Efficacy of hyaluronic acid in the treatment of nasal inflammatory diseases: a systematic review and meta-analysis.

Background: Hyaluronic acid (HA), the main component of the extracellular matrix, has the ability to promote tissue repair and regulate inflammation. It is used in otolaryngology as an adjuvant treatment to alleviate postoperative nasal symptoms. However, there is currently insufficient evidence demonstrating the therapeutic efficacy of HA for patients with nasal inflammatory diseases (NIDs). Therefore, this study aimed to evaluate the efficacy and safety of topical HA in the treatment of NID patients without receiving surgery. Methods: In this meta-analysis, comprehensive searches were conducted in PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science. Keywords searched included "hyaluronic acid," "sinusitis," "allergic rhinitis," "rhinitis," and "randomized controlled trials (RCTs)." The Cochrane Collaboration's "Risk of Bias Assessment" tool was used to assess the quality of the included trials, and the meta-analysis was performed using the RevMan 5.3 and STATA 15 statistical software. Results: A total of 11 articles and 825 participants were enrolled. For the primary outcomes, the pooled results revealed that HA significantly improves nasal obstruction (SMD, -0.53; 95% CI, -0.92 to -0.14; p = 0.008; and I2 = 79%) and rhinorrhea (SMD, -0.71; 95% CI, -1.27 to -0.15; p = 0.01; and I2 = 90%) in patients with NIDs. As for the secondary outcomes, the pooled results demonstrated that when compared with the control group, HA could significantly improve nasal endoscopic scores (p < 0.05), rhinitis scores (p < 0.05), rhinomanometry (p < 0.05), nasal neutrophils (p < 0.05), and mucociliary clearance (p < 0.05). However, no significant differences were observed between the two groups regarding nasal itching, sneezing, hyposmia, quality-of-life scores, and nasal eosinophils. For the risk of bias, 54.5% and 45.5% of trials had a low risk of bias in the randomization process and deviation of the intended intervention, respectively. Conclusion: In the present study, the results reveal that HA might ameliorate symptoms of patients with NIDs. However, more clinical trials with larger participant cohorts are required to confirm this result. Systematic review registration number: clinicaltrials.gov, identifier CRD42023414539.

Unleashing the power of complement activation: unraveling renal damage in human anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (GBM) disease is a rare but life-threatening autoimmune disorder characterized by rapidly progressive glomerulonephritis with or without pulmonary hemorrhage. Renal biopsies of anti-GBM patients predominantly show linear deposition of IgG and complement component 3 (C3), indicating a close association between antigen-antibody reactions and subsequent complement activation in the pathogenesis of the disease. All three major pathways of complement activation, including the classical, lectin, and alternative pathways, are involved in human anti-GBM disease. Several complement factors, such as C3, C5b-9, and factor B, show a positive correlation with the severity of the renal injury and act as risk factors for renal outcomes. Furthermore, compared to patients with single positivity for anti-GBM antibodies, individuals who are double-seropositive for anti-neutrophil cytoplasmic antibody (ANCA) and anti-GBM antibodies exhibit a unique clinical phenotype that lies between ANCA-associated vasculitis (AAV) and anti-GBM disease. Complement activation may serve as a potential "bridge" for triggering both AAV and anti-GBM conditions. The aim of this article is to provide a comprehensive review of the latest clinical evidence regarding the role of complement activation in anti-GBM disease. Furthermore, potential therapeutic strategies targeting complement components and associated precautions are discussed, to establish a theoretical basis for complement-targeted therapies.

Protective effects of ginsenosides in cisplatin-induced kidney injury: A systematic review, meta-analysis.

Although evidence suggests ginsenosides, the primary active and distinctive components of ginseng, have beneficial effects in cisplatin-induced nephrotoxicity, their efficacy and protective mechanisms remain unclear. The aim of the current meta-analysis is to study the effectiveness and mechanisms of ginsenosides in a model of nephrotoxicity induced by cisplatin. Preclinical investigations were conducted in the search of various databases including Medline, Web of Science, Google, CNKI, Embase, and the Wanfang database. 12 studies with 216 animals were included in this review. Stata 15.0 and RevMan 5.3 were used for statistical analyses. The pooled results showed that ginsenosides significantly improved kidney function, and inhibited histological damage. The protective mechanism of ginsenosides is associated with its antioxidative stress, anti-inflammation, anti-apoptosis, and anti-autophagy. The results of our study indicate that ginsenosides have the potential to mitigate nephrotoxicity induced by cisplatin through the modulation of various targets and pathways. Consequently, ginsenosides hold promise as therapeutic agents for the clinical management and prevention of cisplatin-induced nephrotoxicity.

The levels of bone turnover markers and parathyroid hormone and their relationship in chronic kidney disease.

BACKGROUND: Chronic kidney disease-mineral bone disease (CKD-MBD) is a major complication of CKD. Bone turnover markers (BTMs) are important for clinicians to evaluate and manage patients with CKD-MBD. This study aimed to assess BTMs in patients with CKD and their correlation with parathyroid hormone (PTH) and other clinical characteristics of CKD. METHODS: A total of 408 subjects were included in this study. The serum BTMs including N-terminal midfragment osteocalcin (N-MID OC), ß-isomerized C-terminal telopeptides (ß-CTX), and total procollagen type 1 amino-terminal propeptide (tPINP) were measured. Spearman correlation and multiple stepwise regression models were used to investigate the association of N-MID OC, ß-CTX, and tPINP with the clinical characteristics of CKD patients. RESULTS: BTMs was no significant difference between non-CKD and CKD stages 1, 2, and 3. However, N-MID OC, ß-CTX were significantly increased in patients with CKD stage 4 compared to non-CKD patients and patients with CKD stages 1, 2, and 3. Compared with non-dialysis dependent (NDD)-CKD stage 5, BTMs were significantly higher in dialysis patients. The estimated glomerular filtration rate was negatively associated with N-MID OC (r = -0.479, P < 0.001), ß-CTX (r = -0.474, P < 0.001), and tPINP (r = -0.375, P < 0.001). Multiple analysis showed that N-MID OC (ß = 0.67, P < 0.001), ß-CTX (ß = 0.64, P < 0.001), and tPINP (ß = 0.81, P < 0.001) were independently associated with PTH. CKD patients with secondary hyperparathyroidism (SHPT) have higher ß-CTX (P < 0.05), and N-MID OC (P < 0.05) than patients with non-SHPT. CONCLUSIONS: BTMs in advanced CKD stages were significantly higher than in the early disease stages. PTH level was independently and positively associated with the BTM levels in patients with CKD. In the advanced stage of CKD, ß-CTX and N-MID OC levels were significantly higher in those with SHPT than those with non-SHPT.

Dipeptidyl-peptidase-4 inhibitors have anti-inflammatory effects in patients with type 2 diabetes.

AIMS: Systematic low-grade inflammation is considered to be an important factor leading to the development of T2DM and the progression of its complications. Dipeptidyl-peptidase-4 (DPP-4) inhibitors show potential anti-inflammatory effects in patients with T2DM. This meta-analysis aimed to evaluate the anti-inflammatory effects of DPP-4 inhibitors in patients with T2DM. METHODS: A comprehensive search was performed in PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials to identify randomized controlled trials that assess the anti-inflammatory effects of DPP-4 inhibitors. Quantitative data analysis was conducted by a random-effects model. Sensitivity analyses were conducted to determine the robustness of the pooled results. RESULTS: Twenty-two studies with 1595 patients with T2DM were included. Pooled results showed that DPP-4 inhibitor therapy was significantly associated with the reduction of C-reactive protein (CRP) (SMD, - 0.56, p < 0.01), TNF-α (SMD, - 1.69, p < 0.01), IL-6 (SMD, - 0.67, p < 0.01), and IL-1ß (WMD, - 8.21 pg/ml, p < 0.01). Leave-one-out meta-analysis showed no significant change in the pooled results of CRP and TNF-α. CONCLUSION: This meta-analysis demonstrated that DPP-4 inhibitors can significantly attenuate low-grade inflammatory state in patients with T2DM. In addition to improving glycemic control, DDP-4 inhibitors might offer extra therapeutic value by controlling inflammation.

Biopsy-proven granulomatous interstitial nephritis associated with vancomycin in an adult patient: a case report.

Acute kidney injury (AKI) caused by vancomycin mainly manifests as acute interstitial nephritis or acute tubular necrosis. Here, the rare case of a 71-year-old female patient with no history of kidney disease, who was diagnosed with granulomatous interstitial nephritis associated with vancomycin, is reported. The patient had been treated with vancomycin for over a month for an abscess in her right thigh. She presented to the emergency department with a history of fever, scattered rash, oliguria and elevated serum creatinine for >10 days. After hospitalization, the vancomycin trough concentration was confirmed to be >50 µg/ml. The patient received furosemide and continuous renal replacement therapy for AKI, teicoplanin and piperacillin/tazobactam for pulmonary infection, and urapidil, sodium nitroprusside and nifedipine for elevated blood pressure. Percutaneous ultrasound-guided kidney biopsy was performed. Light microscopy revealed granuloma formation, and diffuse infiltration of lymphocytes, monocytes, eosinophils, and some multinucleated giant cells. Finally, the patient was diagnosed with vancomycin-induced granulomatous interstitial nephritis and was treated with high-flux haemodialysis and 16 mg oral methylprednisolone, daily, for 3 weeks, which contributed to a significant recovery of renal function. This case suggests the need for regular vancomycin concentration testing during treatment. When AKI due to vancomycin occurs, a renal biopsy may be performed to help diagnose and treat the condition.

Renal Medullary Overexpression of Sphingosine-1-Phosphate Receptor 1 Transgene Attenuates Deoxycorticosterone Acetate (DOCA)-Salt Hypertension.

BACKGROUND: Our previous studies showed that renal medullary sphingosine-1-phosphate receptor 1 (S1PR1) mediated sodium excretion, high salt intake increased S1PR1 level, deoxycorticosterone acetate (DOCA) blocked high salt-induced S1PR1 in the renal medulla, and that conditional knockout of S1PR1 in the collecting duct aggravated DOCA-salt hypertension. The present study tested the hypothesis that overexpression of S1PR1 transgene in the renal medulla attenuates the sodium retention and hypertension in DOCA-salt mouse model. METHODS: Male C57BL/6J mice received renal medullary transfection of control or S1PR1-expressing plasmids and then DOCA-salt treatment. Renal sodium excretion and arterial pressure were compared between control and S1PR1-overexpressed mice in response to high salt loading or pressure natriuresis. RESULTS: S1PR1-transfected mice showed significantly enhanced urinary sodium excretion in response to acute sodium loading (0.93 ± 0.27 in control vs. 4.72 ± 1.12 µmol/min/gKW in S1PR1-overexpressed mice, P < 0.05) and the pressure natriuresis (3.58 ± 1.77 vs. 9.52 ± 1.38, P < 0.05), less positive sodium balance in response to chronic high-salt intake (3.05 ± 0.39 vs. 1.65 ± 0.39 mmol/72 hr, P < 0.05), and consequently, the attenuation of DOCA-salt hypertension (134.2 ± 6.79 vs. 109.8 ± 3.54 mm Hg, P < 0.05). The αENaC protein amount in the renal medulla was not changed, however, the ßENaC was significantly decreased and the γENaC was significantly increased in S1PR1-overexpressed mice. The immunostaining showed apical membrane translocation of γENaC, while no change of αENaC and ßENaC in control mice, and that the apical membrane translocation of γENaC was blocked in S1PR1-treasffected mice. CONCLUSIONS: These results suggested that activation of S1PR1 in the renal medulla attenuates DOCA-induced sodium retention and salt-sensitive hypertension associated with inhibition of ENaC.

Emodin prevents renal ischemia-reperfusion injury via suppression of p53-mediated cell apoptosis based on network pharmacology.

Background: Previous evidence indicated that emodin has significant advantages for preventing acute kidney injury (AKI). However, the mechanisms responsible for these effects of emodin have yet to be elucidated. Methods: We first used network pharmacology and molecular docking to identify the core targets of emodin for AKI and performed a range of experiments to validate this result. Pretreatment with emodin for 7 days, the rats were treated with bilateral renal artery clipping for 45 min to identify the prevention effect. Hypoxia/reoxygenation (H/R), and vancomycin - induced renal tubular epithelial cells (HK-2 cells) were treated with emodin to explore the related molecular mechanism. Results: Network pharmacology and molecular docking showed that anti-apoptosis might be the core mechanism responsible for the action of emodin on AKI; this anti-apoptotic effect appears to because by regulation p53-related signaling pathway. Our data showed that pretreatment with emodin significantly improved renal function and renal tubular injury in renal I/R model rats (P < 0.05. The prevention effect of emodin was proved to be related to anti - apoptosis of HK-2 cells, possibly by downregulating the levels of p53, cleaved-caspase-3, pro-caspase-9, and upregulated the levels of Bcl-2. The efficacy and mechanism of emodin on anti - apoptosis was also confirmed in vancomycin - induced HK-2 cells. Meanwhile, the data also showed that emodin promoted angiogenesis in I/R damaged kidneys and H/R-induced HK-2 cells, which was associated with decreasing HIF-1α levels and increasing VEGF levels. Conclusions: Our findings indicated that the preventive effect of emodin on AKI is probably attributable to anti-apoptosis response and promoting angiogenesis effect.

Effects of vitamin D on inflammatory state in patients with chronic kidney disease: A controversial issue.

BACKGROUND: The anti-inflammatory effect of vitamin D in patients with chronic kidney disease (CKD) remains controversial. This study aimed to conduct a meta-analysis of randomized controlled trials to assess the anti-inflammatory effects of vitamin D in patients with CKD. METHODS: We searched Embase, Science Citation Index, Medline, Cochrane Central Register of Controlled Trials, and Clinical Trial Registries for randomized controlled trials that comparing vitamin D with control groups for inflammatory markers in patients with CKD. Subgroup analysis was performed based on treatment duration (short-term treatment, long-term treatment), type of patients (predialysis CKD, dialysis, kidney transplant), 25(OH)D levels (25(OH)D deficiency or normal 25(OH)D), and methods of C-reactive protein (CRP) test (standard CRP test or high-sensitivity CRP [hs-CRP] test). RESULTS: Eighteen trials with 1834 patients were included in the present study. There were no significant differences between the vitamin D group and control group for CRP (WMD, -0.3 mg/L; 95% CI, -0.81 to 0.22, p = 0.26, I2  = 62%), interleukin-6 (IL-6) (WMD, -1.07 pg/ml; 95% CI, -2.44 to 0.30, p = 0.12, I2  = 52%), and tumor necrosis factor-α (TNF-α) (WMD, -0.00 pg/ml; 95% CI, -0.36 to 0.35, p = 0.99, I2  = 0%) in patients with CKD. Subgroup analysis showed vitamin D can improve hs-CRP, but not CRP. The rest of subgroups showed that no significant differences were observed between the vitamin D group and control group based on 25(OH)D levels, treatment duration, and predialysis CKD or dialysis patients. CONCLUSION: This meta-analysis demonstrates that vitamin D supplementation does not have anti-inflammatory effects in CKD patients. Well-designed randomized controlled trials with large samples are required to confirm this conclusion. It is still needed to find an effective treatment for inflammatory state in CKD.

Statins Have an Anti-Inflammation in CKD Patients: A Meta-Analysis of Randomized Trials.

Background: Persistent inflammation has been recognized as an important comorbid condition in patients with chronic kidney disease (CKD) and is associated with many complications, mortality, and progression of CKD. Previous studies have not drawn a clear conclusion about the anti-inflammatory effects of statins in CKD. This meta-analysis is aimed at assessing the anti-inflammatory effects of statins therapy in patients with CKD. Methods: A comprehensive literature search was conducted in these databases (Medline, Embase, Cochrane library, and clinical trials) to identify the randomized controlled trials that assess the anti-inflammatory effects of statins. Subgroup, sensitivity, and trim-and-fill analysis were conducted to determine the robustness of pooled results of the primary outcome. Results: 25 eligible studies with 7921 participants were included in this meta-analysis. The present study showed that statins therapy was associated with a decreased C-reactive protein (CRP) (-2.06 mg/L; 95% CI: -2.85 to -1.27, p < 0.01). Subgroup, sensitivity, and trim-and-fill analysis showed that the pooled results of CPR were stable. Conclusion: This meta-analysis demonstrates that statins supplementation has anti-inflammatory effects in patients with CKD. Statins exert an anti-inflammatory effect that is clinically important in improving complications, reducing mortality, and slowing progression in CKD. We believe that the benefits of statins to CKD are partly due to their anti-inflammatory effects. However, stains usually are prescribed in the CKD patients with dyslipidemia, whether statins can reduce inflammation in CKD patients with normal serum lipid needed to explore in the future. Therefore, we suggest that randomized clinical trials need to assess the effect of statins in CKD patients with normal serum lipid. Whether statins can be prescribed for aiming to inhibit inflammation in CKD also needed further study. Trial Registration. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO); registration number: CRD42022310334.

Association of Exercise With Vascular Function in Patients With CKD: A Meta-Analysis of Randomized Controlled Trials.

Background and Aim: Vascular function is associated with an increased risk of cardiovascular events in patients with chronic kidney disease (CKD). Whether exercise improves vascular function in such patients remains controversial. This study aimed to conduct a meta-analysis on the effect of exercise training on the vascular function of patients with CKD. Methods: Embase, the Cochrane Central Register of Controlled Trials, and Medline were searched from inception until November 15, 2021. The terms exercise, CKD, dialysis, kidney transplant, and randomized controlled trial (RCT) were searched alone or in combination. RCTs were included when studies compared exercise with active control, usual care, or no intervention, and the studies reported vascular function on patients with CKD. Results: This meta-analysis included 18 RCTs with 817 patients. Exercise training was significantly associated with decreased pulse wave velocity weighted mean difference (WMD), -0.56; 95% confidence interval (CI), -1.02 to -0.09, P = 0.02 and augmentation index (WMD, -3.26; 95% CI, -5.46 to -1.05, P = 0.004). It was also significantly associated with improved peak VO2 (WMD, 2.64; 95% CI, 1.94-3.35, P < 0.00001), general health (WMD, 7.03; 95% CI, 0.65-13.42, P = 0.03), and vitality (WMD, 9.1; 95% CI, 2.50-15.69, P = 0.007). Conclusions: The meta-analysis suggested that exercise training improved vascular function in patients with CKD. An exercise program should be considered as one of the management strategies for vascular dysfunction in patients with CKD. Further studies are needed to demonstrate that exercise training improves cardiovascular diseases in patients with CKD.

Nephrotoxicity in cancer treatment: An update.

It has been estimated that nearly 80% of anticancer drug-treated patients receive potentially nephrotoxic drugs, while the kidneys play a central role in the excretion of anticancer drugs. Nephrotoxicity has long been a serious complication that hampers the effectiveness of cancer treatment and continues to influence both mortality and length of hospitalization among cancer patients exposed to either conventional cytotoxic agents or targeted therapies. Kidney injury arising from anticancer drugs tends to be associated with preexisting comorbidities, advanced cancer stage, and the use of concomitant non-chemotherapeutic nephrotoxic drugs. Despite the prevalence and impact of kidney injury on therapeutic outcomes, the field is sorely lacking in an understanding of the mechanisms driving cancer drug-induced renal pathophysiology, resulting in quite limited and largely ineffective management of anticancer drug-induced nephrotoxicity. Consequently, there is a clear imperative for understanding the basis for nephrotoxic manifestations of anticancer agents for the successful management of kidney injury by these drugs. This article provides an overview of current preclinical research on the nephrotoxicity of cancer treatments and highlights prospective approaches to mitigate cancer therapy-related renal toxicity.

Loss of sphingosine kinase 2 protects against cisplatin-induced kidney injury.

Cisplatin is an established chemotherapeutic drug for treatment of solid-organ cancers and is the primary drug used in the treatment of head and neck cancer; however, cisplatin-induced nephrotoxicity largely limits its clinical use. Inhibition of sphingosine kinase 2 (SphK2) has been demonstrated to alleviate various kidney diseases. Therefore, we hypothesized that inhibition of SphK2 could also protect against cisplatin-induced nephrotoxicity. Results from the present study showed that the SphK2 inhibitor ABC294640 or knockdown of SphK2 by siRNA blocked the cisplatin-induced increase of cellular injury markers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and cleaved caspase-3) by Western blot analysis in HK-2 cells, a human renal tubular cell line. In addition, SphK2 inhibition blocked cisplatin-induced activation of NF-κB by Western blot analysis and immunostaining analysis. Furthermore, SphK2 inhibition suppressed cisplatin-induced increases of proinflammatory markers (NLR family pyrin domain containing 3, interleukin-1ß, and interleukin-6). Genetic deletion of the SphK2 gene in mice further confirmed that inhibition of SphK2 protected against cisplatin-induced kidney damage in vivo. Compared with wild-type mice, SphK2 knockout mice exhibited less renal dysfunction and reduced promotion of kidney injury markers, inflammatory factors, tubular morphology damage, and fibrotic staining. At the same time, the SphK2 inhibitor ABC294640 failed to interfere with the activity of cisplatin or radiation in two cell culture models of head and neck cancer. It is concluded that inhibition of Sphk2 protects against cisplatin-induced kidney injury. SphK2 may be used as a potential therapeutic target for the prevention or treatment of cisplatin-induced kidney injury.NEW & NOTEWORTHY The present study provides new findings that sphingosine kinase 2 (SphK2) is highly expressed in renal tubules, cisplatin treatment increases the expression of SphK2 in proximal tubular cells and kidneys, and inhibition of SphK2 alleviates cisplatin-induced kidney injury by suppressing the activation of NF-κB, production of inflammatory factors, and apoptosis. SphK2 may serve as a potential therapeutic target for the prevention or treatment of cisplatin-induced nephrotoxicity.

Inactivation of fatty acid amide hydrolase protects against ischemic reperfusion injury-induced renal fibrogenesis.

Although cannabinoid receptors (CB) are recognized as targets for renal fibrosis, the roles of endogenous cannabinoid anandamide (AEA) and its primary hydrolytic enzyme, fatty acid amide hydrolase (FAAH), in renal fibrogenesis remain unclear. The present study used a mouse model of post-ischemia-reperfusion renal injury (PIR) to test the hypothesis that FAAH participates in the renal fibrogenesis. Our results demonstrated that PIR showed upregulated expression of FAAH in renal proximal tubules, accompanied with decreased AEA levels in kidneys. Faah knockout mice recovered the reduced AEA levels and ameliorated PIR-triggered increases in blood urea nitrogen, plasma creatinine as well as renal profibrogenic markers and injuries. Correspondingly, a selective FAAH inhibitor, PF-04457845, inhibited the transforming growth factor-beta 1 (TGF-ß1)-induced profibrogenic markers in human proximal tubular cell line (HK-2 cells) and mouse primary cultured tubular cells. Knockdown of FAAH by siRNA in HK-2 cells had similar effects as PF-04457845. Tubular cells isolated from Faah-/- mice further validated the protection against TGF-ß1-induced damages. The CB 1 or CB2 receptor antagonist and exogenous FAAH metabolite arachidonic acid failed to reverse the protective effects of FAAH inactivation in HK-2 cells. However, a substrate-selective inhibitor of AEA-cyclooxygenase-2 (COX-2) pathway significantly suppressed the anti-profibrogenic actions of FAAH inhibition. Further, the AEA-COX-2 metabolite, prostamide E2 exerted anti-fibrogenesis effect. These findings suggest that FAAH activation and the consequent reduction of AEA contribute to the renal fibrogenesis, and that FAAH inhibition protects against fibrogenesis in renal cells independently of CB receptors via the AEA-COX-2 pathway by the recovery of reduced AEA.

Kidney-Targeted Delivery of Prolyl Hydroxylase Domain Protein 2 Small Interfering RNA with Nanoparticles Alleviated Renal Ischemia/Reperfusion Injury.

Inhibition of hypoxia-inducible factor-prolyl hydroxylase (PHD) has been shown to protect against various kidney diseases. However, there are controversial reports on the effect of PHD inhibition in renoprotection. The present study determined whether delivery of PHD2 small interfering RNA (siRNA) using an siRNA carrier, folic acid (FA)-decorated polyamidoamine dendrimer generation 5 (G5-FA), would mainly target kidneys and protect against renal ischemia/reperfusion injury (I/R). The renal I/R was generated by clipping the renal pedicle for 30 minutes in uninephrectomized mice. Mice were sacrificed 48 hours after I/R. Normal saline or G5-FA complexed with control or PHD2 siRNA was injected via tail vein 24 hours before ischemia. After the injection of near-infrared fluorescent dye-labeled G5-FA, the fluorescence was mainly detected in kidneys but not in other organs. The reduction of PHD2 mRNA and protein was only observed in kidneys but not in other organs after injection of PHD2-siRNA-G5-FA complex. The injection of PHD2-siRNA-G5-FA significantly alleviated renal I/R injury, as shown by the inhibition of increases in serum creatinine and blood urea nitrogen, the blockade of increases in kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, and the improvement of histologic damage compared with mice treated with control siRNA. PHD2 siRNA can be delivered specifically into kidneys using G5-FA, and that local knockdown of PHD2 gene expression within the kidney alleviates renal I/R injury. Therefore, G5-FA is an efficient siRNA carrier to deliver siRNA into the kidney, and that local inhibition of PHD2 within the kidney may be a potential strategy for the management of acute I/R injury. SIGNIFICANCE STATEMENT: Folic acid (FA)-decorated polyamidoamine dendrimer generation 5 (G5-FA) was demonstrated to be an effective carrier to deliver small interfering RNA (siRNA) into kidneys. Delivery of prolyl hydroxylase domain protein 2 siRNA with G5-FA effectively protected the kidneys against the acute renal ischemia/reperfusion injury.

Collecting duct-specific knockout of sphingosine-1-phosphate receptor 1 aggravates DOCA-salt hypertension in mice.

OBJECTIVE: We have previously reported that renal medullary sphingosine-1-phosphate (S1P) regulates sodium excretion via the S1P type-1 receptor (S1PR1). As S1PR1 is predominantly expressed in collecting ducts (CD), the present study tested the hypothesis that the CD-S1PR1 pathway plays a critical role in sodium excretion and contributes to salt-sensitive hypertension. METHODS: CD-specific S1PR1 knockout mice were generated by crossing aquaporin-2-Cre mice with S1PR1-floxed mice. Renal sodium excretion and arterial pressure were compared between wild type and KO mice in response to high-salt challenges and treatment of deoxycorticosterone acetate (DOCA) salt. RESULTS: Protein levels of renal medullary S1PR1 were increased by 100% after high-salt intake, whereas DOCA treatment with high-salt intake blocked the increase of S1PR1 levels. Urinary sodium excretions in knockout mice were decreased by 60% compared with wild type mice after acute intravenous sodium loading (0.84 ±â€Š0.16 vs. 2.22 ±â€Š0.62 µmole/min per g kwt). The pressure natriuresis was impaired in knockout mice compared with wild type mice (4.32 ±â€Š1.04 vs. 8.73 ±â€Š0.19 µmole/min per g kwt). The chronic high-salt intake-induced positive sodium balance was enhanced in knockout mice compared with wild type mice (5.27 ±â€Š0.39 vs. 2.38 ±â€Š1.04 mmol/100 g BW per 24 h). After 10-day DOCA-salt treatment, knockout mice developed more severe hypertension than wild type mice (SBP 142 ±â€Š8 vs. 115 ±â€Š4 mmHg). CONCLUSION: The deletion of CD-S1PR1 reduced sodium excretion, promoted sodium retention, and accelerated DOCA-salt-induced salt-sensitive hypertension, suggesting that the CD-S1PR1 signaling is an important antihypertensive pathway by promoting sodium excretion and that impairment of renal medullary S1PR1 may represent a novel mechanism for salt-sensitive hypertension.

The Mechanisms of the Herbal Components of CRSAS on HK-2 Cells in a Hypoxia/Reoxygenation Model Based on Network Pharmacology.

BACKGROUND: Acute kidney injury is a global problem, which brings a great burden to the society and family. The component of rhubarb, Salvia miltiorrhiza, Astragalus membranaceus, and safflower (CRSAS) has been proved as an useful agent to treat acute kidney injury (AKI) patients in China. OBJECTIVE: To assess the effect of CRSAS on human renal tubular epithelial cells (HK-2) after the hypoxia/reoxygenation (H/R) and investigate the potential mechanisms. METHODS: Network pharmacology was used to predict the potential pathways shared by CRSAS and AKI. Cell counting kit-8 (CCK-8) was used to assess the HK-2 vitality. Apoptosis of HK-2 cells was detected by carboxyfluorescein succinimidyl ester/propidium iodide (CFSF/PI) staining. Expression of GRP78, CHOP, caspase-3, and Bax was detected by western blot and quantitative real-time RT-PCR. RESULT: CRSAS and AKI shared the endoplasmic reticulum stress (ERS) pathway based on network pharmacology analysis. CRSAS increases the vitality of HK-2 cells and reduces the apoptosis of HK-2 cells induced by H/R injury. The expression of GRP78 and CHOP in CRSAS groups was lower than that of control groups. CONCLUSIONS: H/R can induce HK-2 cell apoptosis and ERS. CRSAS can reduce HK-2 cell apoptosis by inhibiting the ERS. Therefore, CRSAS might be able to treat kidney disease due to I/R injury. Animal experiment should be done to further prove our finding.

The efficacy and safety of ciclesonide for the treatment of perennial allergic rhinitis: a systematic review and meta-analysis / Eficácia e segurança da ciclesonida no tratamento da rinite alérgica perene: uma revisão sistemática e metanálise

Abstract Introduction: Allergic rhinitis is a chronic inflammatory disease which affects 1 out of 6 individuals. Perennial allergic rhinitis accounts for 40% of AR cases. Ciclesonide is one of the relatively new intranasal steroid for allergic rhinitis. Objective: The purpose of this study was to evaluate the efficacy and safety of ciclesonide in the treatment of perennial allergic rhinitis. Methods: We searched Pubmed, Scientific Citation Index, Embase, Clinical Trial Registries for randomized controlled trials and Cochrane Central Register of Controlled Trials to find out the randomized controlled Trial comparing ciclesonide with placebo for PAR. Results: Eight studies were included. In comparison with placebo groups, ciclesonide groups significantly decreased Reflective Total Nasal Symptom Score (MD = −0.56; 95% CI −0.72 to 0.39, p < 0.00001) with heterogeneity (p = 0.19, I2 = 24%), Instantaneous Total Nasal Symptom Score (MD = −0.57; 95% CI −0.75 to −0.39, p < 0.00001) with heterogeneity (p = 0.34, I2 = 11%). A significant effect for Reflective Nasal Symptom Score Subtotal (MD = −0.15; 95% CI −0.18 to −0.13, p < 0.00001) with heterogeneity (p = 0.12, I2 = 24%) was also demonstrated. Rhinoconjunctivitis quality of life questionnaire score (RQLQs) (MD = −0.27; 95% CI −0.39 to −0.15, p < 0.00001) with heterogeneity (p = 0.58, I 2 = 0%) in the treatment of ciclesonide was also significantly reduced. In addition, the difference in Treatment-Emergent Adverse Events between the two groups was not significant. Conclusion: Ciclesonide can improve perennial allergic rhinitis without increasing adverse events. Ciclesonide may be another valuable choice for perennial allergic rhinitis in the future.

Resumo Introdução: A rinite alérgica é uma doença inflamatória crônica que afeta um a cada seis indivíduos. A rinite alérgica perene é responsável por 40% dos casos de rinite alérgica. A ciclesonida é um dos corticosteroides intranasais mais novos para o tratamento dessa condição clínica. Objetivo: Avaliar a eficácia e segurança da ciclesonida no tratamento da rinite alérgica perene. Método: Uma busca foi feita nos bancos de dados Pubmed, Scientific Citation Index, Embase e Clinical Trial Registries por ensaios clínicos randomizados e Cochrane Central Register of Controlled Trials por estudos controlados randomizados que comparassem ciclesonida com placebo no tratamento da rinite alérgica perene. Resultados: Oito estudos foram incluídos. Em comparação com os grupos placebo, os grupos ciclesonida mostraram diminuição significante no escore do Reflective Total Nasal Symptom Score (DM = −0,56; IC 95%: −0,72 a −0,39, p < 0,00001) com heterogeneidade (p = 0,19, I2 = 24%), do Instantaneous Total Nasal Symptom Score (DM = −0,57; IC95%: −0,75 a −0,39, p < 0,00001) com heterogeneidade (p = 0,34, I2 = 11%). Um efeito significante no escore do Reflective Nasal Symptom Score Subtotal (DM = −0,15; IC 95%: −0,18 a −0,13, p < 0,00001) com heterogeneidade (p = 0,12, I2 = 24%) também foi demonstrado. O escore do Rhinoconjunctivitis Quality of Life Questionnaire score (RQLQs) (DM = −0,27; IC 95%: −0,39 a −0,15, p < 0,00001) com heterogeneidade (p = 0,58, I2 = 0%) também foi significantemente reduzido no tratamento com ciclesonida. Além disso, a diferença em relação aos eventos adversos emergentes do tratamento entre os dois grupos não foi significante. Conclusão: A ciclesonida pode melhorar a rinite alérgica perene sem aumentar os eventos adversos. Esse fármaco pode ser outra opção valiosa para a rinite alérgica perene no futuro.

Vitamin D supplementation for the improvement of vascular function in patients with chronic kidney disease: a meta-analysis of randomized controlled trials.

BACKGROUND: The efficacy of vitamin D on vascular function remains controversial in chronic kidney disease (CKD) patients. The aim of the present work was to perform a meta-analysis of randomized controlled trials to evaluate the efficacy of vitamin D on vascular function in CKD patients. METHODS: We searched Medline, the Cochrane Central Register of Controlled Trials, Embase, the Science Citation Index, and clinical trial registries for randomized controlled trials comparing vitamin D with a placebo in CKD patients. RESULTS: We included seven trials. For flow-mediated dilation (FMD), there was no significant difference between the two groups (WMD 1.66%; 95% CI - 0.2 to 3.51, p = 0.08; with significant heterogeneity, p < 0.0001, I2 = 89%). We conducted a subgroup analysis. In the cholecalciferol group, compared with the placebo group, cholecalciferol significantly increased FMD (WMD 5.49%; 95% CI 4.36-6.62, p < 0.0001). In the 2 ug paricalcitol group, compared with the placebo group, paricalcitol significantly increased FMD (WMD 2.09%; 95% CI 1.28-2.9, p < 0.0001; without significant heterogeneity, p = 0.47, I2 = 0%). In the 1 ug paricalcitol group, there was no significant difference between the two groups. For pulse wave velocity (PWV), vitamin D significantly decreased PWV compared with the placebo (WMD - 0.93 m/s; 95% CI - 1.71 to - 0.15, p = 0.02; without significant heterogeneity, p = 0.14, I2 = 45%). For calcium (Ca) and parathyroid hormone (PTH), there was a significant difference between the vitamin D group and the placebo group. For 25-hydroxyvitamin D [25(OH)D], there was a significant difference between the inactive vitamin D group and the placebo group. For phosphorus (P), systolic blood pressure (SBP), and diastolic blood pressure (DBP), there were no significant differences between the two groups. CONCLUSIONS: We speculate that vitamin D might be able to improve vascular function in CKD patients. The effect of vitamin D might be associated with its doses and earlier stages of the disease might respond better to vitamin D. Furthermore, trials with larger populations and longer durations are needed in order to provide more reliable evidence.

The efficacy and safety of ciclesonide for the treatment of perennial allergic rhinitis: a systematic review and meta-analysis.

INTRODUCTION: Allergic rhinitis is a chronic inflammatory disease which affects 1 out of 6 individuals. Perennial allergic rhinitis accounts for 40% of AR cases. Ciclesonide is one of the relatively new intranasal steroid for allergic rhinitis. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of ciclesonide in the treatment of perennial allergic rhinitis. METHODS: We searched Pubmed, Scientific Citation Index, Embase, Clinical Trial Registries for randomized controlled trials and Cochrane Central Register of Controlled Trials to find out the randomized controlled Trial comparing ciclesonide with placebo for PAR. RESULTS: Eight studies were included. In comparison with placebo groups, ciclesonide groups significantly decreased Reflective Total Nasal Symptom Score (MD=-0.56; 95% CI -0.72 to 0.39, p<0.00001) with heterogeneity (p=0.19, I2=24%), Instantaneous Total Nasal Symptom Score (MD=-0.57; 95% CI -0.75 to -0.39, p<0.00001) with heterogeneity (p=0.34, I2=11%). A significant effect for Reflective Nasal Symptom Score Subtotal (MD=-0.15; 95% CI -0.18 to -0.13, p<0.00001) with heterogeneity (p=0.12, I2=24%) was also demonstrated. Rhinoconjunctivitis quality of life questionnaire score (RQLQs) (MD=-0.27; 95% CI -0.39 to -0.15, p<0.00001) with heterogeneity (p=0.58, I2=0%) in the treatment of ciclesonide was also significantly reduced. In addition, the difference in Treatment-Emergent Adverse Events between the two groups was not significant. CONCLUSION: Ciclesonide can improve perennial allergic rhinitis without increasing adverse events. Ciclesonide may be another valuable choice for perennial allergic rhinitis in the future.