Circular RNA DNAH14 molecular mechanism in an experimental model of hepatocellular carcinoma treated with Cobalt chloride to mimic the hypoxia-like response of transcatheter arterial chemoembolization.

Transcatheter arterial chemoembolization (TACE) is the primary local treatment for patients with unresectable hepatocellular carcinoma (HCC). Numerous studies have demonstrated the pivotal role of circular RNAs (circRNAs) in TACE efficacy. This study aimed to investigate the function of circular RNA DNAH14 (circDNAH14) in TACE for HCC and to elucidate its molecular mechanisms. To simulate hypoxia conditions experienced during TACE, HCC cells were treated with cobalt chloride. The expression levels of circDNAH14, microRNA-508-3p (miR-508-3p), and Prothymosin Alpha (PTMA) were modulated via transfection for knockdown or overexpression. Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays, flow cytometry, and Transwell assays, along with epithelial-mesenchymal transition (EMT) evaluations, were employed to assess cell proliferation, apoptosis, invasion, migration, and EMT. The results indicated that hypoxia treatment downregulated the expression of circDNAH14 and PTMA while upregulating miR-508-3p. Such treatment suppressed HCC cell proliferation, invasion, migration, and EMT, and induced apoptosis. Knockdown of circDNAH14 or PTMA intensified the suppressive effects of hypoxia on the malignant behaviors of HCC cells. Conversely, upregulation of miR-508-3p or PTMA mitigated the effects of circDNAH14 overexpression and knockdown, respectively. Mechanistically, circDNAH14 was found to competitively bind to miR-508-3p, thereby regulating PTMA expression. In vivo, nude mouse xenograft experiments demonstrated that circDNAH14 knockdown augmented the hypoxia-induced suppression of HCC tumor growth. In conclusion, circDNAH14 mitigates the suppressive effects of hypoxia on HCC, both in vitro and in vivo, by competitively binding to miR-508-3p and regulating PTMA expression.

Renal pedicle lymphatic ligation for non-parasitic chyluria via retroperitoneal laparoscopic surgery: a single-center 12-year experience.

Background: Chyluria is a rare disease in which chylous is excreted in the urine. Currently, management of chyluria includes conservative treatments and surgical measures. This study aimed to report our experience in treating non-parasitic chyluria with retroperitoneal laparoscopic ligation of the renal lymphatic vessels. Methods: Data from 52 patients who underwent retroperitoneoscopic ligation of the renal lymphatic vessels for non-parasitic chyluria between December 2009 and May 2022 were reviewed. After general anesthesia, the patients were passively placed in the healthy lateral decubitus position and underwent three-port retroperitoneal laparoscopy. Detailed medical data, including demographic characteristics, intraoperative outcomes, postoperative data, and complications, were reviewed. Results: Fifty-two patients received surgery treatment at our institution. The mean disease course was 89.3 months. The mean age was 58.8 years, with females accounting for 57.7% (30/52); the majority of patients (33/52) had the laterality of chyluria on the left and 9 (17.3%) had a history of previous thoracic or abdominal surgery. Compared with the urine and blood data before the operation and on the first day after the operation, urinary protein, urinary tract infection, urinary red blood cells, hemoglobin, albumin, and serum total protein significantly improved 3 months after the operation. However, there were no significant differences in blood creatinine and blood urea nitrogen levels among the three groups. The mean surgery time was about 110.0 minutes, and the estimated total blood loss was 81.2 mL. The postoperative drainage volume was 229.9 mL. The average time to start a liquid diet and to be out of bed were 1.5 and 1.9 days, respectively. Transient postoperative gross hematuria occurred in eight patients, and complications occurred in five patients after surgery. The mean length of hospitalization was 6.6 days. The follow-up duration ranged from 3 to 152 months, and except for three patients who did not respond to treatment, the remaining patients had no recurrence and did not require reoperation. Conclusions: Our long-term follow-up results showed that renal pedicle lymphatic ligation via retroperitoneal laparoscopic surgery is an effective, safe, and reliable surgical option for patients with non-parasitic chyluria.

Lifestyle factors, serum parameters, metabolic comorbidities, and the risk of kidney stones: a Mendelian randomization study.

Background and objective: The early identification of modifiable risk factors is important for preventing kidney stones but determining causal associations can be difficult with epidemiological data. We aimed to genetically assess the causality between modifiable factors (lifestyle factors, serum parameters, and metabolic comorbidities) and the risk of kidney stones. Additionally, we aimed to explore the causal impact of education on kidney stones and its potential mediating pathways. Methods: We conducted a two-sample Mendelian randomization (MR) study to explore the causal association between 44 modifiable risk factors and kidney stones. The FinnGen dataset initially explored the causal relationship of risk factors with kidney stones and the UK Biobank dataset was used as the validation set. Then, a meta-analysis was conducted by combining discovery and validation datasets. We used two-step MR to assess potential mediators and their mediation proportions between education and kidney stones. Results: The combined results indicated that previous exposures may increase the risk of kidney stones, including sedentary behavior, urinary sodium, the urinary sodium/potassium ratio, the urinary sodium/creatinine ratio, serum calcium, 25-hydroxyvitamin D (25OHD), the estimated creatinine-based glomerular filtration rate (eGFRcrea), GFR estimated by serum cystatin C (eGFRcys), body mass index (BMI), waist circumference, type 2 diabetes mellitus (T2DM), fasting insulin, glycated hemoglobin, and hypertension. Coffee intake, plasma caffeine levels, educational attainment, and the urinary potassium/creatinine ratio may decrease the risk of kidney stones. Ranked by mediation proportion, the effect of education on the risk of kidney stones was mediated by five modifiable risk factors, including sedentary behavior (mediation proportion, 25.7%), smoking initiation (10.2%), BMI (8.2%), T2DM (5.8%), and waist circumference (3.2%). Conclusion: This study provides MR evidence supporting causal associations of many modifiable risk factors with kidney stones. Sedentary lifestyles, obesity, smoking, and T2DM are mediating factors in the causal relationship between educational attainment and kidney stones. Our results suggest more attention should be paid to these modifiable factors to prevent kidney stones.

Gut Microbiota and Tumor Immune Escape: A New Perspective for Improving Tumor Immunotherapy.

The gut microbiota is a large symbiotic community of anaerobic and facultative aerobic bacteria inhabiting the human intestinal tract, and its activities significantly affect human health. Increasing evidence has suggested that the gut microbiome plays an important role in tumor-related immune regulation. In the tumor microenvironment (TME), the gut microbiome and its metabolites affect the differentiation and function of immune cells regulating the immune evasion of tumors. The gut microbiome can indirectly influence individual responses to various classical tumor immunotherapies, including immune checkpoint inhibitor therapy and adoptive immunotherapy. Microbial regulation through antibiotics, prebiotics, and fecal microbiota transplantation (FMT) optimize the composition of the gut microbiome, improving the efficacy of immunotherapy and bringing a new perspective and hope for tumor treatment.

Transabdominal Laparoscopic Ureteroureterostomy With the Intraoperative Retrograde Ureteroscopy-Assisted Technique for Multiple Ureteral Polyps: A Single-Center 10 Years Experiences.

Background: The purpose of this study was to report our experience in treating multiple ureteral polyps with transabdominal laparoscopic ureteroureterostomy (LAP-UU) with intraoperative retrograde ureteroscopy (RU)-assisted technique. Methods: The data of 32 patients who underwent transabdominal LAP-UU with the intraoperative RU-assisted technique due to multiple ureteral polyps between January 2011 and March 2021 were reviewed at our institute. After administration of anesthesia, patients were placed in a passive position and underwent a three-port transabdominal laparoscopy with RU. Detailed data were reviewed, such as demographic characteristics, intraoperative outcomes, postoperative data, complications, and pathology reports. Results: Thirty-two patients were diagnosed with multiple ureteral polyps underwent this surgery method at our institution. The mean duration of symptoms at the time of diagnosis was approximately 7.1 months. The mean age of patients was 42.4 years, with men accounting for 68.8% (22/32), lesion of left for 56.3% (18/32), and the upper ureter for 62.5% (20/32). Furthermore, the median length of the polyps was 3.6 cm, the mean operative time was 174.6 min, and the estimated blood loss (EBL) was about 86.8 ml. The mean time to begin a liquid diet and to be out of bed were 1.7 and 2.3 days, respectively. The average length of hospital stay was 6.3 days. The ureteral stent was removed by cystoscope 2-3 months after surgery. Follow-up duration ranged from 3 to 112 months and none of the patients required another surgery for recurrence. Conclusion: Transabdominal LAP-UU combined with the intraoperative RU-assisted technique is an effective, safe, and reliable surgical option for patients with multiple ureteral polyps. Further long-term follow-up is recommended.

MicroRNA miR-4709-3p targets Large Tumor Suppressor Kinase 2 (LATS2) and induces obstructive renal fibrosis through Hippo signaling.

Obstructive renal fibrosis is the consequence of abnormal extracellular matrix assembly, which eventually results in renal failure, acute, and end­stage renal infection. MicroRNAs (miRNAs), a particular category of small RNAs, modulate the expression of genes post-transcriptionally and regulate biological activities, including fibrogenesis. The study probed to estimate the key functions of miR-4709-3p in obstructive renal fibrosis. This investigation used TGF-ß1 stimulated HK-2 in-vitro model, unilateral ureteral occlusion (UUO) mice model, and human Diabetic nephropathy (DN) and Renal interstitial fibrosis (RIF) specimens to depict the abundance of the miR-4709-3p level using FISH and RT-qPCR. MiR-4709-3p mimics and inhibitors were utilized to evaluate the functions of miR-4709-3p in-vitro. Luciferase assay was exploited to verify miR-4709-3p and LATS2 3'UTR binding. Finally, to depict the functions of miR-4709-3p in-vivo, the UUO model was injected with miR-4709-3p inhibitors. Results exhibited the upregulation of miR-4709-3p in UUO-induced in-vivo model, TGF-ß1 stimulated HK-2, and human RIF and DN samples. Moreover, it was determined that modulating miR-4709-3p regulated the level of fibrosis markers. Luciferase assay miR-4709-3p modulates renal fibrosis by targeting LATS2. Finally, it was found that miR-4709-3p regulates obstructive renal fibrosis through the Hippo signaling pathway. Overall, the study concludes that aberrant miR-4709-3p expression plays an essential function in the renal fibrosis progression, and miR-4709-3p overexpression could advance obstructive renal fibrosis via LATS2 targeting in Hippo signaling pathway. Therefore, miR-4709-3p inhibition may be a potential renal fibrosis therapy target.

α-Klotho released from HK-2 cells inhibits osteogenic differentiation of renal interstitial fibroblasts by inactivating the Wnt-ß-catenin pathway.

Randall's plaques (RP) are well established as precursor lesions of idiopathic calcium oxalate (CaOx) stones, and the process of biomineralization driven by osteogenic-like cells has been highlighted in RP formation, but the mechanism is poorly understood. Given the inhibitory role of α-Klotho (KL), an aging suppressor protein with high expression in kidneys, in ectopic calcification and the close association between KL gene polymorphisms and urolithiasis susceptibility, we determined the potential role of KL in RP formation. This study found that both soluble KL (s-KL) and transmembrane KL (m-KL) were downregulated, and that s-KL but not m-KL was inversely correlated with upregulation of osteogenic markers in RP tissues. Additionally, s-KL expression was markedly suppressed in human renal interstitial fibroblasts (hRIFs) and slightly suppressed in HK-2 cells after osteogenic induction, intriguingly, which was echoed to the greater osteogenic capability of hRIFs than HK-2 cells. Further investigations showed the inhibitory effect of s-KL on hRIF osteogenic differentiation in vitro and in vivo. Moreover, coculture with recombinant human KL (r-KL) or HK-2 cells suppressed osteogenic differentiation of hRIFs, and this effect was abolished by coculture with KL-silenced HK-2 cells or the ß-catenin agonist SKL2001. Mechanistically, s-KL inactivated the Wnt-ß-catenin pathway by directly binding to Wnt2 and upregulating SFRP1. Further investigations identified activation of the Wnt-ß-catenin pathway and downregulation of SFRP1 and DKK1 in RP tissues. In summary, this study identified s-KL deficiency as a pathological feature of RP and revealed that s-KL released from HK-2 cells inhibited osteogenic differentiation of hRIFs by inactivating the Wnt-ß-catenin pathway, not only providing in-depth insight into the role of s-KL in renal interstitial biomineralization but also shedding new light on the interaction of renal tubular epithelial cells with interstitial cells to clarify RP formation.

Liproxstatin-1 attenuates unilateral ureteral obstruction-induced renal fibrosis by inhibiting renal tubular epithelial cells ferroptosis.

Renal fibrosis is a common pathological process that occurs with diverse etiologies in chronic kidney disease. However, its regulatory mechanisms have not yet been fully elucidated. Ferroptosis is a form of non-apoptotic regulated cell death driven by iron-dependent lipid peroxidation. It is currently unknown whether ferroptosis is initiated during unilateral ureteral obstruction (UUO)-induced renal fibrosis and its role has not been determined. In this study, we demonstrated that ureteral obstruction induced ferroptosis in renal tubular epithelial cells (TECs) in vivo. The ferroptosis inhibitor liproxstatin-1 (Lip-1) reduced iron deposition, cell death, lipid peroxidation, and inhibited the downregulation of GPX4 expression induced by UUO, ultimately inhibiting ferroptosis in TECs. We found that Lip-1 significantly attenuated UUO-induced morphological and pathological changes and collagen deposition of renal fibrosis in mice. In addition, Lip-1 attenuated the expression of profibrotic factors in the UUO model. In vitro, we used RSL3 treatment and knocked down of GPX4 level by RNAi in HK2 cells to induce ferroptosis. Our results indicated HK2 cells secreted various profibrotic factors during ferroptosis. Lip-1 was able to inhibit ferroptosis and thereby inhibit the secretion of the profibrotic factors during the process. Incubation of kidney fibroblasts with culture medium from RSL3-induced HK2 cells promoted fibroblast proliferation and activation, whereas Lip-1 impeded the profibrotic effects. Our study found that Lip-1 may relieve renal fibrosis by inhibiting ferroptosis in TECs. Mechanistically, Lip-1 could reduce the activation of surrounding fibroblasts by inhibiting the paracrine of profibrotic factors in HK2 cells. Lip-1 may potentially be used as a therapeutic approach for the treatment of UUO-induced renal fibrosis.

Knockdown of lncRNA XIST inhibited apoptosis and inflammation in renal fibrosis via microRNA-19b-mediated downregulation of SOX6.

BACKGROUND: Kidney damage often develops into renal fibrosis. Apoptosis and inflammatory response are the main factors driving the process of renal fibrosis. Here we showed that lncRNA XIST/ miR-19b / SOX6 signal axis regulated apoptosis and inflammation of renal fibrosis. METHODS: HK-2 cells were treated with TGF-ß1 to construct cell fibrosis model, and UUO surgery was performed to construct mouse renal fibrosis model. The expression of XIST, miR-19b and SOX6 were examined by qPCR. And levels of fibrosis-related proteins were detected by western blotting. Levels of IL-1ß and TNF-α were assessed by qPCR and ELISA, respectively. Renal pathology and fibrosis were evaluated by HE and Masson staining. Flow cytometry and TUNEL staining were employed to evaluate cell apoptosis in cell fibrosis model and mouse renal fibrosis model, respectively. Besides, dual luciferase reporter assay was employed to verify whether XIST had a binding site to miR-19b, and whether miR-19b had a binding site to SOX6. RESULTS: Here we showed that XIST and SOX6 were upregulated in both HK-2 cells treatment of TGF-ß1 and kidneys of UUO mice, while miR-19b was downregulated. Dual luciferase reporter assay displayed that XIST directly bound to miR-19b, and SOX6 was the target of miR-19b. Knockdown of XIST inhibited apoptosis, inflammation and fibrosis in HK-2 cells treatment of TGF-ß1 via miR-19b-mediated downregulation of SOX6, while inhibition of miR-19b reversed the effect. Similarly, knockdown of XIST in vivo inhibited apoptosis, inflammation and fibrosis in kidneys of UUO mice via miR-19b-mediated downregulation of SOX6. DISCUSSION: These results provided evidence that knockdown of XIST inhibited apoptosis and inflammation of renal fibrosis via miR-19b-mediated downregulation of SOX6.

Comparison of modified hand-assisted retroperitoneoscopic laparoscopic nephrectomy and open nephrectomy in patients with benign inflammatory non-functioning kidney diseases.

BACKGROUND: To assess the validity and feasibility of the modified hand-assisted retroperitoneoscopic laparoscopic nephrectomy (MHARLN) in patients with benign inflammatory non-functioning kidney diseases. METHODS: We retrospectively compared the data of 223 patients who underwent an MHARLN (n=142) or an open nephrectomy (ON) (n=81) with benign inflammatory non-functioning diseases between January 2014 and October 2019 at our hospital. Patients' demographic data, perioperative outcomes, preoperative and postoperative inflammatory data, and postoperative complications were reviewed. RESULTS: The basic demographic data of patients were similar between the 2 groups. The mean operative times for the MHARLN and the ON were 135 and 143 minutes (P=0.181), respectively. The first time at which postoperative ambulation occurred, the visual analog pain scale (VAS) score before discharge and the postoperative complication rate were similar in both groups. However, compared to the MHARLN, the ON was associated with a more severe inflammatory response on the first day after surgery (P=0.045), higher estimated blood loss (309.8 vs. 139.6 mL; P=0.036), more peritoneal ruptures (19.8% vs. 9.2%; P=0.024), higher intraoperative transfusion (14.82% vs. 4.93%; P=0.011), higher VAS scores 24 hours after surgery (5.9 vs. 5.2; P=0.002), additional analgesic use (35.8% vs. 21.8%; P=0.024), and longer hospital stays (5.3 vs. 4.6 days; P=0.048). Before a liquid diet was commenced in the MHARLN and ON groups, the mean time was 1.2 and 1.5 days, respectively (P=0.004). CONCLUSIONS: When performed by a skilled laparoscopic surgeon, the use of the MHARLN in patients with benign inflammatory non-functioning kidney diseases is reliable and safe. The MHARLN may help to treat challenging cases and result in less trauma successfully.

Periprostatic fat thickness measured on MRI correlates with lower urinary tract symptoms, erectile function, and benign prostatic hyperplasia progression.

This study investigated the correlation between periprostatic fat thickness (PPFT) measured on magnetic resonance imaging and lower urinary tract symptoms, erectile function, and benign prostatic hyperplasia (BPH) progression. A total of 286 treatment-naive men diagnosed with BPH in our department between March 2017 and February 2019 were included. Patients were divided into two groups according to the median value of PPFT: high (PPFT >4.35 mm) PPFT group and low (PPFT <4.35 mm) PPFT group. After the initial evaluation, all patients received a combination drug treatment of tamsulosin and finasteride for 12 months. Of the 286 enrolled patients, 244 completed the drug treatment course. Patients with high PPFT had larger prostate volume (PV; P = 0.013), higher International Prostate Symptom Score (IPSS; P = 0.008), and lower five-item version of the International Index of Erectile Function (IIEF-5) score (P = 0.002) than those with low PPFT. Both high and low PPFT groups showed significant improvements in PV, maximum flow rate, IPSS, and quality of life score and a decrease of IIEF-5 score after the combination drug treatment. The decrease of IIEF-5 score was more obvious in the high PPFT group than that in the low PPFT group. In addition, more patients in the high PPFT group underwent prostate surgery than those in the low PPFT group. Moreover, Pearson's correlation coefficient analysis indicated that PPFT was positively correlated with age, PV, and IPSS and negatively correlated with IIEF-5 score; however, body mass index was only negatively correlated with IIEF-5 score.

Long non-coding RNA H19 promotes osteogenic differentiation of renal interstitial fibroblasts through Wnt-ß-catenin pathway.

Randall's plaque (RP) serves as a nidus on which idiopathic calcium oxalate stones form. Renal interstitial mineralization may be the cause underlying RP, and recent studies demonstrated the similarities between the interstitial mineralization and ectopic calcification. The present study aimed to investigate whether human renal interstitial fibroblasts (hRIFs) could form calcification under osteogenic conditions, and whether long non-coding RNA H19 participated in regulating osteogenic differentiation of hRIFs through Wnt-ß-catenin pathway. HRIFs were isolated and induced for osteogenic differentiation under osteogenic conditions. Runx2, OCN, alkaline phosphatase (ALP) activity, and the mineralized nodule formation were used to assess the osteogenic phenotype. Molecule expressions were determined by qRT-PCR, immunofluorescence staining, and western blot. The mineralized nodules were assessed by Alizarin red staining. Compared to the normal renal papillary tissue, Runx2, OCN, and H19 were significantly upregulated in RP. After hRIFs were induced with osteogenic medium, osteogenic markers (Runx2, OCN and ALP), ß-catenin and H19 were significantly upregulated, and the mineralized nodules are formed. Additionally, overexpression of H19 promoted the osteogenic phenotype of hRIFs and increased the expression of ß-catenin, whereas knock-down of H19 or XAV939 (inhibitor of Wnt-ß-catenin signaling pathway) significantly repressed the osteogenic phenotype of hRIFs and decreased the ß-catenin. Moreover, XAV939 was shown to abolish the osteogenic differentiation of hRIFs promoted by H19. The study demonstrated that ectopic calcification partly participated in the formation of RP, and H19 promoted osteogenic differentiation of hRIFs by activating Wnt-ß-catenin pathway, which shed new light on the molecular mechanism of the RP formation.

PTEN improve renal fibrosis in vitro and in vivo through inhibiting FAK/AKT signaling pathway.

Renal fibrosis, the ultimate common pathway of progressive nephropathy, is characterized by excess accumulation and deposition of extracellular matrix (ECM) within the renal interstitium and glomeruli, finally resulting in end-stage kidney failure. TGFß1 is not only abnormally increased during fibrosis but also involved in ECM induction and accumulation. Based on the bioinformative analyses, phosphatase and tensin homolog deleted on chromosome ten (PTEN) and focal adhesion kinase (FAK) signaling pathway might be involved in TGFß1 functions on renal fibrosis development. In the present study, fibrosis was induced in HK-2 cells using TGFß1 and PTEN expression was significantly suppressed by 24 or 48 hours TGFß1 treatment. PTEN overexpression in HK-2 cells improved TGFß1-induced fibrosis within α-SMA and E-cadherin. According to the KEGG signaling pathway annotation analyses on microarray profiles (GSE23338 and GSE20247) and immunoblotting validation, FAK signaling might be involved in PTEN functions in TGFß1-induced fibrosis. PTEN overexpression significantly inhibited TGFß1- or unilateral ureteral obstruction (UUO)-induced FAK signaling pathway activation both in vitro and in vivo; more importantly, PTEN silence enhanced TGFß1- or UUO-induced fibrosis, while FAK inhibitor PF567721 significantly reversed the effects of PTEN silence, indicating that PTEN exerted its effects on TGFß1- and UUO-induced fibrotic development in vitro and in vivo via inhibiting FAK signaling pathway. In summary, these findings indicate that PTEN could improve cellular fibrotic changes and renal fibrosis via inhibiting FAK/AKT signaling pathway. Restoring PTEN expression to target FAK/AKT signaling pathway might be a potent strategy for renal fibrosis treatment.

Dihydroartemisinin attenuates renal fibrosis through regulation of fibroblast proliferation and differentiation.

AIMS: Renal fibrosis is the most common final stage of progressive renal disease, characterized by fibroblast proliferation, fibroblast-to-myofibroblast differentiation and excessive accumulation of extracellular matrix. Dihydroartemisinin (DHA) exerts antitumor, antibacterial, and antifibrotic effects. The aim of this study was to determine whether DHA has beneficial effects on unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice and to examine explore the underlying possible mechanisms. MATERIALS AND METHODS: Eight-week-old male C57BL/6 mice were intragastrically administered DHA for 14 consecutive days after UUO operation. Afterward, interstitial collagen deposition, expression of collagen I and III, fibronectin, α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), and S100 calcium-binding protein A4 (S100A4) were assessed in the kidneys. Transforming growth factor beta 1 (TGF-ß1)-induced primary human kidney fibroblasts were treated with DHA to further investigate the mechanism underlying its action. KEY FINDINGS: In vivo, DHA reduced UUO-induced morphological and pathological changes and the degree of renal fibrosis. In addition, DHA mitigated fibroblast proliferation and differentiation in kidney tissue induced by UUO. In vitro, DHA significantly attenuated the TGF-ß1-induced primary human kidney fibroblast proliferation and fibroblast-to-myofibroblast differentiation. Moreover, treatment with DHA attenuated the up-regulation of phosphorylation of phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT) in UUO model and TGF-ß1-induced primary human kidney fibroblasts. SIGNIFICANCE: We provide in vivo and in vitro evidence that DHA may relieve renal fibrosis through regulation of fibroblast proliferation and differentiation by mitigating the PI3K/AKT pathway. DHA may potentially be used as a therapeutic antifibrotic agent for the treatment of renal fibrosis.

Klotho gene polymorphisms are associated with healthy aging and longevity: Evidence from a meta-analysis.

Klotho gene polymorphisms have been implicated in healthy aging, but inconsistences in findings from previous case-control studies have raised concerns regarding the associations between KLOTHO gene polymorphisms and susceptibility to aging-related diseases and longevity. Hence, this meta-analysis was performed. We assessed the associations between two polymorphisms (G-395 A/rs1207568 and F352 V/rs9536314) and five parameters (urolithiasis, cognitive impairment, cardiovascular disease, cancer, and longevity) by calculating pooled odds ratios with 95% confidence intervals. According to the pooled results, the G allele of the G-395 A polymorphism conferred a significantly higher risk of urolithiasis; G-395 A was related to the susceptibility to cardiovascular disease under allele, dominant, and recessive models. There was no significant association between the G-395 A polymorphism and cognitive impairment among the elderly. The F allele of the F352 V polymorphism protected against breast and ovarian cancer susceptibility. Interestingly, based on the results of the subgroup analysis, the F352 V polymorphism was associated with the overall risk of neoplasms in BRCA1 mutation carriers but not in BRCA2 mutation carriers. Moreover, the F allele played a protective role in determining human longevity. In conclusion, Klotho G-395 A polymorphisms were associated with urolithiasis and cardiovascular disease but not with cognitive impairment. Additionally, Klotho F352 V polymorphisms were associated with cancers and longevity.

Effects of tumor necrosis factor-α polymorphism on the brain structural changes of the patients with major depressive disorder.

Single Nucleotide Polymorphic (SNP) variations of proinflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α) have been reported to be closely associated with the major depressive disorder (MDD). However, it is unclear if proinflammatory genetic burden adversely affects the regional gray matter volume in patients with MDD. The aim of this study was to test whether rs1799724, an SNP of TNF-α, contributes to the neuroanatomical changes in MDD. In this cross-sectional study, a total of 144 MDD patients and 111 healthy controls (HC) well matched for age, sex and education were recruited from Shanghai Mental Health Center. Voxel-based morphometry (VBM) followed by graph theory based structural covariance analysis was applied to locate diagnosis x genotype interactions. Irrespective of diagnosis, individuals with the high-risk genotype (T-carriers) had reduced volume in left angular gyrus (main effect of genotype). Diagnosis x genotype interaction was exclusively localized to the visual cortex (right superior occipital gyrus). The same region also showed reduced volume in patients with MDD than HC (main effect of diagnosis), with this effect being most pronounced in patients carrying the high-risk genotype. However, neither global nor regional network of structural covariance was found to have group difference. In conclusion, a genetic variation which can increase TNF-α expression selectively affects the anatomy of the visual cortex among the depressed subjects, with no effect on the topographical organization of multiple cortical regions. This supports the notion that anatomical changes in depression are in part influenced by the genetic determinants of inflammatory activity.