The ratio of high aspartate aminotransferase to alanine aminotransferase: an independent risk factor associated with poor prognosis in IgA nephropathy.

OBJECTIVE: To investigate the relationship between the aspartate aminotransferase to alanine aminotransferase ratio (AAR) and the prognosis of IgA nephropathy (IgAN). METHODS: Clinical, pathological and follow-up data of 271 patients with IgAN from January 1, 2013, to July 31, 2023, were collected. A 50% decrease in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD) was used as renal composite end point events. A receiver operating characteristic (ROC) curve was plotted to predict the composite end point events by AAR. The optimal cutoff value of 1.24 was determined, and patients were allocated to high AAR and low AAR groups. Kaplan‒Meier (K‒M) curves and Cox proportional hazard models were used to evaluate the predictive effect of AAR on renal composite end point events. RESULTS: After a mean follow-up of 29 months, 39 patients achieved renal composite end point events. Among them, 9 and 30 patients in the low and high AAR groups achieved renal composite end point events, respectively, with a significant difference (P < 0.001). After adjustment for confounding factors, AAR was found to be an independent prognostic factor for renal composite end point events (HR = 3.283, 95% CI: 1.489-7.238, P = 0.003). Kaplan‒Meier analysis showed that high AAR was associated with achieving renal composite end point events in patients with IgAN. Moreover, the clinical features in the high AAR group were more severe. Further subgroup analysis showed that high AAR had a better predictive effect in patients with more severe clinicopathological manifestations. CONCLUSION: AAR is an independent prognostic factor in patients with IgAN.

A meta-analysis of risk factors for a Dacron-cuffed catheter related infection in hemodialysis.

OBJECTIVE: To provide theoretical basis for prevention of a Dacron-cuffed catheter related infection (CRI), the risk factors of CRI in hemodialysis patients were systematically evaluated. METHODS: Eight databases, including PubMed, Cochrane library, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Database (CBM), Wanfang Database and Chinese Scientific Journal Database (VIP), were searched to screen out literatures related to the risk factors of long-term indwelling a Dacron-cuffed CRI in hemodialysis. Meta-analysis of risk factors for a Dacron-cuffed CRI in hemodialysis and publication bias test were performed using RevMan 5.4 software. RESULTS: After screening, 13 literatures involving a Dacron-cuffed CRI were included, with a total of 625 patients, and the infection rate was 11.7%. The combined OR value and 95% confidence interval (CI) of all factors were: Combined with Diabetes (1.94, 1.51 ~ 2.50), Hb (1.82, 1.35 ~ 2.44), age (2.38, 1.06 ~ 5.34), catheter indwelling time (1.79, 1.21 ~ 2.66), serum albumin (2.26, 1.25 ~ 4.08), catheter indwelling site (3.29, 1.74 ~ 6.23) and the number of tube placement (5.40, 2.65 ~ 11.02). CONCLUSIONS: The main risk factors for a Dacron-cuffed CRI in hemodialysis were combined with diabetes, hemoglobin level, age, catheter indwelling time, serum albumin level, femoral vein catheter indwelling and catheterization times. In other words, hemodialysis patients are at higher risk of CRI if they have diabetes, or if they have a lower hemoglobin level, or if they are older, or if they have a longer duration of catheterization, or if they have a lower serum albumin level, or if they have a femoral vein catheter, or if they have more catheters.

Circular RNAs in osteosarcoma: An update of recent studies (Review).

Osteosarcoma (OS) prevailing in children and adolescents mainly occurs at the metaphysis of long bones. As it is associated with a high invasive and metastatic ability, resistance to chemotherapy, and a low 5­year survival rate, the diagnosis and treatment of OS post a global healthy issue. Over the past decades, RNA biology has shed new light onto the pathogenesis of OS. As a type of non­coding RNAs, circular RNAs (circRNAs) have been found to play crucial roles in cellular activities. Recently, a large number of circRNAs have been identified in OS and some of them have been validated to be functional in OS. In the present review, abnormally expressed and different types of circRNAs in OS are summarized. Functional studies on circRNAs have revealed that circRNAs can regulate gene expression at different levels, such as gene transcription, precursor mRNA splicing, miRNA sponges and translation into proteins/peptides. Mechanistic analyses on circRNAs show that circRNAs can regulate JAK­STAT3, NF­κB, PI3K­AKT, Wnt/ß­catenin signaling pathways during the occurrence and development of OS. Furthermore, the potential clinical applications of circRNAs are also emphasized. The present review focus on the current knowledge on the functions and mechanisms of circRNAs in the pathogenesis of OS, aiming to provide new insight into the OS diagnosis and treatment of OS.

Oridonin inhibits the occurrence and development of colorectal cancer by reversing the Warburg effect via reducing PKM2 dimer formation and preventing its entry into the nucleus.

BACKGROUND: The Warburg effect is prevalent in human cancer. Oridonin (ORI) has excellent anticancer effects, but its exact anticancer mechanism is still unclear. METHODS: CCK8, EdU, and flow cytometry assay were performed to detect the effect of ORI on cell viability, proliferation and apoptosis, respectively. RNA-seq was carried out to search the underlying mechanisms. Total PKM2, dimeric PKM2, nuclear PKM2 was detected by Western blot. The epidermal growth factor receptor/extracellular signal regulated kinase (EGFR/ERK) signaling was assayed. The binding ability of Importin-α5 to PKM2 was performed by Co-IP experiments. The effect of ORI combined with cysteine (Cys) or fructose-1, 6-diphosphate (FDP) on cancer cells was detected. Mouse xenograft model was established to confirm the molecular mechanisms in vivo. RESULTS: ORI inhibited viability, proliferation and promoted apoptosis of CRC cells. RNA-seq revealed ORI attenuated the Warburg effect in cancer cells. ORI reduced dimeric PKM2 and prevented it from entering the nucleus. ORI did not affect the EGFR/ERK signaling, but reduced Importin-α5 binding to the PKM2 dimer. Cys or FDP reversed or enhanced the effect of ORI. Animal model assay confirmed the molecular mechanisms in vivo. CONCLUSIONS: Our study first shows that ORI could have anticancer activity by inhibiting the Warburg effect as a novel activator of PKM2.

Analysis of predictive factors of thrombosis in autogenous arteriovenous fistula.

PURPOSE: To investigate the predictors of early diagnosis of thrombus of autogenous arteriovenous fistula (aAVF). METHODS: The included patients were divided into the thrombus group with aAVF failure or thrombosis and the control group with good internal fistula function. The general data of the patients, including age, sex, diabetes mellitus, were collected. Platelets (PLT), platelet crit (P-LCR), platelet distribution width (PDW), mean platelet volume (MPV), homocysteine (HCY), and other biochemical data were collected. The predictors of thrombus of aAVF were obtained by the t test and logistic regression analysis, and receiver operating characteristic (ROC) curve analysis was used to compare the area under the ROC curve (AUC) between the combined predictors and the original indicators. The optimal critical value was determined when the Youden index reached its maximum value, and the sensitivity, specificity, accuracy, diagnostic index, and so on were calculated. Finally, prediction was performed by substituting each value in individually. RESULTS: PLT, PDW, P-LCR, MPV, and HCY showed significant differences between two groups (p < 0.05). Logistic regression analysis showed that, for PLT (OR = 1.014, 95% CI 1.006-1.022, p = 0.01), PDW (OR = 1.295, 95% CI 1.009-1.661, p = 0.042), P-LCR (OR = 1.230, 95% CI 1.089-1.389, p = 0.001), MPV (OR = 1.696, 95% CI 1.101-2.613, p = 0.017), and HCY (OR = 1.332, 95% CI 1.182-1.502, p = 0.01), the difference was significant; PLT, PDW, P-LCR, MPV, and HCY were positively correlated with thrombogenesis (p < 0.05). By logistic regression, a group of the five predictors of PLT, PDW, P-LCR, MPV, and HCY was obtained, and the combined predictors were 0.014*PLT + 0.258*PDW + 0.207*P-LCR + 0.528*MPV + 0.287*HCY. The area under the curve of the combined predictor was 0.933, the sensitivity was 92.4%, the specificity was 81.2%, the maximum diagnostic index was 0.736, the diagnostic cutoff point was 21.790, and the accuracy rate was 87%. CONCLUSION: PLT, PDW, P-LCR, MPV, and HCY are predictors of thrombus of aAVF. They can better predict thrombus of aAVF, and the combination of these five indicators is better than a single indicator.

A novel apolipoprotein E mutation, ApoE Ganzhou (Arg43Cys), in a Chinese son and his father with lipoprotein glomerulopathy: two case reports.

BACKGROUND: Lipoprotein glomerulopathy is a rare and newly recognized glomerular disease that can lead to kidney failure. Its pathological features include the presence of lipoprotein embolus in the loop cavity of glomerular capillaries. It is believed that apolipoprotein E gene mutation is the initiator of the disease. Since the discovery of lipoprotein glomerulopathy, 16 different apolipoprotein E mutations have been reported worldwide, but most of these cases are sporadic. Here we report two cases of lipoprotein glomerulopathy, a Chinese son and his father, with a novel apolipoprotein E mutation, ApoE Ganzhou (Arg43Cys). CASE PRESENTATION: Case 1, a 33-year-old Chinese man, was hospitalized on 3 March 2014 owing to edema and weakness of facial and lower limbs for 1 month. Laboratory data showed urine protein 3+, hematuria 2+, serum creatinine 203 µmol/L, uric acid 670 µmol/L, total cholesterol 12.91 mmol/L, triglyceride 5.61 mmol/L, high-density lipoprotein 1.3 mmol/L, low-density lipoprotein 7.24 mmol/L, apolipoprotein B 2.48 g/L, and lipid protein (a) 571 mg/L. Renal tissue examined by immunofluorescence and electron microscopy indicated lipoprotein glomerulopathy. Case 2, 55-year-old father of case 1, was hospitalized on 12 January 2016 owing to edema of his lower extremities for 6 months. Laboratory data showed urine protein 2+, hematuria 2+, serum creatinine 95 µmol/L, uric acid 440 µmol/L, total cholesterol 4.97 mmol/L, triglyceride 1.91 mmol/L, high-density lipoprotein 1.18 mmol/L, low-density lipoprotein 3.12 mmol/L, apolipoprotein B 2.48 g/L, and lipid protein (a) 196 mg/L. Renal tissue examined by immunofluorescence and electron microscopy indicated lipoprotein glomerulopathy. Apolipoprotein E mutation test showed that they had the same gene mutation, a novel type of apolipoprotein E mutation. Based on their clinical presentation and examination findings, they were diagnosed with lipoprotein glomerulopathy. Case 1 was treated with prednisone and dual plasma replacement, followed by simvastatin, nifedipine, triptolide, and angiotensin II receptor blocker drug therapy. After 1 month, the edema symptoms of the patient were alleviated, and urinary protein, serum creatinine, and uric acid were quantitatively reduced. Case 2 was treated with Tripterygium wilfordii and angiotensin II receptor blocker drugs for 3 weeks, and his edema symptoms were alleviated, and urinary protein, serum creatinine, and uric acid were quantitatively reduced. CONCLUSIONS: The apolipoprotein E mutation in the two cases we reported was a familial aggregation phenomenon, and the mutation is a novel type, which we named ApoE Ganzhou (Arg43Cys). The location of the gene mutation is close to the most common mutation type of lipoprotein glomerulopathy, ApoE Kyoto (Arg25Cys), so we speculate that its pathogenic role might be the similar to that of ApoE Kyoto (Arg25Cys).

DHX9 contributes to the malignant phenotypes of colorectal cancer via activating NF-κB signaling pathway.

Colorectal cancer (CRC) is the leading cause of cancer-related mortality worldwide, which makes it urgent to identify novel therapeutic targets for CRC treatment. In this study, DHX9 was filtered out as the prominent proliferation promoters of CRC by siRNA screening. Moreover, DHX9 was overexpressed in CRC cell lines, clinical CRC tissues and colitis-associated colorectal cancer (CAC) mouse model. The upregulation of DHX9 was positively correlated with poor prognosis in patients with CRC. Through gain- and loss-of function experiments, we found that DHX9 promoted CRC cell proliferation, colony formation, apoptosis resistance, migration and invasion in vitro. Furthermore, a xenograft mouse model and a hepatic metastasis mouse model were utilized to confirm that forced overexpression of DHX9 enhanced CRC outgrowth and metastasis in vivo, while DHX9 ablation produced the opposite effect. Mechanistically, from one aspect, DHX9 enhances p65 phosphorylation, promotes p65 nuclear translocation to facilitate NF-κB-mediated transcriptional activity. From another aspect, DHX9 interacts with p65 and RNA polymerase II (RNA Pol II) to enhance the downstream targets of NF-κB (e.g., Survivin, Snail) expression to potentiate the malignant phenotypes of CRC. Together, our results suggest that DHX9 may be a potential therapeutic target for prevention and treatment of CRC patients.

Effects of imperatorin on apoptosis and synaptic plasticity in vascular dementia rats.

In view of the complicated pathophysiological process of vascular dementia (VD), drugs for the clinical treatment of VD mainly target related risk factors, while drugs with excellent efficacy in cognitive function are still relatively lacking. Imperatorin (IMP), an active constituent extracted from angelica dahuricae and notopterygium Notopterygii, which has anti-inflammatory, vasodilator, anticoagulant, block calcium channel, anticonvulsant, and anti oxygen free radical injury properties. Therefore,the present study examined its effects on VD rats and the underlying molecular mechanisms, in order to provide promising therapeutic methods. VD was established by modified ligation of perpetual two-vessel occlusion (2VO). After 2VO surgery, IMP (2.5, 5, and 10 mg/kg) was administered by intraperitoneal injection for 12 consecutive weeks to evaluate therapeutic effects. Cognitive function was verified by the Morris water maze. The neuronal morphological changes were examined via Hematoxylin-Eosin staining. Real-Time PCR and Western blot were used for detecting pro- and antiapoptotic biomarkers, and the hippocampus synaptic damage was examined by Transmission electron microscope. We revealed that 2VO-induced cognitive impairment, hippocampus CA1 neuron damage, apoptosis and synaptic damage. IMP-treatment significantly improved 2VO-induced cognitive deficits and hippocampus neuron damage. Molecular analysis revealed that IMP inhibited apoptosis through the down regulation of Bax, Caspase-3 and upregulation of Bcl-2. Meanwhile, IMP-treatment markedly improved synaptic ultrastructure morphology, increased the SAZ length, PSD thickness and up-regulated PSD-95 expression. Collectively, our findings demonstrated that IMP was effective in the treatment of 2VO-induced VD via inhibiting apoptosis of hippocampus neurons and reducing the synaptic plasticity destroy.

Polysaccharides from the Fleshy Fruits of Camellia oleifera Attenuate the Kidney Injury in High-Fat Diet/Streptozotocin-Induced Diabetic Mice.

The fleshy fruits of Camellia oleifera Abel are the immature fruits of C. oleifera, which are infected by Exobasidium vexans Massee and then turn to be intumescent and hollowed. They contain rich trace elements and vitamin C and are eaten directly as wild fruits in the Chinese countryside. Recent studies report that C. oleifera has anti-inflammatory and antioxidative effects. The current study, for the first time, evaluates the renal protective capacity of polysaccharides from the fleshy fruits of C. oleifera (CFFP) in streptozotocin-induced diabetic mice fed high-fat diets. The diabetic mice were orally administered CFFP for 3 months to evaluate the renoprotective function of CFFP. Our results indicated that 250 mg/kg CFFP significantly alleviated diabetes-induced renal injury by decreasing serum creatine, blood urea nitrogen levels, the kidney/body weight ratio, expression of fibronectin and collagen, as well as the secretion of tumor necrosis factor-α and interleukin-6. Additionally, 250 mg/kg CFFP could significantly ameliorate renal oxidative stress through increasing glutathione levels and lowering malondialdehyde contents. We confirmed that CFFP could exert antioxidative, anti-inflammatory, and antifibrosis activities. CFFP might be a potential therapeutic agent, and the fleshy fruits of C. oleifera might be a diet therapy for diabetic patients in the future.

Terminus-Associated Non-coding RNAs: Trash or Treasure?

3' untranslated regions (3' UTRs) of protein-coding genes are well known for their important roles in determining the fate of mRNAs in diverse processes, including trafficking, stabilization, translation, and RNA-protein interactions. However, non-coding RNAs (ncRNAs) scattered around 3' termini of the protein-coding genes, here referred to as terminus-associated non-coding RNAs (TANRs), have not attracted wide attention in RNA research. Indeed, whether TANRs are transcriptional noise, degraded mRNA products, alternative 3' UTRs, or functional molecules has remained unclear for a long time. As a new category of ncRNAs, TANRs are widespread, abundant, and conserved in diverse eukaryotes. The biogenesis of TANRs mainly follows the same promoter model, the RNA-dependent RNA polymerase activity-dependent model, or the independent promoter model. Functional studies of TANRs suggested that they are significantly involved in the versatile regulation of gene expression. For instance, at the transcriptional level, they can lead to transcriptional interference, induce the formation of gene loops, and participate in transcriptional termination. Furthermore, at the posttranscriptional level, they can act as microRNA sponges, and guide cleavage or modification of target RNAs. Here, we review current knowledge of the potential role of TANRs in the modulation of gene expression. In this review, we comprehensively summarize the current state of knowledge about TANRs, and discuss TANR nomenclature, relation to ncRNAs, cross-talk biogenesis pathways and potential functions. We further outline directions of future studies of TANRs, to promote investigations of this emerging and enigmatic category of RNA.

Enhancing KCNQ Channel Activity Improves Neurobehavioral Recovery after Spinal Cord Injury.

Spinal cord injury (SCI) usually leads to acute neuronal death and delayed secondary degeneration, resulting in sensory dysfunction, paralysis, and chronic pain. Excessive excitation is one of the critical factors leading to secondary neural damage initiated by various insults. KCNQ/Kv7 channels are highly expressed in spinal neurons and axons and play an important role in controlling their excitability. Enhancing KCNQ channel activity by using its specific opener retigabine could thus be a plausible treatment strategy to reduce the pathology after SCI. We produced contusive SCI at T10 in adult male rats, which then received 10 consecutive days' treatment with retigabine or vehicle starting 3 hours or 3 days after contusion. Two different concentrations and two different delivery methods were applied. Delivery of retigabine via Alzet osmotic pumps, but not intraperitoneal injections 3 hours after contusion, promoted recovery of locomotor function. Remarkably, retigabine delivery in both methods significantly attenuated the development of mechanical stimuli-induced hyperreflexia and spontaneous pain; however, no significant difference in the thermal threshold was observed. Although retigabine delivered 3 days after contusion significantly attenuated the development of mechanical hypersensitivity and spontaneous pain, the locomotor function is not improved by the delayed treatments. Finally, we found that early application of retigabine attenuates the inflammatory activity in the spinal cord and increases the survival of white matter after SCI. Our results suggest that decreasing neuronal excitability by targeting KCNQ/Kv7 channels at acute stage aids the recovery of locomotor function and attenuates the development of neuropathic pain after SCI. SIGNIFICANCE STATEMENT: Several pharmacological interventions have been proposed for spinal cord injury (SCI) treatment, but none have been shown to be both effective and safe in clinical trials. Necrotic neuronal death and chronic pain are often the cost of pathological neural excitation after SCI. We show that early, brief application of retigabine could aid locomotor and sensory neurobehavioral recovery after SCI, supporting the use of this drug in the clinic to promote motor and sensory function in patients with SCI.

Oridonin induces autophagy via inhibition of glucose metabolism in p53-mutated colorectal cancer cells.

The Warburg effect is an important characteristic of tumor cells, making it an attractive therapeutic target. Current anticancer drug development strategies predominantly focus on inhibitors of the specific molecular effectors involved in tumor cell proliferation. These drugs or natural compounds, many of which target the Warburg effect and the underlying mechanisms, still need to be characterized. To elucidate the anticancer effects of a natural diterpenoid, oridonin, we first demonstrated the anticancer activity of oridonin both in vitro and in vivo in colorectal cancer (CRC) cells. Then miRNA profiling of SW480 cells revealed those intracellular signaling related to energy supply was affected by oridonin, suggesting that glucose metabolism is a potential target for CRC therapy. Moreover, our results indicated that oridonin induced metabolic imbalances by significantly inhibiting glucose uptake and reducing lactate export through significantly downregulating the protein levels of GLUT1 and MCT1 in vitro and vivo. However, the ATP level in oridonin-treated CRC cells was not decreased when oridonin blocked the glucose supply, indicating that oridonin induced autophagy process, an important ATP source in cancer cells. The observation was then supported by the results of LC3-II detection and transmission electron microscopy analysis, which confirmed the presence of autophagy. Furthermore, p-AMPK was rapidly deactivated following oridonin treatment, resulting in downregulation of GLUT1 and induction of autophagy in the cancer cells. Thus our finding helped to clarify the anticancer mechanisms of oridonin and suggested it could be applied as a glucose metabolism-targeting agent for cancer treatment.

Activation of KCNQ Channels Suppresses Spontaneous Activity in Dorsal Root Ganglion Neurons and Reduces Chronic Pain after Spinal Cord Injury.

A majority of people who have sustained spinal cord injury (SCI) experience chronic pain after injury, and this pain is highly resistant to available treatments. Contusive SCI in rats at T10 results in hyperexcitability of primary sensory neurons, which contributes to chronic pain. KCNQ channels are widely expressed in nociceptive dorsal root ganglion (DRG) neurons, are important for controlling their excitability, and their activation has proven effective in reducing pain in peripheral nerve injury and inflammation models. The possibility that activators of KCNQ channels could be useful for treating SCI-induced chronic pain is strongly supported by the following findings. First, SCI, unlike peripheral nerve injury, failed to decrease the functional or biochemical expression of KCNQ channels in DRG as revealed by electrophysiology, real-time quantitative polymerase chain reaction, and Western blot; therefore, these channels remain available for pharmacological targeting of SCI pain. Second, treatment with retigabine, a specific KCNQ channel opener, profoundly decreased spontaneous activity in primary sensory neurons of SCI animals both in vitro and in vivo without changing the peripheral mechanical threshold. Third, retigabine reversed SCI-induced reflex hypersensitivity, adding to our previous demonstration that retigabine supports the conditioning of place preference after SCI (an operant measure of spontaneous pain). In contrast to SCI animals, naïve animals showed no effects of retigabine on reflex sensitivity or conditioned place preference by pairing with retigabine, indicating that a dose that blocks chronic pain-related behavior has no effect on normal pain sensitivity or motivational state. These results encourage the further exploration of U.S. Food and Drug Administration-approved KCNQ activators for treating SCI pain, as well as efforts to develop a new generation of KCNQ activators that lack central side effects.

[Efficacy of immunoadsorption therapy in the treatment of myasthenia gravis and the mechanism].

OBJECTIVE: To evaluate the effect of immunoadsorption therapy in patients with myasthenia gravis (MG) and explore the mechanism. METHODS: This investigation involved 20 patients with MG treated with immunoadsorption combined with hormonal therapy and another 20 with only hormonal therapy, and 15 healthy subjects served as the control group. Enzyme-linked immunosorbent assay (ELISA) was used to measure the changes in serum tumor necrosis factor-α (TNF-α) and interleukin-18 (IL-18) after the treatments, and the therapeutic effect of the treatments was evaluated using clinical scores. RESULTS: The clinical scores were significantly decreased after immunoadsorption therapy, showing a significant difference from that in the hormonal treatment group (P<0.05). The serum TNF-a and IL-18 levels were significantly higher in the two patient groups than in the control group (P<0.05), but in the former two groups, their levels were significantly lower in immunoadsorption therapy group (P<0.01). CONCLUSION: Immunoadsorption therapy eliminates the inflammatory cytokines and free radicals as well as the circulating autoantibodies to improve the clinical symptoms of MG.