Diabetic cardiomyopathy (DCM) is a serious cardiac dysfunction induced by changes in the structure and contractility of the myocardium that are initiated in part by alterations in energy substrates. The underlying mechanisms of DCM are still under controversial. The observation of lipids, especially lipidomics profiling, can provide an insight into the know the biomarkers of DCM. The aim of our research was to detect changes of myocardial lipidomics profiling in a rat model of diabetic cardiomyopathy.

Recent studied have reported that impaired striatal synaptic plasticity played a crucial role in Parkinson's disease (PD). Previous studies have suggested that electroacupuncture (EA) alleviated the motor deficits in PD patients and animal models. However, the mechanisms underlying this protection need to be further elucidated. In this study, we found that EA-induced improvement of motor deficits in the 6-hydroxydopamine (6-OHDA) rat model doesn't act through dopaminergic system. EA rescued the decreased striatal long-term potentiation (LTP) in 6-OHDA rats. In addition, the declined expression of N-methyl-D-aspartic acid receptor subunit 2B (NR2B) in the striatum was remarkably up-regulated by EA. The EA-induced improvement of LTP can be eliminated by NR2B-selective inhibitor. It is indicated that EA-induced recovery of striatal LTP was correlated with the up-regulation of NR2B subunit. EA was also found to rescue the decreased dendritic arborization and the spine density in the striatum of 6-OHDA rats. Meanwhile, EA suppressed striatal glutamate content and vesicular glutamate transporter 1 which is expressed in cortico-striatal glutamatergic projections. The decrease of striatal glutamate content induced by decortication, EA treatment or a combination of both reversed the loss of striatal spine density in 6-OHDA rats. It is indicated that EA-induced reduction of cortico-striatal glutamate transmission contributes to the recovery of striatal spine density. In conclusion, the therapeutic effect of EA on the motor deficits of 6-OHDA rats was mediated by rescuing cortico-striatal glutamate transmission and striatal synaptic plasticity.

Sustained retina drug delivery and rational drug combination are considered essential for enhancing the efficacy of therapy for wet age-related macular degeneration (wAMD) due to the conservative structure of the posterior ocular segment and the multi-factorial pathological mechanism. Designing a drug co-delivery system that can simultaneously achieve deep penetration and long-lasting retention in the vitreous is highly desired, yet remains a huge challenge. In this study, we fabricated Bor/RB-M@TRG as an intravitreal-injectable hydrogel depot for deep penetration into the posterior ocular segment and long-lasting distribution in the retinal pigment epithelium (RPE) layer. The Bor/RB-M@TRG consisted of borneol-decorated rhein and baicalein-coloaded microemulsions (Bor/RB-M, the therapy entity) and a temperature-responsive hydrogel matrix (the intravitreal depot). Bor/RB-M exhibited the strongest in vitro anti-angiogenic effects among all the groups studied, which is potentially associated with improved cellular uptake, as well as the synergism of rhein and baicalein, acting via anti-angiogenic and anti-oxidative stress pathways, respectively. Importantly, a single intravitreal (IVT) injection with Bor/RB-M@TRG displayed significant inhibition against the CNV of wAMD model mice, compared to all other groups. Particularly, coumarin-6-labeled Bor/RB-M@TRG (Bor/C6-M@TRG) could not only deeply penetrate into the retina but also stably accumulate in the RPE layer for at least 14 days. Our design integrates the advantages of borneol-decorated microemulsions and hydrogel depots, offering a promising new approach for clinically-translatable retinal drug delivery and synergistic anti-wAMD treatment.

Berberine (BR) shows promise as a candidate for treating irritable bowel syndrome with diarrhea (IBS-D). However, the undesired physicochemical properties and poor oral absorption limit its clinical translation. A ketogenic diet (KD) can induce intestinal overexpression of cannabidiol (CB) receptors, which may offer a potential target for IBS-D-specific delivery of BR.

The exaggerated beta synchronized oscillation in the cortico-basal ganglia circuit is a hallmark of disease-specific motor symptoms in Parkinson's disease (PD). The functional connectivity between the cortex and basal ganglia was influenced by anesthesia. However, the correlation between anesthesia-dependent brain states and the alterations of synchronized network oscillations remains unclear. In this study, local field potentials (LFPs) were simultaneously recorded in the motor cortex and striatum of dopamine-intact and dopamine-depleted hemiparkinsonian rats. Levodopa and three anesthetics (urethane, pentobarbital, and isoflurane) were utilized to assess the changes in neural activity under different brain states. Enhanced high beta (25-40 Hz) oscillations and coherence between the cortex and striatum were found under the wakefulness in 6-OHDA-lesioned rats. Urethane-anesthetized rats exhibited both the activated state and slow wave activity intermittently, while the enhanced synchronized low beta oscillations between the cortex and striatum were observed only during the activated state, which exhibiting a pattern of activity analogous to those observed during the awake state. Notably, urethane significantly reduced the beta peak frequency during the activated state compared to wakefulness in 6-OHDA-lesioned rats. Although both pentobarbital and isoflurane commonly reduced beta oscillations and coherence between the cortex and striatum in 6-OHDA-lesioned rats, they exhibited the distinct influence over the alpha band activity. In addition, isoflurane regulated the burst suppression in a dose-dependent manner. Our data support that synchronized high beta oscillations are directly related to the motor symptoms of PD. Anesthesia regimes influence the excessive synchronized oscillations between the cortex and striatum in a brain state-dependent manner.

This study aimed to identify monogenic mutations from Chinese patients with childhood absence epilepsy (CAE) and summarize their characteristics. A total of 100 patients with CAE were recruited in Peking University First Hospital from 2005 to 2016 and underwent telephone and outpatient follow-up review. We used targeted disease-specific gene capture sequencing (involving 300 genes) to identify pathogenic variations for these patients. We identified three de novo epilepsy-related gene mutations, including missense mutations of SCN1A (c. 5399 T > A; p. Val1800Asp), SCN8A (c. 2371 G > T; p. Val791Phe), and CLCN2 (c. 481 G > A; p. Gly161Ser), from three patients, separately. All recruited patients presented typical CAE features and good prognosis. To date, CAE has been considered a complex disease caused by multiple susceptibility genes. In this study, we observed that 3% of typical CAE patients had a de novo mutation of a known monogenic epilepsy-related gene. Our study suggests that a significant proportion of typical CAE cases may be monogenic forms of epilepsy. For genetic generalized epilepsies, such as CAE, further studies are needed to clarify the contributions of de novo or inherited rare monogenic coding, noncoding and copy number variants.

The abnormal amyloid β (Aβ) accumulation and Aβ-related neural network dysfunction are considered central to the pathogenesis of Alzheimer's disease (AD) at the early stage. Deep-brain reachable low field magnetic stimulation (DMS), a novel noninvasive approach that was designed to intervene the network activity in brains, has been found to alleviate stress-related cognitive impairments.

Osteoarthritis (OA) is a chronic degenerative disease wherein the articular cartilage exhibits inflammation and degradation. Scutellarin (SCU) is a flavonoid glycoside with a range of pharmacological activities, as shown in previous studies demonstrating its anti-inflammatory activity. How SCU impacts the progression of OA, however, has not been explored to date. Herein, we assessed the impact of SCU on murine chondrocytes in an OA model system. In in vitro assays, we measured chondrocyte expression of key OA-associated factors such as matrix metalloproteinase 13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) via qRT-PCR and Western blotting, the expression of interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2) were detected by qRT-PCR. Our results showed that the downregulation of MMP-13, ADAMTS-5, COX-2, and iNOS expression by SCU and the overproduction of IL-6, TNF-α, and PGE2 induced by IL-1β were all inhibited by SCU in a concentration-dependent manner. Moreover, SCU was able to reverse aggrecan and collagen II degradation and nuclear factor-κB (NF-κB) and nuclear factor erythroid-derived 2-like 2 (Nrf2) signaling pathway activation both in vivo and in vitro. We further used a destabilization of the medial meniscus (DMM) murine model of OA to explore the therapeutic benefits of SCU in vivo. Together, our findings suggest SCU to be a potentially valuable therapeutic agent useful for treating OA.

Depression is a state of low mood and aversion to activity, affecting a person's thoughts, behavior, motivation, feelings and sense of well-being, which is associated with dramatical gene expression changes in hippocampus. Rodents induced by chronic unpredictable mild stress (CUMS) demonstrate typical depression-like behaviors similar to clinical patients, therefore, are commonly used as a model for depression and antidepressant study. In order to enhance our understanding of the molecular mechanisms of the pathogenesis of depression, in the present study, the hippocampal mRNA expression profile of mice exposed to CUMS for 5 weeks was sequenced using Illumina HiSeq 4000 platform followed by enrichment analysis, including Hierarchical Cluster, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) network. Totally, 346 differently expressed mRNAs, including 208 downregulated and 138 upregulated, were identified in the hippocampus of the CUMS mice. KEGG biological pathway analysis showed that the upregulated and downregulated mRNAs were mostly enriched in 29 pathways and 8 pathways, respectively. PPI network analysis exposed that glyceraldehyde 3-phosphate dehydrogenase was the crucial node with high connectivity degree. Additionally, most of these genes in PPI network analysis have previously been linked to energy metabolism and corticosterone responses. Overall, our results indicate the possible novel molecular targets for the therapy of depression.

There is no existing report on the quality of randomized controlled trials (RCTs) of melasma treatment currently conducted in China. This study aims to assess the quality of RCT- reporting in the treatment of melasma conducted in China.

Whether large conductance Ca(2+)-activated potassium (BK) channels are present in the substantia nigra pars reticulata (SNr) is a matter of debate. Using the patch-clamp technique, we examined the functional expression of BK channels in neurons of the SNr and showed that the channels were activated or inhibited by internal high-energy phosphates (IHEPs) at positive and negative membrane potentials, respectively. SNr neurons showed membrane potential hyperpolarization under glucose-deprivation conditions which was attenuated by paxilline, a specific BK channel blocker. In addition, Fluo-3 fluorescence recording detected an increase in the level of internal free calcium ([Ca(2+)](i)) during ischemic hyperpolarization. These results confirm that BK channels are present in SNr neurons and indicate that their unique IHEP sensitivity is requisite in neuronal ischemic responses. Bearing in mind that the K(ATP) channel blocker tolbutamide also attenuated the hyperpolarization, we suggest that BK channels may play a protective role in the basal ganglia by modulating the excitability of SNr neurons along with K(ATP) channels under ischemic stresses.

Glutathione (GSH) is the main component of the mitochondrial thiol pool and plays key roles in the biological processes. Many evidences have suggested that cysteine and homocysteine also exist in mitochondria and are interrelated with GSH in biological systems. The fluctuation of the levels of mitochondrial thiols has been linked to many diseases and cells' dysfunction. Therefore, the monitoring of mitochondrial thiol status is of great significance for clinical studies. We report here a novel fluorescence resonance energy transfer based two-photon probe MT-1 for mitochondrial thiols detection. MT-1 was constructed by integrating the naphthalimide moiety (donor) and rhodamine B (accepter and targeting group) through a newly designed linker. MT-1 shows a fast response, high selectivity, and sensitivity to thiols, as well as a low limit of detection. The two-photon property of MT-1 allows the direct visualization of thiols in live cells and tissues by two-photon microscopy. MT-1 can serve as an effective tool to unravel the diverse biological functions of mitochondrial thiols in living systems.

Conventional dissolving microneedles (DMNs) face significant challenges in anti-melanoma therapy due to the lack of active thrust to achieve efficient transdermal drug delivery and intra-tumoral penetration.

The nucleus ambiguus (nAmb) provides parasympathetic control of cardiorespiratory functions as well as motor control of the upper airways and striated esophagus. A subset of nAmb neurons innervates the heart through the vagus nerve to control cardiac function at rest and during key autonomic reflexes such as the mammalian diving reflex. These cardiovagal nAmb neurons may be molecularly and anatomically distinct, but how they differ from other nAmb neurons in the adult brain remains unclear. We therefore classified adult mouse nAmb neurons based on their genome-wide expression profiles, innervation of cardiac ganglia, and ability to control HR. Our integrated analysis of single-nucleus RNA-sequencing data predicted multiple molecular subtypes of nAmb neurons. Mapping the axon projections of one nAmb neuron subtype, Npy2r-expressing nAmb neurons, showed that they innervate cardiac ganglia. Optogenetically stimulating all nAmb vagal efferent neurons dramatically slowed HR to a similar extent as selectively stimulating Npy2r+ nAmb neurons, but not other subtypes of nAmb neurons. Finally, we trained mice to perform voluntary underwater diving, which we use to show Npy2r+ nAmb neurons are activated by the diving response, consistent with a cardiovagal function for this nAmb subtype. These results together reveal the molecular organization of nAmb neurons and its control of heart rate.

Electroacupuncture (EA) has been reported to alleviate motor deficits in Parkinson's disease (PD) patients, and PD animal models. However, the mechanisms by which EA improves motor function have not been investigated. We have employed a 6-hydroxydopamine (6-OHDA) unilateral injection induced PD model to investigate whether EA alters protein expression in the motor cortex. We found that 4weeks of EA treatment significantly improved spontaneous floor plane locomotion and rotarod performance. High-throughput proteomic analysis in the motor cortex was employed. The expression of 54 proteins were altered in the unlesioned motor cortex, and 102 protein expressions were altered in the lesioned motor cortex of 6-OHDA rats compared to sham rats. Compared to non-treatment PD control, EA treatment reversed 6 proteins in unlesioned and 19 proteins in lesioned motor cortex. The present study demonstrated that PD induces proteomic changes in the motor cortex, some of which are rescued by EA treatment. These targeted proteins were mainly involved in increasing autophagy, mRNA processing and ATP binding and maintaining the balance of neurotransmitters.

IL23/Th17 axis acts as an inflammatory pathway in gastric carcinogenesis. MicroRNA- (miRNA-) binding site single-nucleotide polymorphisms (SNPs) of inflammatory genes may alter gastric cancer (GC) susceptibility. In this study, four miRNA binding site SNPs (rs3748067 of IL17A, rs887796, rs1468488 of IL17RA, and rs10889677 of IL23R) were genotyped from 500 patients and 500 controls. Unconditional logistic regression analyses and multifactor dimensionality reduction software were used to evaluate the relationships of SNPs with GC and gene-environment interactions, respectively. Quantitative real-time PCR, Western blot analysis, and luciferase report gene assay were applied for function verification. We found that CT (ORadj = 0.59; 95% CI: 0.44-0.79), CT + TT (ORadj = 0.58; 95% CI: 0.43-0.77) genotypes, and T allele (ORadj = 0.77; 95% CI: 0.47-0.80) of rs3748067 reduced GC risk; the rs10889677 CC genotype (ORadj = 2.22; 95% CI: 1.27-3.87) and C allele (ORadj = 1.24; 95% CI: 1.02-1.52) increased GC risk. A meaningful interaction among ever smoked, family history of GC, and rs3748068 could intensify GC risk by 2.25-fold. Functional tests demonstrated the inhibitory effect of miR-10a-3p on IL17A expression in SGC-7901 cells. These results suggested that miRNA binding site SNPs within IL23/Th17 inflammatory pathway genes and their interactions with environmental factors could be associated with GC risk.

Although individuals with coronavirus disease 2019 (COVID-19) are known to be at increased risk for other conditions resulting from pathogenic changes (including metaplastic or anaplastic) in the lungs and other organs and organ systems, it is still unknown whether COVID-19 affects childhood intelligence. The present two-sample Mendelian randomization study aims to identify the genetic causal link between COVID-19 and childhood intelligence. Four COVID-19 genetic instrumental variants (IVs) were chosen from the largest genome-wide association studies (GWAS) for COVID-19 (hospitalized vs. population) (6406 cases and 902 088 controls of European ancestry). The largest childhood intelligence GWAS (n = 12 441 individuals of European ancestry) was used to evaluate the effect of the identified COVID-19-associated genetic IVs on childhood intelligence. We found that as the genetic susceptibility to COVID-19 increased, childhood intelligence followed a decreasing trend, according to mr_egger (β = -0.156; p = 0.601; odds ratio [OR] = 0.856; 95% confidence interval [CI]: 0.522-1.405), simple mode (β = -0.126; p = 0.240; OR = 0.882; 95% CI: 0.745-1.044), and weighted mode (β = -0.121; p = 0.226; OR = 0.886; 95% CI: 0.758-1.036) analyses. This trend was further demonstrated by the weighted median (β = -0.134; p = 0.031; OR = 0.875; 95% CI: 0.774-0.988) and the inverse variance weighted (β = -0.152; p = 0.004; OR = 0.859; 95% CI: 0.776-0.952). Our analysis suggests a causal link between genetically increased COVID-19 and decreased childhood intelligence. Thus, COVID-19 may be a risk factor for declines in childhood intelligence.

Glutamine family amino acids such as glutamate, pyroglutamate, and glutamine have been shown to play important roles in COVID-19. However, it is still unclear about the role of pyroglutamate in COVID-19. Thus, we use a two-sample Mendelian randomization (MR) study to identify the genetic causal link between blood pyroglutamine levels and COVID-19 risk.

Random skin flaps are frequently applied in plastic and reconstructive surgery for patients suffering from soft tissue defects caused by congenital deformities, trauma and tumor resection. However, ischemia and necrosis in distal parts of random skin flaps remains a common challenge that limits the clinical application of this procedure. Recently, chemically modified mRNA (modRNA) was found to have great therapeutic potential. Here, we explored the potential of fibroblasts engineered to express modified mRNAs encoding the stromal cell-derived factor-1α (SDF-1α) to improve vascularization and survival of therapeutic random skin flaps. Our study showed that fibroblasts pre-treated with SDF-1α modRNA have the potential to salvage ischemic skin flaps. Through a detailed analysis, we revealed that a fibroblast SDF-1α modRNA combinatorial treatment dramatically reduced tissue necrosis and significantly promoted neovascularization in random skin flaps compared to that in the control and vehicle groups. Moreover, SDF-1α modRNA transcription in fibroblasts promoted activation of the SDF-1α/CXCR4 pathway, with concomitant inactivation of the MEK/ERK, PI3K/AKT, and JAK2/STAT3 signaling pathways, indicating a possible correlation with cell proliferation and migration. Therefore, fibroblast-mediated SDF-1α modRNA expression represents a promising strategy for random skin flap regeneration.

To summarize and assess the credibility and strength of non-genetic factors and genetic variation on gastric cancer risk, we performed a field synopsis and meta-analysis to identify the risk of gastric cancer in Chinese population. Cumulative evidence was graded according to the Venice criteria, and attributable risk percentage (ARP) and population attributable risk percentage (PARP) were used to evaluate the epidemiological effect. A total of 956 studies included non-genetic (404 studies) and genetic factors (552 studies) were quantified, and data on 1161 single nucleotide polymorphisms (SNPs) were available. We identified 14 non-genetic factors were significantly associated with gastric cancer risk. For the analysis of time trends, H. pylori infection rate in gastric cancer and population showed a downward trend. Meanwhile 22 variants were identified significantly associated with gastric cancer: 3 (PLCE1 rs2274223, PSCA rs2976392, MUC1 rs4072037) were high and 19 SNPs were intermediate level of summary evidence, respectively. For non-genetic factors, the top three for ARP were 54.75% (pickled food), 65.87% (stomach disease), and 49.75% (smoked and frying). For PARP were 34.22% (pickled food), 34.24% (edible hot food) and 23.66%(H. pylori infection). On the basis of ARP and PARP associated with SNPs of gastric cancer, the top three for ARP were 53.91% (NAT2, rs1799929),53.05% (NAT2 phenotype), and 42.85% (IL-10, rs1800896). For PARP (Chinese Han in Beijing) were 36.96% (VDR, rs731236), 25.58% (TGFBR2, rs3773651) and 20.56% (MUC1, rs4072037). Our study identified non-genetic risk factors and high-quality biomarkers of gastric cancer susceptibility and their contribution to gastric cancer.