrates the importance of spatial scale in public health studies.

Prognostic and therapeutic value of disruptor of telomeric silencing-1-like (DOT1L) expression in patients with ovarian cancer.

BACKGROUND: Epigenetics has been known to play a critical role in regulating the malignant phenotype. This study was designed to examine the expression of DOT1L (histone 3 lysine 79 methyltransferase) and H3K79 methylation in normal ovarian tissues and ovarian tumors and to explore the function of DOT1L and its underline mechanisms in ovarian cancer. METHODS: The expression of DOT1L and H3K79 methylation in 250 ovarian tumor samples and 24 normal ovarian samples was assessed by immunohistochemistry. The effects of DOT1L on cell proliferation in vitro were evaluated using CCK8, colony formation and flow cytometry. The DOT1L-targeted genes were determined using chromatin immune-precipitation coupled with high-throughput sequencing (ChIP-seq) and ChIP-PCR. Gene expression levels were measured by real-time PCR and immunoblotting. The effects of DOT1L on tumor growth in vivo were evaluated using an orthotopic ovarian tumor model. RESULTS: DOT1L expression and H3K79 methylation was significantly increased in malignant ovarian tumors. High DOT1L expression was associated with International Federation of Gynecology and Obstetrics (FIGO) stage, histologic grade, and lymphatic metastasis. DOT1L was an independent prognostic factor for the overall survival (OS) and progression-free survival (PFS) of ovarian cancer, and higher DOT1L expression was associated with poorer OS and PFS. Furthermore, DOT1L regulates the transcription of G1 phase genes CDK6 and CCND3 through H3K79 dimethylation; therefore, blocking DOT1L could result in G1 arrest and thereby impede the cell proliferation in vitro and tumor growth in vivo. CONCLUSIONS: Our findings first demonstrate that DOT1L over-expression has important clinical significance in ovarian cancer and also clarify that it drives cell cycle progression through transcriptional regulation of CDK6 and CCND3 through H3K79 methylation, suggesting that DOT1L might be potential target for prognostic assessment and therapeutic intervention in ovarian cancer.