Parkinson's disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are common features of ...PD. Previous studies revealed that terazosin (TZ) enhances the activity of phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis and increasing cellular ATP levels. Therefore, we asked whether enhancement of PGK1 activity would change the course of PD. In toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, TZ increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function. Because TZ is prescribed clinically, we also interrogated 2 distinct human databases. We found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs. These findings suggest that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD.
The COVID lockdown has posted a great challenge to paediatric patients with type 1 diabetes (T1D) and their caregivers on the disease management. This systematic review and meta-analysis sought to ...compare the glycaemic control among paediatric patients with T1D (aged under 18 years) pre- during, and post-lockdown period.
We did a systematic search of three databases (PubMed, Embase, and the WHO COVID-19 Global literature) for the literature published between 1 Jan 2019 to 10 Sep 2022. Studies meeting the following inclusion criteria were eligible for this study: (1) a COVID-19 related study; (2) inclusion of children aged 18 years old or under with established T1D; (3) comparing the outcomes of interest during or after the COVID lockdown with that before the lockdown. Study endpoints included mean difference (MD) in HbA1c, blood glucose, time in range (TIR, 70-180 mg/dl), time above range (TAR, >180mg/dl), time below range (TBR,<70mg/dl) and glucose variability (coefficient of variation CV) between pre-lockdown and during lockdown and/or between pre- and post-lockdown period. The MD and its corresponding 95% CI of each endpoint were pooled using random-effect model considering the potential between-study heterogeneity in COVID restrictions and T1D management.
Initial search identified 4488 records and 22 studies with 2106 paediatric patients with T1D were included in the final analysis. Compared with pre-lockdown period, blood glucose was significantly decreased by 0.11 mmol/L (95%CI: -0.18, -0.04) during lockdown period and by 0.42 mmol/L (95%CI: -0.73, -0.11) after lockdown. The improvement was also found for TIR, TAR, TBR, and CV during and post-lockdown (all p values<0.05) except for the post-lockdown TBR (
=0.35). No significant change in HbA1c was observed during and post- lockdown period when compared with the pre-lockdown value. There was moderate to high between-study heterogeneity for most of the analyses.
Compared with pre-lockdown period, there was significant improvement in T1D paediatric patients' glucose metrics during and post-lockdown. The underlying reasons for this positive impact warrant further investigation to inform future paediatric diabetes management.
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022359213.
DCs act as sentinels for the immune system. DCs capture antigens locally and become mature, characterized by up-regulation of chemokine receptors (CCR7 and CXCR4), adhesion molecule (L-selectin), ...co-stimulator molecules (CD40, CD80 and CD86) and MHC II. Under high concentration of CCL21 in draining lymph nodes (LNs), mature DCs traffic to LNs via afferent lymph vessels and present antigens to T cells, resulting in the development of arthritis. HCQ impaires DC maturation via blocking TLR9 signaling, retrains DC migration to LNs, and prevents the initiation and progression of RA.
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•HCQ efficiently inhibited DC phenotypic and functional maturation stimulated by serum from RA patients.•HCQ prevented progression of arthritis by inhibiting DC maturation and migration from peripheral blood to LNs.•HCQ inhibited CpG ODN 1826-activated BMDC maturation and migration.•The effect of HCQ on DCs was related to the block in TLR9 signaling.•The development of arthritis was impaired in TLR9−/− mice.
Hydroxychloroquine (HCQ) is one of the most commonly prescribed immune-suppressants in treating rheumatoid arthritis (RA). Our previous research showed that HCQ suppressed RA development by inhibiting T follicular helper (Tfh) cells directly. Dendritic cells (DCs) serve as the link between innate and acquired immunity. Whether HCQ suppressed Tfh cell through DCs was not clear. In current study, we found that HCQ efficiently inhibited CD86, chemokine (C-X-C motif) receptor 4 (CXCR4) expression and interferon-α (IFN-α) secretion of healthy donor derived purified DCs stimulated by RA patient serum. To mimic RA, collagen-induced arthritis (CIA) mouse model was used and treated with HCQ daily for fifty-four days prior to sacrifice. We found HCQ inhibited DC maturation and migration to lymph nodes (LNs), manifested as down-regulated expression of CD40, CD80, CD86, MHCII (I-Aq) on LN DCs. In addition, HCQ reduced the level of chemokine receptor 7 (CCR7) and L-selectin on peripheral blood DCs and diminished percentage of LN DCs. Of note, HCQ only inhibited CpG ODN 1826-induced IL-12 secretion by bone marrow DCs (BMDCs) stimulated by various toll like receptor (TLR) agonists. Mechanistically, HCQ down-regulated the expression of TLR9 not only in healthy donor PBMC-derived DCs stimulated by RA patient serum, but also in LN DCs of CIA mice and CpG-activated BMDCs. Furthermore, arthritis scores in TLR9−/− mice were much lower than that in wild type mice with impaired maturity and migration capability of DCs. Collectively, activation of DCs contributes to the pathogenesis of RA and HCQ shows protective effects on RA by inhibition of DC activation via blocking TLR9.
As fundamental processes in mitochondrial dynamics, mitochondrial fusion, fission and transport are regulated by several core components, including Miro. As an atypical Rho-like small GTPase with ...high molecular mass, the exchange of GDP/GTP in Miro may require assistance from a guanine nucleotide exchange factor (GEF). However, the GEF for Miro has not been identified. While studying mitochondrial morphology in Drosophila, we incidentally observed that the loss of vimar, a gene encoding an atypical GEF, enhanced mitochondrial fission under normal physiological conditions. Because Vimar could co-immunoprecipitate with Miro in vitro, we speculated that Vimar might be the GEF of Miro. In support of this hypothesis, a loss-of-function (LOF) vimar mutant rescued mitochondrial enlargement induced by a gain-of-function (GOF) Miro transgene; whereas a GOF vimar transgene enhanced Miro function. In addition, vimar lost its effect under the expression of a constitutively GTP-bound or GDP-bound Miro mutant background. These results indicate a genetic dependence of vimar on Miro. Moreover, we found that mitochondrial fission played a functional role in high-calcium induced necrosis, and a LOF vimar mutant rescued the mitochondrial fission defect and cell death. This result can also be explained by vimar's function through Miro, because Miro's effect on mitochondrial morphology is altered upon binding with calcium. In addition, a PINK1 mutant, which induced mitochondrial enlargement and had been considered as a Drosophila model of Parkinson's disease (PD), caused fly muscle defects, and the loss of vimar could rescue these defects. Furthermore, we found that the mammalian homolog of Vimar, RAP1GDS1, played a similar role in regulating mitochondrial morphology, suggesting a functional conservation of this GEF member. The Miro/Vimar complex may be a promising drug target for diseases in which mitochondrial fission and fusion are dysfunctional.
Increasing evidence suggests that dysregulation of long non-coding RNAs (lncRNAs) is implicated in chemoresistance in cancers. However, the function and molecular mechanisms of lncRNAs in gastric ...cancer chemoresistance are still not well understood. In this study, we aimed to investigate the functional role and the underlying molecular mechanisms of lncRNA HOXD cluster antisense RNA 1 (HOXD-AS1) in cisplatin (DDP) resistance in gastric cancer. Our results revealed that HOXD-AS1 was upregulated in DDP-resistant gastric cancer tissues and cells. Patients with gastric cancer with high HOXD-AS1 expression levels had a poor prognosis. Knockdown of HOXD-AS1 facilitated the sensitivity of DDP-resistant gastric cancer cells to DDP. Additionally, HOXD-AS1 epigenetically silenced PDCD4 through binding to the histone methyltransferase enhancer of zeste homologue 2 (EZH2) on the promoter of PDCD4, thus increasing H3K27me3. More importantly, PDCD4 silencing counteracted HOXD-AS1 knockdown-mediated enhancement of DDP sensitivity in DDP-resistant gastric cancer cells. In summary, HOXD-AS1 led to DDP resistance in gastric cancer by epigenetically suppressing PDCD4 expression, providing a novel therapeutic strategy for patients with gastric cancer with chemoresistance.
Interaction between humans and the gut microbiota is important for human physiology. Here, the gut microbiota was analyzed via metagenomic sequencing, and the fluctuations in the gut microbiota under ...the conditions of spaceflight were characterized. The composition and function of the gut microbiota were substantially affected by spaceflight; however, individual specificity was uncompromised. We further confirmed the species fluctuations and functional genes from both missions. Resistance and virulence genes in the gut microbiota were affected by spaceflight, but the species attributions remained stable. Spaceflight markedly affected the composition and function of the human gut microbiota, implying that the human gut microbiota is sensitive to spaceflight.
Retinoblastoma is a childhood retinal tumour that is the most common primary malignant intraocular tumour. However, it has been challenging to identify the cell types associated with genetic ...complexity. Here, we performed single-cell RNA sequencing on 14,739 cells from two retinoblastoma samples to delineate the heterogeneity and the underlying mechanism of retinoblastoma progression. Using a multiresolution network-based analysis, we identified two major cell types in human retinoblastoma. Cell trajectory analysis yielded a total of 5 cell states organized into two main branches, and the cell cycle-associated cone precursors were the cells of origin of retinoblastoma that were required for initiating the differentiation and malignancy process of retinoblastoma. Tumour cells differentiation reprogramming trajectory analysis revealed that cell-type components of multiple tumour-related pathways and predominantly expressed UBE2C were associated with an activation state in the malignant progression of the tumour, providing a potential novel "switch gene" marker during early critical stages in human retinoblastoma development. Thus, our findings improve our current understanding of the mechanism of retinoblastoma progression and are potentially valuable in providing novel prognostic markers for retinoblastoma.
Small non-coding RNAs (sRNAs) facilitate host-microbe interactions. They have a central function in the post-transcriptional regulation during pathogenic lifestyles. Hfq, an RNA-binding protein that ...many sRNAs act in conjunction with, is required for Y. pestis pathogenesis. However, information on how Yersinia pestis modulates the expression of sRNAs during infection is largely unknown.
We used RNA-seq technology to identify the sRNA candidates expressed from Y. pestis grown in vitro and in the infected lungs of mice. A total of 104 sRNAs were found, including 26 previously annotated sRNAs, by searching against the Rfam database with 78 novel sRNA candidates. Approximately 89% (93/104) of these sRNAs from Y. pestis are shared with its ancestor Y. pseudotuberculosis. Ninety-seven percent of these sRNAs (101/104) are shared among more than 80 sequenced genomes of 135 Y. pestis strains. These 78 novel sRNAs include 62 intergenic and 16 antisense sRNAs. Fourteen sRNAs were selected for verification by independent Northern blot analysis. Results showed that nine selected sRNA transcripts were Hfq-dependent. Interestingly, three novel sRNAs were identified as new members of the transcription factor CRP regulon. Semi-quantitative analysis revealed that Y. pestis from the infected lungs induced the expressions of six sRNAs including RyhB1, RyhB2, CyaR/RyeE, 6S RNA, RybB and sR039 and repressed the expressions of four sRNAs, including CsrB, CsrC, 4.5S RNA and sR027.
This study is the first attempt to subject RNA from Y. pestis-infected samples to direct high-throughput sequencing. Many novel sRNAs were identified and the expression patterns of relevant sRNAs in Y. pestis during in vitro growth and in vivo infection were revealed. The annotated sRNAs accounted for the most abundant sRNAs either expressed in bacteria grown in vitro or differentially expressed in the infected lungs. These findings suggested these sRNAs may have important functions in Y. pestis physiology or pathogenesis.
Brain aging may accelerate after rodents reach middle age. However, the endogenous mediator that promotes this acceleration is unknown. We predict that the mediator may be expressed after an organism ...reaches middle age and dysregulates mitochondrial function. In the neurons of wild-type Drosophila (flies), we observed that mitochondria were fragmented in aged flies, and this fragmentation was associated with mitochondrial calcium overload. In a previous study, we found that mitochondrial fragmentation induced by calcium overload was reversed by the loss of Vimar, which forms a complex with Miro. Interestingly, Vimar expression was increased after the flies reached middle age. Overexpression of Vimar in neurons resulted in premature aging and mitochondrial calcium overload. In contrast, downregulation of Vimar in flies older than middle age promoted healthy aging. As the mouse homolog of Vimar, RAP1GDS1 expression was found to be increased after mice reached middle age; RAP1GDS1-transgenic and RAP1GDS1-knockdown mice displayed similar responses to flies with overexpressed and reduced Vimar expression, respectively. This research provides genetic evidence of a conserved endogenous mediator that promotes accelerated brain aging.
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