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Diabetic kidney disease (DKD) is one of the chronic microvascular complications caused by diabetes, which is characterized by persistent albuminuria and/or progressive decline of estimated glomerular filtration rate (eGFR), and has been the major cause of dialysis around the world. At present, although the treatments for DKD including lifestyle modification, glycemic control and even using of Sodium-glucose cotransporter 2 (SGLT2) inhibitors can relieve kidney damage caused to a certain extent, there is still a lack of effective treatment schemes that can prevent DKD progressing to ESRD. It is urgent to find new complementary and effective therapeutic agents. Growing animal researches have shown that mitophagy makes a great difference to the pathogenesis of DKD, therefore, exploration of new drugs that target the restoration of mitophagy maybe a potential perspective treatment for DKD. The use of Chinese botanical drugs (CBD) has been identified to be an effective treatment option for DKD. There is growing concern on the molecular mechanism of CBD for treatment of DKD by regulating mitophagy. In this review, we highlight the current findings regarding the function of mitophagy in the pathological damages and progression of DKD and summarize the contributions of CBD that ameliorate renal injuries in DKD by interfering with mitophagy, which will help us further explain the mechanism of CBD in treatment for DKD and explore potential therapeutic strategies for DKD.

ObjectiveIntestinal flora homeostasis in rats with type 2 diabetes mellitus (T2DM) was evaluated to explore the effects of total Astragalus saponins (TAS) on hepatic insulin resistance (IR).MethodsSix-week-old male Sprague–Dawley rats were fed high-fat and high-sugar diet for 4 weeks and intraperitoneally injected with streptozotocin to induce T2DM, and they were then randomly divided into control, model, metformin, and TAS groups. Stool, serum, colon, and liver samples were collected after 8 weeks of drug administration for relevant analyses.ResultsTAS reduced fasting blood glucose, 2-hour postprandial blood glucose, area under the curve of oral glucose tolerance test, glycated serum protein, homeostasis model assessment of insulin resistance, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels in T2DM rats but increased insulin, C-peptide, and high-density lipoprotein cholesterol levels. Moreover, TAS improved the morphology and structure of liver and colon tissues and improved the composition of the intestinal microbiome and bacterial community structure at different taxonomic levels. In addition, TAS increased the protein expression of hepatic IRS-1, PI3K, PDK1, and p-AKT and decreased the protein expression of p-GSK-3β. Meanwhile, TAS increased the mRNA expression of liver PDK1, PI3K, and GS and decreased the mRNA expression of GSK-3β.ConclusionTAS can ameliorate T2DM-related abnormal glucose and blood lipid metabolism, intestinal dysbiosis, and IR.

Learning to read may result in network reorganization in the developing brain. The thalamus and striatum are two important subcortical structures involved in learning to read. It remains unclear whether the thalamus and striatum may form two independent cortico-subcortical reading pathways during reading acquisition. In this prospective longitudinal study, we aimed to identify whether there may be two independent cortico-subcortical reading pathways involving the thalamus and striatum and to examine the longitudinal predictions between these two cortico-subcortical pathways and reading development in school-age children using cross-lagged panel modeling. A total of 334 children aged 6–12 years completed two reading assessments and resting functional imaging scans at approximately 12-month intervals. The results showed that there were two independent cortico-subcortical pathways, the thalamo-occipital and fronto-striatal circuits. The former may be part of a visual pathway and was predicted longitudinally by reading ability, and the prediction was stronger in children in lower grades and weaker in children in higher grades. The latter may be part of a cognitive pathway related to attention, memory, and reasoning, which was bidirectionally predicted with reading ability, and the predictive effect gradually increasing with reading development. These results extend previous findings on the relationship between functional connectivity and reading competence in children, highlighting the dynamic relationships between the thalamo-occipital and fronto-striatal circuits and reading acquisition.

For Chronic Kidney Disease (CKD), the study of microRNA as a biomarker has become an exciting area, so we carried out a meta-analysis to investigate the potential diagnostic values of miRNAs in CKD. We searched Pubmed, Cochrane Library, Embase, and Web of science databases to identify relevant publications published from the establishment of the database to April 30, 2021. We included a total of 26 articles containing 56 studies. There were 4,098 patients with CKD and 2,450 patients without CKD. We found that the overall sensitivity and specificity of miRNAs in CKD diagnosis were 0.86 (95% CI: 0.83–0.89) and 0.79 (95% CI: 0.75–0.83), respectively. In addition, we plotted the summary receiver operator characteristic (SROC) curve to assess diagnostic accuracy, with the area under the curve (AUC) of 0.90 (95% CI: 0.87–0.92). Subgroup analysis showed that sensitivity, specificity, and AUC of miRNAs in plasma and serum were 0.84, 0.78, 0.88; and 0.79, 0.76, 0.83, respectively, while miRNAs in urine were 0.89 for sensitivity, 0.82 for specificity, and 0.92 for AUC. Moreover, we found that the panel of microRNAs (miRNAs) could improve the pooled sensitivity (0.88, 0.81, and 0.91 for sensitivity, specificity, and AUC, respectively). We believe that miRNAs have great potential to become an effective diagnostic biomarker for CKD. Panels of miRNA have higher accuracy than single miRNAs. Additionally, miRNAs in both blood and urine have significant accuracy in the diagnosis of CKD; nevertheless, urine is superior.

Inflammation plays an important role in aortic dissection (AD). Macrophages are critically involved in the inflammation after aortic injury. Neuraminidases (NEUs) are a family of enzymes that catalyze the cleavage of terminal sialic acids from glycoproteins or glycolipids, which is emerging as a regulator of macrophage-associated immune responses. However, the role of neuraminidase 1 (NEU1) in pathological vascular remodeling of AD remains largely unknown. This study sought to characterize the role and identify the potential mechanism of NEU1 in pathological aortic degeneration. After β-aminopropionitrile monofumarate (BAPN) administration, NEU1 elevated significantly in the lesion zone of the aorta. Global or macrophage-specific NEU1 knockout (NEU1 CKO) mice had no baseline aortic defects but manifested improved aorta function, and decreased mortality due to aortic rupture. Improved outcomes in NEU1 CKO mice subjected to BAPN treatment were associated with the ameliorated vascular inflammation, lowered apoptosis, decreased reactive oxygen species production, mitigated extracellular matrix degradation, and improved M2 macrophage polarization. Furthermore, macrophages sorted from the aorta of NEU1 CKO mice displayed a significant increase of M2 macrophage markers and a marked decrease of M1 macrophage markers compared with the controls. To summarize, the present study demonstrated that macrophage-derived NEU1 is critical for vascular homeostasis. NEU1 exacerbates BAPN-induced pathological vascular remodeling. NEU1 may therefore represent a potential therapeutic target for the treatment of AD.

Recent studies have unveiled that myocardial hypertrophic preconditioning (HP), which is produced by de-banding (De-TAC) of short-term transverse aortic constriction (TAC), protects the heart against hypertrophic responses caused by subsequent re-constriction (Re-TAC) in mice. Although cardiac substrate metabolism is impaired in heart failure, it remains unclear about the role of HP-driven energetics in the development of cardiac hypertrophy. Here, we investigated energy metabolism, cardiac hypertrophy, and function following variational loading conditions, as well as their relationships in HP. Male C57BL/6J mice (10–12 weeks old) were randomly subjected to Sham, HP [TAC for 3days (TAC 3d), de-banding the aorta for 4 days (De-TAC 4d), and then re-banding the aorta for 4 weeks (Re-TAC 4W)], and TAC (TAC for 4 weeks without de-banding). Cardiac echocardiography, hemodynamics, and histology were utilized to evaluate cardiac remodeling and function. The mRNA expression levels of fetal genes (ANP and BNP), glucose metabolism-related genes (glut4, pdk4), and fatty acid oxidation-related genes (mcad, pgc1α, mcd, pparα) were quantitated by real-time quantitative PCR. Activation of hypertrophy regulators ERK1/2, a metabolic stress kinase AMP-activated protein kinase (AMPK), and its downstream target acetyl-coA carboxylase (ACC) were explored by western blot. Compared with TAC 4W mice, Re-TAC 4W mice showed less impairment in glucose and fatty acid metabolism, as well as less cardiac hypertrophy and dysfunction. Moreover, no significant difference was found in myocardial hypertrophy, fibrosis, and cardiac function in TAC 3d and De-TAC 4d groups compared with Sham group. However, glut4, pdk4, mcad, pgc1α, mcd, and pparα were all decreased, while AMPK and ACC were activated in TAC 3d and returned to Sham level in De-TAC 4d, suggesting that the change in myocardial energy metabolism in HP mice was earlier than that in cardiac structure and function. Collectively, HP improves energy metabolism and delays cardiac remodeling, highlighting that early metabolic improvements drive a potential beneficial effect on structural and functional restoration in cardiac hypertrophy.

We present a method utilizing the coupling between a pre-bunched electron beam and a silicon subwavelength grating to generate coherent terahertz waves. The grating that is connected to two opposite-traveling in-plane waveguides functions as a resonator. An example operating around 2 THz shows that, when the velocity and repetition frequency of the electron bunches respectively match the phase velocity and resonant frequency of the Bragg resonance in the grating, the strong electron-wave coupling leads to coherent radiation through the waveguide. The repetition frequency of the electron bunches can be halved by using its second harmonic to match the resonant frequency. This study might offer a potential approach for on-chip terahertz sources.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel plays a critical role in regulating the resting membrane potential and integrating synaptic transmission. Variants of HCN1 have been recognized as causes of epilepsy, and mutant HCN1 channels could act with loss-of-function (LOF), loss- and gain-of-function (LOF and GOF) and gain-of-function (GOF) mechanisms. However, phenotypes and pathogenesis of HCN1-related epilepsy are still poorly understood. This study enrolled five epileptic cases carrying five different HCN1 variants: two pathogenic variants (I380F and S710Rfs*71), two likely pathogenic variants (E240G and A395G), and a paternally inherited variant (V572A). Four variants were novel. Electrophysiological experiments revealed impaired biophysical properties of the identified mutants, including current densities and activation/deactivation kinetics. Moreover, three variants exerted effects on the biophysical properties of wild-type HCN1 channels in heterozygous conditions. Immunofluorescence experiments showed that two variants reduced the protein expression of HCN1channels in neurons. Neurons expressing E240G (GOF) variant showed increased input resistance. However, the variant of I380F (LOF) increased the neuronal firing rate, thus leading to neuronal hyperexcitability. In conclusion, the present study expands the genotypic and phenotypic spectrum of patients with HCN1-related epilepsy and clarifies the underlying mechanisms. We reported five new cases including four unreported likely/pathogenic variants. We provided assessments of biophysical function for each variant, which could help patients to receive individual therapy in the future. We confirmed that HCN1 variants contributed to neuronal hyperexcitability by regulating input resistance and the action potential firing rate, and we have shown that they can affect protein expression in neurons for the first time.

Edaravone dexborneol is a novel neuroprotective drug that comprises edaravone and (+)-borneol in a 4:1 ratio. Phase II and III studies have demonstrated that Chinese patients treated with edaravone dexborneol within 48 h of AIS onset have better functional outcomes than those treated with edaravone alone. However, the effect of edaravone dexborneol on subarachnoid hemorrhage (SAH) has not yet been elucidated. This study aimed to investigate the therapeutic effects of edaravone dexborneol on SAH-induced brain injury and long-term behavioral deficits and to explore the possible mechanisms. The experimental rat SAH model was induced by an intraluminal puncture of the left middle cerebral artery (MCA). Edaravone dexborneol or edaravone at a clinical dose was infused into the tail vein for 3 days post-SAH surgery. Behavioral outcomes were assessed by a modified Garcia scoring system and rotarod, foot-fault, and corner tests. Immunofluorescence, Western blot, and ELISA methods were used to evaluate neuronal damage and oxidative stress. Our results showed that a post-SAH therapeutic regimen with edaravone dexborneol helped improve neurological function up to 21 days after SAH surgery and demonstrated a greater beneficial effect than edaravone alone, accompanied by an obvious inhibition of neuronal apoptosis in the CA1 hippocampus and basal cortex regions. Mechanistically, edaravone dexborneol not only suppressed the lipid peroxidation product malondialdehyde (MDA) but also improved the total antioxidant capability (TAC) 3 days after SAH. Notably, edaravone dexborneol treatment significantly inhibited the expression of another lipid peroxidation product, 4-hydroxynonenal (4-HNE), in the CA1 hippocampus and basal cortex, which are vital participants in the process of neuronal oxidative damage and death after SAH because of their acute cytotoxicity. Together, our results demonstrate that edaravone dexborneol confers neuroprotection and stabilizes long-term behavioral ability after SAH injury, possibly by suppressing 4-HNE-associated oxidative stress. These results may help develop new clinical strategies for SAH treatment.

ObjectiveTo explore the etiology of infantile spasms (IS) in a large Chinese cohort based on the United States National Infantile Spasms Consortium (NISC) classification.MethodsIn the present study, we recruited IS patients diagnosed at a single center (Xiangya Hospital, Central South University) between Jan 2010 and Aug 2019. Thereafter, we collected their clinical and genetic information retrospectively. Their underlying etiologies were classified according to the NISC classification and then compared in different scenarios to understand their distribution.ResultsA total of 541 patients with IS from 18 provinces were included in this study. The underlying etiology was identified in 53.2% of the cases: structural-acquired, 25.3%; genetic, 12.9%; genetic-structural, 7.2%; structural-congenital, 5.0%; metabolic, 2.4%; infections, 0.4% and immune, 0%. Whole-exome sequencing (WES) provided the highest diagnostic yield (26.9%). In structural-acquired IS, the proportion of hypoglycemic brain injuries was significant, second only to hypoxic-ischemic encephalopathy. There was no patient discovered to have Down syndrome. STXBP1, CDKL5, TSC2, KCNQ2, IRF2BPL, and TSC1 were the most frequently implicated genes. Genetic causes were found to be the most common cause of IS in the early onset group, while structural-acquired etiologies were common in males and preterm babies. Patients with pre-spasm seizures were associated with a higher proportion of identified causes than those without. Non-acquired structural etiologies were more common in patients without hypsarrhythmia than in those with hypsarrhythmia.SignificanceThe most prevalent cause of IS was structural acquired followed by genetic causes. When brain MRI fails to detect the etiology, we propose WES as the next step. Structural-acquired IS and cases with genetic disorders are characteristic of the Chinese cohort, however, the etiology differs with the patient's age of onset, gestation age at birth, sex, and the presence/absence of both pre-spasm seizures, and hypsarrhythmia.

ObjectiveThe limitations of adrenocorticotrophic hormone (ACTH) treatment for infantile spasms (ISs), such as high costs, limited availability, and adverse effects (AEs), make it necessary to explore whether corticosteroids are optimal alternatives. Many other compelling treatments have gone through trials due to the suboptimal effectiveness of hormonal therapy. A systematic review and meta-analysis were performed to evaluate the effectiveness and safety of hormonal therapy for patients with ISs.MethodsEMBASE, Ovid MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and online registers were searched through April 2021 for randomized controlled trials (RCTs).ResultsA total of 19 RCTs (N = 1,279) were included. There was no significant difference in the effectiveness of oral corticosteroids and ACTH in electro-clinical response (risk ratio [RR] = 0.85, 95% CI 0.41–1.76). Low-dose ACTH had similar effectiveness in electro-clinical response compared to usual-dose group (RR = 0.94, 95% CI 0.60–1.47) but conferred a lower risk of AEs (RR = 1.71, 95% CI 1.08–2.71). ACTH was more beneficial in controlling spasms than vigabatrin (VGB) (RR = 1.31, 95% CI 1.05–1.64) for patients without tuberous sclerosis complex (TSC). All RCTs were connected through network meta-analysis, and we found that ketogenic diet (KD), zonisamide, methylprednisolone, or combined treatment of hormonal therapy with topiramate (TPM) or pyridoxine was not different in electro-clinical response compared to usual-dose ACTH.ConclusionOur analysis showed that oral corticosteroids could be optional alternatives when ACTH is not applicable, and ACTH is more beneficial for patients without TSC. Moreover, low-dose ACTH is recommended due to comparative effectiveness but lower risk of AEs. However, due to the high heterogeneity of included patients and treatment protocols, these results must be interpreted with caution. RCTs with multicentric involvement and larger sample size are needed for solid evaluation of other alternative treatments.

Background and purpose: The clinical and radiological features of myelin oligodendrocyte glycoprotein antibody (MOG-Ab) diseases vary among the patients and studies. In addition, the clinical significance of MOG-Ab for the diagnosis, treatment, and prognosis is not yet established. Therefore, we aimed to evaluate the clinical, radiological, treatments and outcome features of MOG-Ab diseases in Central Southern part of China.Methods: A retrospective study of children with MOG-Ab disease was carried out from January 2015 to October 2018. Demographics, clinical features, treatments, and outcomes were reviewed. Some of the clinical information was compared including the annualized relapse rates (ARRs) before and after treatment with disease-modifying drugs (DMDs).Results: Twenty-five patients with MOG-Ab disease were recruited. The onset age ranged from 3 to 12.4 years old. 13 were females and 12 were males. The median follow-up period was 15 months (range 7–63). Most of the cases that aged ≤9 years presented with fever (47.4%), encephalopathy (47.4%), and lesions on white matter and/or deep gray matter (52.6%). While most of those aged above 9 years presented with optic neuritis (ON) (66.7%), and lesions on spinal cord and/or optic nerve (50%). Until the last follow-up, 10 (40%) cases had multiphasic courses while 15 (60%) had a monophasic course, and the mean follow-up time was statistically significant (10.67 vs. 31 months, p = 0.0001). DMDs such as rituximab (RTX) or/and azathioprine (AZP) or mycophenolate mofetil (MMF) were used at least once in 56% of the cases. The ARR before and after treatment was 2.4 and 0 respectively (p < 0.05). The median Expanded Disability Status Scale scores of our study were 0 (range 0–2). 96% (24/25) of the cases had a full recovery.Conclusions: MOG-Ab disease among Chinese children share the same clinical characteristics with Caucasians. However, the Chinese children seem to have a better prognosis than Caucasians. There is an age-dependent phenotypes, as brain involvement is more frequently seen in children younger or equal to 9 years while ON and neuromyelitis optica spectrum disorders are commonly seen in children older than 9 years. DMDs, such as AZA, MMF or RTX, can reduce the ARR.

Background: Febrile infection-related epilepsy syndrome (FIRES) is a fatal epileptic encephalopathy associated with super-refractory status epilepticus (SRSE). Several treatment strategies have been proposed for this condition although the clinical outcomes are poor. Huge efforts from neurointensivists have been focused on identifying the characteristics of FIRES and treatment to reduce the mortality associated with this condition. However, the role of ketogenic diet (KD) in FIRES is not fully understood.Methods: We performed a retrospective review of patients who met the diagnostic criteria of FIRES, SRSE, and were treated with KD between 2015 and 2018 at the Department of Pediatrics, Xiangya Hospital of Central South University. The following data were recorded: demographic features, clinical presentation, anticonvulsant treatment, timing and duration of KD and follow-up information. Electroencephalography recordings were reviewed and analyzed.Results: Seven patients with FIRES were put on KD (5 via enteral route, and 2 via intravenous line) for SRSE in the PICU. The median age was 8. Four patients were male and 3 were female. Although patients underwent treatment with a median of 4 antiepileptic drugs and 2 anesthetic agents, the status epilepticus (SE) persisted for 7–31 days before KD initiation. After KD initiation, all patients achieved ketosis and SE disappeared within an average of 5 days (IQR 3.5), although there were minor side effects. In 6 patients, a unique pattern was identified in the EEG recording at the peak period. After initiation of KD, the number of seizures reduced, the duration of seizure shortened, the background recovered and sleep architecture normalized in the EEG recordings. The early initiation of KD (at the onset of SE) in the acute phase of patients decreased the mRS score in the subsequent period (p = 0.012, r = 0.866).Conclusions: The characteristic EEG pattern in the acute phase promoted timely diagnosis of FIRES. Our data suggest that KD may be a safe and promising therapy for FIRES with SRSE, and that early initiation of KD produces a favorable prognosis. Therefore, KD should be applied earlier in the course of FIRES. Intravenous KD can be an effective alternative route of administration for patients who may not take KD enterally.