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Parkinson's disease (PD) is characterized by the accumulation of misfolded α-synuclein protein and the loss of dopaminergic neurons in the substantia nigra. Abnormal α-synuclein aggregates form toxic Lewy bodies, ultimately inducing neuronal injury. Mitochondrial dysfunction was reported to be involved in the neurotoxicity of α-synuclein aggregates in PD. However, the specific mechanism by which abnormal α-synuclein aggregates cause mitochondrial disorders remains poorly defined. Previously, we found that cofilin-1, a member of the actin-binding protein, regulates α-synuclein pathogenicity by promoting its aggregation and spreading in vitro and in vivo. In this study, we further investigated the effect of cofilin-1 on α-synuclein induced mitochondrial damage. We discovered that α-synuclein aggregates accelerate the translocation of cofilin-1 to mitochondria, promote its combination with the mitochondrial outer membrane receptor Tom 20, and ultimately activate the oxidative damage and apoptosis pathway in mitochondria. All these results demonstrate the important regulatory role of cofilin-1 in the mitochondrial neurotoxicity of pathological α-synuclein during the progression of PD.

BackgroundDue to cosmetic disfigurement, melasma can negatively affect the quality of life and emotional and mental health, further leading to depression.ObjectivePrevalence rates of depression in patients with melasma vary widely across studies. The aim of this systematic review and meta-analysis was to estimate the prevalence of depression among melasma patients.MethodsThe PubMed, Embase, Web of Science, and Scopus databases were searched to identify articles evaluating the prevalence of depression in melasma patients from their inception to 12 July 2023. Studies were reviewed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and a meta-analysis was performed using the Stata 14.0 software.ResultsSixteen studies met the eligibility criteria out of the 859 studies, containing a total of 2,963 melasma patients for this systematic review and meta-analysis. Meta-analyses revealed that the pooled prevalence of depression among patients with melasma was 43.4% (95% CI 30.5–56.2%, Q-value = 808.859, d.f. = 15, p

Objective: To investigate the safety and efficacy of selective intraarterial hypothermia combined with mechanical thrombectomy in the treatment of acute cerebral infarction based on microcatheter technology. Methods: A total of 142 patients with anterior circulation large vessel occlusion were randomly assigned to the hypothermic treatment group (test group) and the conventional treatment group (control group). National Institutes of Health Stroke Scale (NIHSS) scores, postoperative infarct volume, the 90-day good prognosis rate (modified Rankin Scale (mRS) score =2 points), and the mortality rate of the two groups were compared and analyzed. Blood specimens were collected from patients before and after treatment. Serum levels of superoxide dismutase (SOD), malondialdehyde (MDA), interleukin-6 (IL-6), IL-10, and RNA-binding motif protein 3 (RBM3) were measured. Results: The 7-day postoperative cerebral infarct volume [(63.7 ± 22.1) ml vs. (88.5 ± 20.8) ml] and NIHSS scores at postoperative Days 1, 7, and 14 [(6.8 ± 3.8) points vs. (8.2 ± 3.5) points; (2.6 ± 1.6) points vs. (4.0 ± 1.8) points; (2.0 ± 1.2) points vs. (3.5 ± 2.1) points] in the test group were significantly lower than those in the control group. The good prognosis rate at 90 days postoperatively (54.9 vs. 35.2%, P = 0.018) was significantly higher in the test group than in the control group. The 90-day mortality rate was not statistically significant (7.0 vs. 8.5%, P=0.754). Immediately after surgery and 1 day after surgery, SOD, IL-10, and RBM3 levels in the test group were relatively higher than those in the control group, and the differences were statistically significant. Immediately after surgery and 1 day after surgery, MDA and IL-6 levels in the test group were relatively reduced compared with those in the control group, and the differences were statistically significant (P < 0.05). In the test group, RBM3 was positively correlated with SOD and IL-10. Conclusion: Mechanical thrombectomy combined with intraarterial cold saline perfusion is a safe and effectivemeasure for the treatment of acute cerebral infarction. Postoperative NIHSS scores and infarct volumes were significantly improved with this strategy compared with simple mechanical thrombectomy, and the 90-day good prognosis rate was improved. The mechanism by which this treatment exerts its cerebral protective effect may be by inhibiting the transformation of the ischaemic penumbra of the infarct core area, scavenging some oxygen free radicals, reducing inflammatory injury to cells after acute infarction and ischaemia-reperfusion, and promoting RBM3 production in cells. [ABSTRACT FROM AUTHOR]

ObjectiveTo investigate the safety and efficacy of selective intraarterial hypothermia combined with mechanical thrombectomy in the treatment of acute cerebral infarction based on microcatheter technology.MethodsA total of 142 patients with anterior circulation large vessel occlusion were randomly assigned to the hypothermic treatment group (test group) and the conventional treatment group (control group). National Institutes of Health Stroke Scale (NIHSS) scores, postoperative infarct volume, the 90-day good prognosis rate (modified Rankin Scale (mRS) score ≤ 2 points), and the mortality rate of the two groups were compared and analyzed. Blood specimens were collected from patients before and after treatment. Serum levels of superoxide dismutase (SOD), malondialdehyde (MDA), interleukin-6 (IL-6), IL-10, and RNA-binding motif protein 3 (RBM3) were measured.ResultsThe 7-day postoperative cerebral infarct volume [(63.7 ± 22.1) ml vs. (88.5 ± 20.8) ml] and NIHSS scores at postoperative Days 1, 7, and 14 [(6.8 ± 3.8) points vs. (8.2 ± 3.5) points; (2.6 ± 1.6) points vs. (4.0 ± 1.8) points; (2.0 ± 1.2) points vs. (3.5 ± 2.1) points] in the test group were significantly lower than those in the control group. The good prognosis rate at 90 days postoperatively (54.9 vs. 35.2%, P = 0.018) was significantly higher in the test group than in the control group. The 90-day mortality rate was not statistically significant (7.0 vs. 8.5%, P = 0.754). Immediately after surgery and 1 day after surgery, SOD, IL-10, and RBM3 levels in the test group were relatively higher than those in the control group, and the differences were statistically significant. Immediately after surgery and 1 day after surgery, MDA and IL-6 levels in the test group were relatively reduced compared with those in the control group, and the differences were statistically significant (P < 0.05). In the test group, RBM3 was positively correlated with SOD and IL-10.ConclusionMechanical thrombectomy combined with intraarterial cold saline perfusion is a safe and effective measure for the treatment of acute cerebral infarction. Postoperative NIHSS scores and infarct volumes were significantly improved with this strategy compared with simple mechanical thrombectomy, and the 90-day good prognosis rate was improved. The mechanism by which this treatment exerts its cerebral protective effect may be by inhibiting the transformation of the ischaemic penumbra of the infarct core area, scavenging some oxygen free radicals, reducing inflammatory injury to cells after acute infarction and ischaemia–reperfusion, and promoting RBM3 production in cells.

Although the role of hypoxia has been greatly explored and unveiled in glioblastoma (GBM), the mechanism of hypoxia-related long non-coding (lnc) RNAs has not been clearly understood. This study aims to reveal the crosstalk among hypoxia-related lncRNAs, tumor microenvironment (TME), and tumorigenesis for GBM. Gene expression profiles of GBM patients were used as a basis for identifying hypoxia-related lncRNAs. Unsupervised consensus clustering was conducted for classifying samples into different molecular subtypes. Gene set enrichment analysis (GSEA) was performed to analyze the enrichment of a series of genes or gene signatures. Three molecular subtypes were constructed based on eight identified hypoxia-related lncRNAs. Oncogenic pathways, such as epithelial mesenchymal transition (EMT), tumor necrosis factor-α (TNF-α) signaling, angiogenesis, hypoxia, P53 signaling, and glycolysis pathways, were significantly enriched in C1 subtype with poor overall survival. C1 subtype showed high immune infiltration and high expression of immune checkpoints. Furthermore, we identified 10 transcription factors (TFs) that were highly correlated with lncRNA-FAM66C. Three key lncRNAs (ADAMTS9-AS2, LINC00968, and LUCAT1) were screened as prognostic biomarkers for GBM. This study shed light on the important role of hypoxia-related lncRNAs for TME modulation and tumorigenesis in GBM. The eight identified hypoxia-related lncRNAs, especially FAM66C may serve as key regulators involving in hypoxia-related pathways.

BackgroundThe long-term outcomes of acute large vessel occlusion (LVO) in anterior circulation treated by endovascular treatment (EVT) remains to be determined. The aim of this study was to assess the 5-year outcomes of patients with LVO who underwent EVT.MethodsThis study was an observational, nationwide registry of consecutive patients with acute LVO who received EVT in 28 comprehensive stroke centers in China. The primary outcome was the proportion of favorable outcome [modified Rankin Scale score (mRS) 0–2] at 5 years. Secondary outcomes included proportions of patients with excellent outcome (mRS 0–1), all-cause mortality and risk of stroke recurrence at 5 years.ResultsA total of 807 patients were included into the study and had 90-day follow-up data, 657 patients had 5-year follow-up data. At 90 days, 218 patients (27.0%) had an excellent outcome, 349 patients (43.2%) had a favorable functional outcome. 199 patients (24.7%) died. At 5 years, 190 patients (28.9%) had an excellent outcome, 261 patients (39.7%) had a favorable functional outcome, 317 patients (48.2%) died and 129 (28.2%) had stroke recurrence. Because of missing 5-year follow-up data, among available 269 patients who achieved functional independence at 90 days, 208 (77.3%) maintained favorable outcome, 19 (7.1%) had disability (mRS 3–5) and 42 (15.6%) died at 5 years. Furthermore, among available 189 patients with mRS 3–5 at 90 days, 53 (28.0%) patients achieved favorable functional outcome, 60 (31.7%) patients maintained unfavorable functional outcome and 76 (40.2%) patients died within 5 years. Multivariate analyses identified that younger age [odds ratio (OR): 0.96; 95% CI, 0.93–0.99; P = 0.009], lower mRS at 90 days (OR: 0.15; 95% CI, 0.10–0.23; P < 0.001) and absence of stroke recurrence (OR: 0.001; 95% CI, 0.000–0.006; P < 0.001) were significantly associated with favorable outcome at 5 years. Advanced age (OR: 1.06, 95% CI, 1.04–1.08; P < 0.001), higher mRS at 90 days (OR: 0.84; 95% CI, 0.73–0.98; P = 0.021) and atrial fibrillation (OR: 1.63; 95% CI, 1.02–2.60; P = 0.04) were independent factors for stroke recurrence.ConclusionOur results indicated that the beneficial effect of EVT in patients with acute LVO can be sustained during the course of at least 5 years. Reducing the risk of stroke recurrence by anticoagulation for atrial fibrillation may be a crucial strategy to improve long-term outcome.

Identifying structural elements in long and complex RNAs, such as long non-coding and RNA viruses, can shed light on the functionality and mechanisms of such RNAs. Here we present RNAvigator, a tool able to identify elements of structural importance by using experimental SHAPE data or SHAPE-like predictions in conjunction with stability and entropy assessments. RNAvigator recognizes regions that are the most stable, unambiguous, and structured on RNA molecules, and thus potentially functional. When relying on predictions, RNAvigator uses the CROSS algorithm, a neural network trained on experimental data that achieved an AUC of 0.74 on hepatitis C virus SHAPE-MaP data and which was able to improve the predictive power of Superfold. By using RNAvigator, we can identify known functional regions on the complete hepatitis C virus genome, including the regulatory regions CRE and IRES, and the 3’ UTR of dengue virus, a region known for the presence of structural elements essential for its replication, and functional regions of long non-coding RNAs such as XIST and HOTAIR. We envision that RNAvigator will be a useful tool for studying long and complex RNA molecules using known chemical probing data or, if they are not available, by employing predicted profiles.

Background: Recently, chronic kidney disease (CKD)-mineral and bone disorder (MBD) has become one of common complications occurring in CKD patients. Therefore, development of a new treatment for CKD-MBD is very important in the clinic. In China, Fucoidan (FPS), a natural compound of Laminaria japonica has been frequently used to improve renal dysfunction in CKD. However, it remains elusive whether FPS can ameliorate CKD-MBD. FGF23-Klotho signaling axis is reported to be useful for regulating mineral and bone metabolic disorder in CKD-MBD. This study thereby aimed to clarify therapeutic effects of FPS in the CKD-MBD model rats and its underlying mechanisms in vivo and in vitro, compared to Calcitriol (CTR). Methods: All male rats were divided into four groups: Sham, CKD-MBD, FPS and CTR. The CKD-MBD rat models were induced by adenine administration and uninephrectomy, and received either FPS or CTR or vehicle after induction of renal injury for 21 days. The changes in parameters related to renal dysfunction and renal tubulointerstitial damage, calcium-phosphorus metabolic disorder and bone lesion were analyzed, respectively. Furthermore, at sacrifice, the kidneys and bone were isolated for histomorphometry, immunohistochemistry and Western blot. In vitro, the murine NRK-52E cells were used to investigate regulative actions of FPS or CTR on FGF23-Klotho signaling axis, ERK1/2-SGK1-NHERF-1-NaPi-2a pathway and Klotho deficiency. Results: Using the modified CKD-MBD rat model and the cultured NRK-52E cells, we indicated that FPS and CTR alleviated renal dysfunction and renal tubulointerstitial damage, improved calcium-phosphorus metabolic disorder and bone lesion, and regulated FGF23-Klotho signaling axis and ERK1/2-SGK1-NHERF-1-NaPi-2a pathway in the kidney. In addition, using the shRNA-Klotho plasmid-transfected cells, we also detected, FPS accurately activated ERK1/2-SGK1-NHERF-1-NaPi-2a pathway through Klotho loss reversal. Conclusion: In this study, we emphatically demonstrated that FPS, a natural anti-renal dysfunction drug, similar to CTR, improves renal injury-related calcium-phosphorus metabolic disorder and bone abnormality in the CKD-MBD model rats. More importantly, we firstly found that beneficial effects in vivo and in vitro of FPS on phosphorus reabsorption are closely associated with regulation of FGF23-Klotho signaling axis and ERK1/2-SGK1-NHERF-1-NaPi-2a pathway in the kidney. This study provided pharmacological evidences that FPS directly contributes to the treatment of CKD-MBD. [ABSTRACT FROM AUTHOR]

Background: Fucoidan (FPS) has been widely used to treat renal fibrosis (RF) in patients with diabetic kidney disease (DKD); however, the precise therapeutic mechanisms remain unclear. Recently, research focusing on inflammation-derived podocyte pyroptosis in DKD has attracted increasing attention. This phenomenon is mediated by the activation of the nucleotide-binding oligomerization domain (Nod)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, leading to RF during DKD progression. Therefore, we designed a series of experiments to investigate the ameliorative effects of FPS on RF in DKD and the mechanisms that are responsible for its effect on NLRP3 inflammasome-mediated podocyte pyroptosis in the diabetic kidney.Methods: The modified DKD rat models were subjected to uninephrectomy, intraperitoneal injection of streptozotocin, and a high-fat diet. Following induction of renal injury, the animals received either FPS, rapamycin (RAP), or a vehicle for 4 weeks. For in vitro research, we exposed murine podocytes to high glucose and MCC950, an NLRP3 inflammasome inhibitor, with or without FPS or RAP. Changes in the parameters related to RF and inflammatory podocyte injury were analyzed in vivo. Changes in podocyte pyroptosis, NLRP3 inflammasome activation, and activation of the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1)/NLRP3 signaling axis involved in these changes were analyzed in vivo and in vitro.Results: FPS and RAP ameliorated RF and inflammatory podocyte injury in the DKD model rats. Moreover, FPS and RAP attenuated podocyte pyroptosis, inhibited NLRP3 inflammasome activation, and regulated the AMPK/mTORC1/NLRP3 signaling axis in vivo and in vitro. Notably, our data showed that the regulative effects of FPS, both in vivo and in vitro, on the key signaling molecules, such as p-AMPK and p-raptor, in the AMPK/mTORC1/NLRP3 signaling axis were superior to those of RAP, but similar to those of metformin, an AMPK agonist, in vitro.Conclusion: We confirmed that FPS, similar to RAP, can alleviate RF in DKD by inhibiting NLRP3 inflammasome-mediated podocyte pyroptosis via regulation of the AMPK/mTORC1/NLRP3 signaling axis in the diabetic kidney. Our findings provide an in-depth understanding of the pathogenesis of RF, which will aid in identifying precise targets that can be used for DKD treatment.

Gut microbiota is a complex aggregation of microbial organisms, which offers diverse protective benefits to the host. Dysbiosis of intestinal microbiota is frequently associated with many diseases. Vitamin D3 (VD), which was originally associated with bone health, also possesses antimicrobial activities and can act through antimicrobial peptide. Cathelicidin is a type of antimicrobial peptide in host to maintain the balance of gut microbiome. Our current study sought to evaluate the protective effect of VD and cathelicidin in mice intestines by administration of VD or mCRAMP-encoding L. lactis. We herein provided a comprehensive profile of the impact of VD and mCRAMP on gut microbiota using 16S rRNA sequencing, followed by bioinformatics and statistical analysis. Our results revealed an increased richness of bacterial community in mice intestines due to VD administration. Moreover, we showed a beneficial effect of VD and mCRAMP by enhancing the colonization of bacterial taxa that are associated with protective effects to the host but repressing the propagation of bacterial taxa that are associated with harmful effects to the host. Various metabolic pathways related to amino acid and lipid metabolism were affected in this process. We further established a bacterial panel as a reliable biomarker to evaluate the efficacy of remodeling the mice gut microbiota by VD and mCRAMP administration. The uncovered effects will deepen the comprehension about the antibacterial mechanisms of VD and mCRAMP and provide new insights for therapeutic implication of them.

BackgroundSquamous cell cancers in the hypopharynx (HP) and cervical esophagus (CE) are different diseases with different staging systems and treatment approaches. Pharyngoesophageal junction (PEJ) tumor involves both the hypopharynx and the cervical esophagus simultaneously, but few reports focused on PEJ tumors. This study aimed to clarify clinical characteristics and the treatment approaches of PEJ tumors.Patients and MethodsA total of 222 patients with squamous cell carcinoma in the HP, PEJ, and CE were collected between January 2008 and June 2018 in Fudan University Shanghai Cancer Center. We compared different lymph node metastatic patterns of three diseases above and the survival of different tumor locations, different lymph node metastasis, and different radiotherapy approaches.ResultsFor HP, PEJ, and CE cancer, the upper and middle cervical lymph node metastatic rates were 85.7%, 47.1%, and 5.8%, respectively; the lower cervical lymph node metastatic rates were 36.7%, 42.9%, and 35.0%, respectively; and the mediastinal lymph node metastatic rates were 2.0%, 72.9%, and 80.6%, respectively. The 3-year overall survival rates were 69.5% in the HP group, 52.0% in the PEJ group, and 69.6% in the CE group (p = 0.024). No survival differences were found between the involved-field-irradiation and elective-node-irradiation subgroups among PEJ tumors (p = 0.717 for OS and p = 0.454 for PFS, respectively).ConclusionHP cancers had a high prevalence in all cervical lymph node metastases, while CE cancers had a lower prevalence in the cervical and mediastinal lymph node metastases. PEJ cancer had the combined metastatic patterns of both HP and CE cancers. Involved field irradiation was feasible in chemoradiotherapy for PEJ cancers.

Background: The proximal renal tubule plays a critical role in diabetic kidney disease (DKD) progression. Early glomerular disease in DKD triggers a cascade of injuries resulting in renal tubulointerstitial disease. These pathophysiological responses are collectively described as diabetic tubulopathy (DT). Thus, therapeutic strategies targeting DT hold significant promise for early DKD treatment. Shenkang injection (SKI) has been widely used to treat renal tubulointerstitial fibrosis in patients with chronic kidney disease in China. However, it is still unknown whether SKI can alleviate DT. We designed a series of experiments to investigate the beneficial effects of SKI in DT and the mechanisms that are responsible for its effect on epithelial-to-mesenchymal transition (EMT) and endoplasmic reticulum (ER) stress-induced apoptosis in DT.Methods: The modified DKD rat models were induced by uni-nephrectomy, streptozotocin intraperitoneal injection, and a high-fat diet. Following the induction of renal injury, these animals received either SKI, rosiglitazone (ROS), or vehicle, for 42 days. For in vitro research, we exposed NRK-52E cells to high glucose (HG) and 4-phenylbutyric acid (4-PBA) with or without SKI or ROS. Changes in parameters related to renal tubular injury and EMT were analyzed in vivo. Changes in the proportion of apoptotic renal tubular cells and ER stress, and the signaling pathways involved in these changes, were analyzed both in vivo and in vitro.Results: SKI and ROS improved the general condition, the renal morphological appearance and the key biochemical parameters, and attenuated renal injury and EMT in the rat model of DKD. In addition, SKI and ROS alleviated apoptosis, inhibited ER stress, and suppressed PERK-eIF2α-ATF4-CHOP signaling pathway activation both in vivo and in vitro. Notably, our data showed that the regulatory in vitro effects of SKI on PERK-eIF2α-ATF4-CHOP signaling were similar to those of 4-PBA, a specific inhibitor of ER stress.Conclusion: This study confirmed that SKI can alleviate DT in a similar manner as ROS, and SKI achieves this effect by inhibiting EMT and ER stress-induced apoptosis. Our findings thereby provide novel information relating to the clinical value of SKI in the treatment of DT.

Background: The total flavones of Abelmoschus manihot (TFA), a compound that is extracted from Abelmoschus manihot, has been widely used in China to reduce podocyte injury in diabetic kidney disease (DKD). However, the mechanisms underlying the therapeutic action of this compound have yet to be elucidated. Podocyte pyroptosis is characterized by activation of the NLRP3 inflammasome and plays an important role in inflammation-mediated diabetic kidneys. Regulation of the PTEN/PI3K/Akt pathway is an effective strategy for improving podocyte damage in DKD. Previous research has also shown that N6-methyladenosine (m6A) modification is involved in DKD and that m6A-modified PTEN regulates the PI3K/Akt pathway. In this study, we investigated whether TFA alleviates podocyte pyroptosis and injury by targeting m6A modification-mediated NLRP3-inflammasome activation and PTEN/PI3K/Akt signaling.Methods: We used MPC-5 cells under high glucose (HG) conditions to investigate the key molecules that are involved in podocyte pyroptosis and injury, including activation of the NLRP3 inflammasome and the PTEN/PI3K/Akt pathway. We detected alterations in the levels of three methyltransferases that are involved in m6A modification. We also investigated changes in the levels of these key molecules in podocytes with the overexpression or knockdown of methyltransferase-like (METTL)3.Results: Analysis showed that TFA and MCC950 protected podocytes against HG-induced pyroptosis and injury by reducing the protein expression levels of gasdermin D, interleukin-1β, and interleukin-18, and by increasing the protein expression levels of nephrin, ZO-1, WT1 and podocalyxin. TFA and 740Y-P inhibited activation of the NLRP3 inflammasome via the PI3K/Akt pathway by inhibiting the protein levels of NIMA-related kinase7, NLRP3, ASC, and caspase-1, and by increasing the protein expression levels of p-PI3K and p-Akt. TFA improved pyroptosis and injury in HG-stimulated podocytes by regulating METTL3-dependent m6A modification.Conclusion: Collectively, our data indicated that TFA could ameliorate pyroptosis and injury in podocytes under HG conditions by adjusting METTL3-dependent m6A modification and regulating NLRP3-inflammasome activation and PTEN/PI3K/Akt signaling. This study provides a better understanding of how TFA can protect podocytes in DKD.

Oxidative stress caused by an imbalance between the production and elimination of reactive metabolites and free radicals can lead to the development of a variety of diseases. Over the past years, with the development of science and technology, circular RNA (circRNA) has been found to be closely associated with oxidative stress, which plays an important role in the process of oxidative stress. Currently, the understanding of circRNAs in the mechanism of oxidative stress is limited. In this review, we described the relationship between oxidative stress and circRNAs, the circRNAs related to oxidative stress, and the role of circRNAs in promoting or inhibiting the occurrence and development of diseases associated with the oxidative stress system.

Background: Recently, chronic kidney disease (CKD)-mineral and bone disorder (MBD) has become one of common complications occurring in CKD patients. Therefore, development of a new treatment for CKD–MBD is very important in the clinic. In China, Fucoidan (FPS), a natural compound of Laminaria japonica has been frequently used to improve renal dysfunction in CKD. However, it remains elusive whether FPS can ameliorate CKD–MBD. FGF23-Klotho signaling axis is reported to be useful for regulating mineral and bone metabolic disorder in CKD–MBD. This study thereby aimed to clarify therapeutic effects of FPS in the CKD–MBD model rats and its underlying mechanisms in vivo and in vitro, compared to Calcitriol (CTR).Methods: All male rats were divided into four groups: Sham, CKD–MBD, FPS and CTR. The CKD–MBD rat models were induced by adenine administration and uninephrectomy, and received either FPS or CTR or vehicle after induction of renal injury for 21 days. The changes in parameters related to renal dysfunction and renal tubulointerstitial damage, calcium-phosphorus metabolic disorder and bone lesion were analyzed, respectively. Furthermore, at sacrifice, the kidneys and bone were isolated for histomorphometry, immunohistochemistry and Western blot. In vitro, the murine NRK-52E cells were used to investigate regulative actions of FPS or CTR on FGF23-Klotho signaling axis, ERK1/2-SGK1-NHERF-1-NaPi-2a pathway and Klotho deficiency.Results: Using the modified CKD–MBD rat model and the cultured NRK-52E cells, we indicated that FPS and CTR alleviated renal dysfunction and renal tubulointerstitial damage, improved calcium-phosphorus metabolic disorder and bone lesion, and regulated FGF23-Klotho signaling axis and ERK1/2-SGK1-NHERF-1-NaPi-2a pathway in the kidney. In addition, using the shRNA-Klotho plasmid-transfected cells, we also detected, FPS accurately activated ERK1/2-SGK1-NHERF-1-NaPi-2a pathway through Klotho loss reversal.Conclusion: In this study, we emphatically demonstrated that FPS, a natural anti-renal dysfunction drug, similar to CTR, improves renal injury-related calcium-phosphorus metabolic disorder and bone abnormality in the CKD–MBD model rats. More importantly, we firstly found that beneficial effects in vivo and in vitro of FPS on phosphorus reabsorption are closely associated with regulation of FGF23-Klotho signaling axis and ERK1/2-SGK1-NHERF-1-NaPi-2a pathway in the kidney. This study provided pharmacological evidences that FPS directly contributes to the treatment of CKD–MBD.

BackgroundRecently, progression of chronic renal failure (CRF) has been closely associated with gut microbiota dysbiosis and intestinal metabolite-derived microinflammation. In China, total flavones of Abelmoschus manihot (TFA), a component of Abelmoschus manihot, has been widely used to delay CRF progression in clinics for the past two decades. However, the overall therapeutic mechanisms remain obscure. In this study, we designed experiments to investigate the renoprotective effects of TFA in CRF progression and its underlying mechanisms involved in gut microbiota and microinflammation, compared with febuxostat (FEB), a potent non-purine selective inhibitor of xanthine oxidase.MethodsIn vivo, the CRF rat models were induced by uninephrectomy, potassium oxonate, and proinflammatory diet, and received either TFA suspension, FEB, or vehicle after modeling for 28 days. In vitro, the RAW 264.7 cells were exposed to lipopolysaccharide (LPS) with or without TFA or FEB. Changes in parameters related to renal injury, gut microbiota dysbiosis, gut-derived metabolites, and microinflammation were analyzed in vivo. Changes in macrophage polarization and autophagy and its related signaling were analyzed both in vivo and in vitro.ResultsFor the modified CRF model rats, the administration of TFA and FEB improved renal injury, including renal dysfunction and renal tubulointerstitial lesions; remodeled gut microbiota dysbiosis, including decreased Bacteroidales and Lactobacillales and increased Erysipelotrichales; regulated gut-derived metabolites, including d-amino acid oxidase, serine racemase, d-serine, and l-serine; inhibited microinflammation, including interleukin 1β (IL1β), tumor necrosis factor-α, and nuclear factor-κB; and modulated macrophage polarization, including markers of M1/M2 macrophages. More importantly, TFA and FEB reversed the expression of beclin1 (BECN1) and phosphorylation of p62 protein and light chain 3 (LC3) conversion in the kidneys by activating the adenosine monophosphate-activated protein kinase-sirtuin 1 (AMPK-SIRT1) signaling. Further, TFA and FEB have similar effects on macrophage polarization and autophagy and its related signaling in vitro.ConclusionIn this study, we demonstrated that TFA, similar to FEB, exerts its renoprotective effects partially by therapeutically remodeling gut microbiota dysbiosis and inhibiting intestinal metabolite-derived microinflammation. This is achieved by adjusting autophagy-mediated macrophage polarization through AMPK-SIRT1 signaling. These findings provide more accurate information on the role of TFA in delaying CRF progression.

Huangkui capsule (HKC), a Chinese modern patent medicine extracted from Abelmoschus manihot (L.) medic, has been widely applied to clinical therapy in the early diabetic nephropathy (DN) patients. However, it remains elusive whether HKC can ameliorate the inchoate glomerular injuries in hyperglycemia. Recently the activation of phosphatidylinositol-3-kinase (PI3K)/serine-threonine kinase (Akt)/mammalian target of rapamycin (mTOR) signaling and its downstream regulator, 70-kDa ribosomal protein S6 kinase (p70S6K), play important roles in the early glomerular pathological changes of DN including glomerular hypertrophy, glomerular basement membrane (GBM) thickening and mild mesangial expansion. This study thereby aimed to clarify therapeutic effects of HKC during the initial phase of DN and its underlying mechanisms. Fifteen rats were randomly divided into 3 groups: the normal group, the model group and the HKC group. The early DN model rats were induced by unilateral nephrectomy combined with intraperitoneal injection of streptozotocin, and administered with either HKC suspension or vehicle after modeling and for a period of 4 weeks. Changes in the incipient glomerular lesions-related parameters in urine and blood were analyzed. Kidneys were isolated for histomorphometry, immunohistochemistry, immunofluorescence and Western blotting (WB) at sacrifice. In vitro, murine mesangial cells (MCs) were used to investigate inhibitory actions of hyperoside (HYP), a bioactive component of HKC, on cellular hypertrophy-associated signaling pathway by WB, compared with rapamycin (RAP). For the early DN model rats, HKC ameliorated micro-urinary albumin, body weight and serum albumin, but had no significant effects on renal function and liver enzymes; HKC improved renal shape, kidney weight and kidney hypertrophy index; HKC attenuated glomerular hypertrophy, GBM thickening and mild mesangial expansion; HKC inhibited the phosphorylation of Akt, mTOR and p70S6K, and the protein over-expression of transforming growth factor-β1 in kidneys. In vitro, the phosphorylation of PI3K, Akt, mTOR and p70S6K in MCs induced by high-glucose was abrogated by treatment of HYP or RAP. On the whole, this study further demonstrated HKC safely and efficiently alleviates the early glomerular pathological changes of DN, likely by inhibiting Akt/mTOR/p70S6K signaling activity in vivo and in vitro, and provided the first evidence that HKC directly contributes to the prevention of the early DN.

Identifying structural elements in long and complex RNAs, such as long non-coding and RNA viruses, can shed light on the functionality and mechanisms of such RNAs. Here we present RNAvigator, a tool able to identify elements of structural importance by using experimental SHAPE data or SHAPE-like predictions in conjunction with stability and entropy assessments. RNAvigator recognizes regions that are the most stable, unambiguous, and structured on RNA molecules, and thus potentially functional. When relying on predictions, RNAvigator uses the CROSS algorithm, a neural network trained on experimental data that achieved an AUC of 0.74 on hepatitis C virus SHAPE-MaP data and which was able to improve the predictive power of Superfold. By using RNAvigator, we can identify known functional regions on the complete hepatitis C virus genome, including the regulatory regions CRE and IRES, and the 3' UTR of dengue virus, a region known for the presence of structural elements essential for its replication, and functional regions of long non-coding RNAs such as XIST and HOTAIR. We envision that RNAvigator will be a useful tool for studying long and complex RNA molecules using known chemical probing data or, if they are not available, by employing predicted profiles. [ABSTRACT FROM AUTHOR]