Changes in Circulating CD44+CD62L- Treg Subsets and CD44-CD62L+ Treg Subsets Reflect the Clinical Status of Patients with Allergic Rhinitis.

INTRODUCTION: This study clarified the expression changes and clinical significance of CD44+CD62L- Treg and CD44-CD62L+ Treg subsets in the peripheral blood of patients with allergic rhinitis (AR). METHODS: The peripheral blood of 39 patients with AR and 42 healthy controls was collected. Clinical data, such as sex, age, IgE titer, allergen screening information and visual analogue scale (VAS) score, were recorded. Changes in serum IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ were detected using the cytometric bead array method. Flow cytometry was used to detect the proportions of Th1, Th2, Th17, TFH, and Th9 cells and the proportions of CD44+CD62L- Treg and CD44-CD62L+ Treg subsets. Correlation analysis was performed between the CD44+CD62L- Treg subsets and the CD44-CD62L+ Treg subsets with clinical indicators (VAS score, total IgE titer), cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ), and Th1/Th2/Th17/TFH/Th9 cell proportions. RESULTS: Compared to the control group, the proportion of total Treg cells and CD44+CD62L- Treg cells in the AR group decreased, and the proportion of CD44-CD62L+ Treg cells increased (p < 0.05). The proportions of CD44+CD62L- Treg cells significantly negatively correlated with Th2 cells (R = -0.5270, p < 0.05) and positively correlated with Treg cytokine IL-10 (R = 0.6447, p < 0.05). In addition, CD44+CD62L- Treg cells negatively correlated with the VAS score (R = -0.4956, p < 0.05), total IgE level (R = -0.4177, p < 0.05) and Th2 cytokine IL-6 level (R = -0.3034, p < 0.05) but positively correlated with the Th1 cytokine IL-2 (R = 0.4331, p < 0.05). In contrast, the proportion of CD44+CD62L- Treg cells significantly positively correlated with the Th2 cells (R = 0.6187, p < 0.05). Moreover, the proportion of CD44-CD62L+ Treg cells positively correlated with the VAS score (R = 0.4060, p < 0.05), total IgE level (R = 0.5224, p < 0.05) and Th2 cytokine IL-4 (R = 0.2647, p < 0.05) and IL-6 levels (R = 0.3824, p < 0.05) but negatively correlated with Th1 cytokine IL-2 (R = -0.3451, p < 0.05) and IL-10 (R = -0.3277, p < 0.05). CONCLUSION: A greater proportion of CD44+CD62L- Tregs correlated with better reversal of the Th1/Th2 imbalance and milder clinical symptoms in AR patients. The presence of more CD44-CD62L+ Tregs correlated with a weaker immunosuppressive effect on Th2 cells and more severe clinical symptoms in AR patients. These findings provide new perspectives for the treatment and disease monitoring of AR.

The stress granule protein G3BP1 promotes pre-condensation of cGAS to allow rapid responses to DNA.

Cyclic GMP-AMP synthase (cGAS) functions as a key sensor for microbial invasion and cellular damage by detecting emerging cytosolic DNA. Here, we report that GTPase-activating protein-(SH3 domain)-binding protein 1 (G3BP1) primes cGAS for its prompt activation by engaging cGAS in a primary liquid-phase condensation state. Using high-resolution microscopy, we show that in resting cells, cGAS exhibits particle-like morphological characteristics, which are markedly weakened when G3BP1 is deleted. Upon DNA challenge, the pre-condensed cGAS undergoes liquid-liquid phase separation (LLPS) more efficiently. Importantly, G3BP1 deficiency or its inhibition dramatically diminishes DNA-induced LLPS and the subsequent activation of cGAS. Interestingly, RNA, previously reported to form condensates with cGAS, does not activate cGAS. Accordingly, we find that DNA - but not RNA - treatment leads to the dissociation of G3BP1 from cGAS. Taken together, our study shows that the primary condensation state of cGAS is critical for its rapid response to DNA.

Pubertal exposure to Microcystin-LR arrests spermatogonia proliferation by inducing DSB and inhibiting SIRT6 dependent DNA repair in vivo and in vitro.

The reproduction toxicity of pubertal exposure to Microcystin-LR (MC-LR) and the underlying mechanism needs to be further investigated. In the current study, pubertal male ICR mice were intraperitoneally injected with 2 µg/kg MC-LR for four weeks. Pubertal exposure to MC-LR decreased epididymal sperm concentration and blocked spermatogonia proliferation. In-vitro studies found MC-LR inhibited cell proliferation of GC-1 cells and arrested cell cycle in G2/M phase. Mechanistically, MC-LR exposure evoked excessive reactive oxygen species (ROS) and induced DNA double-strand break in GC-1 cells. Besides, MC-LR inhibited DNA repair by reducing PolyADP-ribosylation (PARylation) activity of PARP1. Further study found MC-LR caused proteasomal degradation of SIRT6, a monoADP-ribosylation enzyme which is essential for PARP1 PARylation activity, due to destruction of SIRT6-USP10 interaction. Additionally, MG132 pretreatment alleviated MC-LR-induced SIRT6 degradation and promoted DNA repair, leading to the restoration of cell proliferation inhibition. Correspondingly, N-Acetylcysteine (NAC) pre-treatment mitigated the disturbed SIRT6-USP10 interaction and SIRT6 degradation, causing recovered DNA repair and subsequently restoration of cell proliferation inhibition in MC-LR treated GC-1 cells. Together, pubertal exposure to MC-LR induced spermatogonia cell cycle arrest and sperm count reduction by oxidative DNA damage and simultaneous SIRT6-mediated DNA repair failing. This study reports the effect of pubertal exposure to MC-LR on spermatogenesis and complex mechanism how MC-LR induces spermatogonia cell proliferation inhibition.

1-Nitropyrene disrupts testicular steroidogenesis via oxidative stress-evoked PERK-eIF2α pathway.

Our previous study showed 1-Nitropyrene (1-NP) exposure disrupted testicular testosterone synthesis in mouse, but the exact mechanism needs further investigation. The present research found 4-phenylbutyric acid (4-PBA), an endoplasmic reticulum (ER) stress inhibitor, recovered 1-NP-induced ER stress and testosterone synthases reduction in TM3 cells. GSK2606414, a protein kinase-like ER kinase (PERK) kinase inhibitor, attenuated 1-NP-induced PERK-eukaryotic translation initiation factor 2α (eIF2α) signaling activation and downregulation of steroidogenic proteins in TM3 cells. Both 4-PBA and GSK2606414 attenuated 1-NP-induced steroidogenesis disruption in TM3 cells. Further studies used N-Acetyl-L-cysteine (NAC) as a classical antioxidant to explore whether oxidative stress-activated ER stress mediated 1-NP-induced testosterone synthases reduction and steroidogenesis disruption in TM3 cells and mouse testes. The results showed NAC pretreatment mitigated oxidative stress, and subsequently attenuated ER stress, particularly PERK-eIF2α signaling activation, and downregulation of testosterone synthases in 1-NP-treated TM3 cells. More importantly, NAC extenuated 1-NP-induced testosterone synthesis in vitro and in vivo. The current work indicated that oxidative stress-caused ER stress, particularly PERK-eIF2α pathway activation, mediates 1-NP-downregulated steroidogenic proteins and steroidogenesis disruption in TM3 cells and mouse testes. Significantly, the current study provides a theoretical basis and demonstrates the experimental evidence for the potential application of antioxidant, such as NAC, in public health prevention, particularly in 1-NP-induced endocrine disorder.

Glial expression of disease-associated poly-glutamine proteins impairs the blood-brain barrier in Drosophila.

Expansion of poly-glutamine (polyQ) stretches in several proteins has been linked to neurodegenerative diseases. The effects of polyQ-expanded proteins on neurons have been extensively studied, but their effects on glia remain unclear. We found that expression of distinct polyQ proteins exclusively in all glia or specifically in the blood-brain barrier (BBB) and blood-retina barrier (BRB) glia caused cell-autonomous impairment of BBB/BRB integrity, suggesting that BBB/BRB glia are most vulnerable to polyQ-expanded proteins. Furthermore, we also found that BBB/BRB leakage in Drosophila is reflected in reversed waveform polarity on the basis of electroretinography (ERG), making ERG a sensitive method to detect BBB/BRB leakage. The polyQ-expanded protein Atxn3-84Q forms aggregates, induces BBB/BRB leakage, restricts Drosophila lifespan and reduces the level of Repo (a pan-glial transcriptional factor required for glial differentiation). Expression of Repo in BBB/BRB glia can rescue BBB/BRB leakage, suggesting that the reduced expression of Repo is important for the effect of polyQ on BBB/BRB impairment. Coexpression of the chaperon HSP40 and HSP70 effectively rescues the effects of Atxn3-84Q, indicating that polyQ protein aggregation in glia is deleterious. Intriguingly, coexpression of wild-type Atxn3-27Q can also rescue BBB/BRB impairment, suggesting that normal polyQ protein may have a protective function.

A multifunctional nanocarrier for efficient TRAIL-based gene therapy against hepatocellular carcinoma with desmoplasia in mice.

The anticancer efficacy of TNF-related apoptosis-inducing ligand (TRAIL)-based therapy is limited because of systemic toxicity, poor bioavailability, and development of TRAIL resistance. We developed a tumor-targeted LCPP (lipid/calcium/phosphate/protamine) nanoparticle (NP) to deliver TRAIL plasmid DNA (pDNA) into hepatocellular carcinoma (HCC) cells in a mouse model of HCC. TRAIL pDNA was encapsulated in a pH stimuli-responsive calcium phosphate (CaP) core, and protamine was added to facilitate nuclear delivery of pDNA. In addition, intracellular release of Ca2+ from the CaP core overcame TRAIL resistance by calcium influx-dependent DR5 up-regulation. TRAIL expression also attenuated fibrosis in liver tissues surrounding HCCs by reverting activated hepatic stellate cells (HSCs) to a quiescent state or by directly inducing apoptosis in activated HSCs. CONCLUSION: TRAIL pDNA delivered by HCC-targeted LCPP NPs in combination with conventional sorafenib treatment attenuated HCC progression as well as liver fibrosis. Overall, our study presents an effective TRAIL-based cancer therapy that could be developed for clinical applications. (Hepatology 2018;67:899-913).

Protodioscin ameliorates oxidative stress, inflammation and histology outcome in Complete Freund's adjuvant induced arthritis rats.

Protective effect of protodioscin or methyl protodioscin against inflammation had been reported in various inflammation diseases. This study aimed to investigate the effect of protodioscin against Complete Freund's adjuvant (CFA)-induced arthritis rats. Rats randomly divided into model groups were injected with CFA, companied with different dose of protodioscin (50, 100, and 200 mg/kg body weight). The histology, changes in biochemical parameters and inflammatory cytokines expression were detected for anti-inflammation effect evaluation of protodioscin. CFA treatment induced arthritic rats with swelling paw, ankle inflammation, and area of lymphocyte infiltration, upregulated inflammatory cytokines (IL-1ß, TNF-α, cyclo-oxygenase 2, and IL-6 as well as prostaglandin E2), articular elastase, myeloperoxidase, lipid peroxidase and nitrite oxide levels, downregulated glutathione, catalase, and superoxide dismutase. In contrast, protodioscin ameliorated all the changes induced by CFA in rats, suggesting the anti-inflammatory effect of protodioscin. We concluded that protodioscin administration into CFA-induced arthritis rats protected against CFA-induced oxidative stress, neutrophil infiltration, and inflammation, suggesting the anti-inflammatory effect and the therapeutic potential of protodioscin for arthritis.

Molecular cloning and expression analysis of cytochrome c oxidase subunit II from Sitophilus zeamais.

Cytochrome c oxidase subunit II (COX II) containing a dual core CuA active site is one of the core subunits of mitochondrial Cytochrome c oxidase (Cco), which plays a significant role in the physiological process. In this report, the full-length cDNA of COXII gene was cloned from Sitophilus zeamais, which had an open reading frame (ORF) of 684 bp encoding 227 amino acids residues. The predicted COXII protein had a molecular mass of 26.2 kDa with pI value of 6.37. multiple sequence alignment and phylogenetic analysis indicated that Sitophilus zeamais COXII had high sequence identity with the COXII of other insect species. The gene was subcloned into the expression vector pET-32a, and induced by isopropyl ß-d-thiogalactopyranoside (IPTG) in E. coli Transetta (DE3) expression system. Finally the recombinant COXII with 6-His tag was purified using affinity chromatography with Ni(2+)-NTA agarose. Western Blotting (WB) showed the recombinant protein was about 44 kD, and the concentration of fusion protein was 50 µg/mL. UV-spectrophotometer and infrared spectrometer analysis showed that recombinant COXII could catalyze the oxidation of substrate Cytochrome C (Cyt c), and influenced by allyl isothiocyanate (AITC). By using molecular docking method, It was found that a sulfur atom of AITC structure could form a length of 2.9 Å hydrogen bond with Leu-31. These results suggested that tag-free COXII was functional and one of the action sites of AITC, which will be helpful to carry out a point mutation in binding sites for the future research.

Correlation of Cytochrome P450 Oxidoreductase Expression with the Expression of 10 Isoforms of Cytochrome P450 in Human Liver.

Human cytochrome P450 oxidoreductase (POR) provides electrons for all microsomal cytochromes P450 (P450s) and plays an indispensable role in drug metabolism catalyzed by this family of enzymes. We evaluated 100 human liver samples and found that POR protein content varied 12.8-fold, from 12.59 to 160.97 pmol/mg, with a median value of 67.99 pmol/mg; POR mRNA expression varied by 26.4-fold. POR activity was less variable with a median value of 56.05 nmol/min per milligram. Cigarette smoking and alcohol consumption clearly influenced POR activity. Liver samples with a 2286822 TT genotype had significantly higher POR mRNA expression than samples with CT genotype. Homozygous carriers of POR2286822C>T, 2286823G>A, and 3823884A>C had significantly lower POR protein levels compared with the corresponding heterozygous carriers. Liver samples from individuals homozygous at 286823G>A, 1135612A>G, and 10954732G>A generally had lower POR activity levels than those from heterozygous or wild-type samples, whereas the common variant POR*28 significantly increased POR activity. There was a strong association between POR and the expression of P450 isoforms at the mRNA and protein level, whereas the relationship at the activity level, as well as the effect of POR protein content on P450 activity, was less pronounced. POR transcription was strongly correlated with both hepatocyte nuclear factor 4 alpha and pregnane X receptor mRNA levels. In conclusion, we have elucidated some potentially important correlations between POR single-nucleotide polymorphisms and POR expression in the Chinese population and have developed a database that correlates POR expression with the expression and activity of 10 P450s important in drug metabolism.

Dual-Functional Nanoparticles Targeting CXCR4 and Delivering Antiangiogenic siRNA Ameliorate Liver Fibrosis.

The progression of liver fibrosis, an intrinsic response to chronic liver injury, is associated with hepatic hypoxia, angiogenesis, abnormal inflammation, and significant matrix deposition, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Due to the complex pathogenesis of liver fibrosis, antifibrotic drug development has faced the challenge of efficiently and specifically targeting multiple pathogenic mechanisms. Therefore, CXCR4-targeted nanoparticles (NPs) were formulated to deliver siRNAs against vascular endothelial growth factor (VEGF) into fibrotic livers to block angiogenesis during the progression of liver fibrosis. AMD3100, a CXCR4 antagonist that was incorporated into the NPs, served dual functions: it acted as a targeting moiety and suppressed the progression of fibrosis by inhibiting the proliferation and activation of hepatic stellate cells (HSCs). We demonstrated that CXCR4-targeted NPs could deliver VEGF siRNAs to fibrotic livers, decrease VEGF expression, suppress angiogenesis and normalize the distorted vessels in the fibrotic livers in the carbon tetrachloride (CCl4) induced mouse model. Moreover, blocking SDF-1α/CXCR4 by CXCR4-targeted NPs in combination with VEGF siRNA significantly prevented the progression of liver fibrosis in CCl4-treated mice. In conclusion, the multifunctional CXCR4-targeted NPs delivering VEGF siRNAs provide an effective antifibrotic therapeutic strategy.

Delivery of siRNA Using CXCR4-targeted Nanoparticles Modulates Tumor Microenvironment and Achieves a Potent Antitumor Response in Liver Cancer.

Antiangiogenic therapy has recently emerged as a highly promising therapeutic strategy for treating hepatocellular carcinoma (HCC). However, the only clinically approved systemic antiangiogenic agent for advanced HCC is sorafenib, which exerts considerable toxicity. Moreover, acquired resistance to antiangiogenic therapy often develops and restricts the therapeutic efficacy of this treatment. Hence, in this study, we develop a CXCR4-targeted lipid-based nanoparticle (NP) formulation to specifically deliver vascular endothelial growth factor (VEGF) siRNA as an antiangiogenic substance into HCC. AMD3100, a CXCR4 antagonist, is added into NPs to serve as both a targeting moiety and a sensitizer to antiangiogenic therapy. We demonstrate that AMD-modified NPs (AMD-NPs) can efficiently deliver VEGF siRNAs into HCC and downregulate VEGF expression in vitro and in vivo. Despite the upregulation of the SDF1α/CXCR4 axis upon the induction of hypoxia after antiangiogenic therapy, CXCR4 inhibition by AMD-NPs in combination with either conventional sorafenib treatment or VEGF siRNA prevents the infiltration of tumor-associated macrophages. These dual treatments also induce synergistic antiangiogenic effects and suppress local and distant tumor growth in HCC. In conclusion, the tumor-targeted multifunctional AMD-NPs that co-deliver VEGF siRNA and AMD3100 provide an effective approach for overcoming tumor evasion of antiangiogenic therapy, leading to delayed tumor progression in HCC.

Lymph Node Ratio as an Alternative to the Number of Metastatic Lymph Nodes for the Prediction of Esophageal Carcinoma Patient Survival.

BACKGROUND: The prognostic value of metastatic lymph node ratio (LNR) is still controversial in esophageal cancer. AIM: This study aimed to compare the impact of AJCC N staging system (pN) and LNR on the prediction of long-term survival of patients with esophageal carcinoma. METHODS: A total of 496 patients were retrospectively analyzed who underwent esophageal resection at Henan Tumor Hospital from January 2006 to December 2010. The Kaplan-Meier method and log-rank test were used to estimate survival curves. Univariate and multivariate analyses were performed to compare prognostic factors for long-term survival. The difference between pN and LNR with overall survival (OS) was compared by receiver operating characteristic (ROC) curve and area under the curve (AUC). RESULTS: The 1-, 3-, 5-year overall survival rates of 496 patients were 73.6, 47.1 and 34.2 %, respectively. Univariate analyses showed that diseased region, tumor length, depth of tumor invasion, pN and LNR affected the prognosis, and multivariate analyses demonstrated that depth of tumor invasion, pN and LNR were independent risk factors. Among the three significant variables verified by multivariate analyses, LNR was the best for inadequately staged patients (<12 examined LNs). ROC analyses showed that compared with pN (AUC = 0.579, p = 0.037), LNR (AUC = 0.680, p = 0.002) had better predictive value (z = 2.275, p = 0.029). CONCLUSIONS: LNR has greater prognostic value than pN for esophageal squamous cell carcinoma, especially for patients with <12 LNs removed.

[Clinical characteristics and treatment outcomes of microscopic polyangiitis combined with autoimmune hemolytic anemia].

OBJECTIVE: To investigate the clinical characteristics, laboratory features, outcome and prognosis of microscopic polyangiitis (MPA) patients with autoimmune hemolytic anemia (AIHA). METHODS: In this study, 63 cases diagnosed as MPA from October 2006 to November 2013 in Peking University People's Hospital were reviewed. The clinical characteristics, outcome and prognosis of MPA patients with AIHA were retrospectively analyzed. RESULTS: There were 12.7% (8/63) MPA patients with AIHA. The patients with AIHA had higher prevalence of fever, fatigue, hematuresis, albuminuria and new-onset hypertension, compared with non-AIHA group(87.5% vs.29.1%;100% vs. 49.1%; 100% vs. 60%; 75% vs. 20%, all P<0.05). In patients with AIHA, there were significantly lower levels of red blood cell(RBC), hemoglobin(Hb), alanine albumin(Alb) and complement C3[(2.3±0.5)×10(12)/L vs.(3.0±0.7)×10(12)/L;(66.2±13.1) g/L vs.(90.0±20.3) g/L; (26.1±4.4) g/L vs. (33.5±6.4) g/L; (0.7±0.2) g/L vs.(0.9±0.3) g/L,all P<0.05]. However, the levels of erythrocyte sedimentation rate (ESR), IgG and Birmingham Vasculitis Activity Score (BVAS) were higher, compared with those in the patients without AIHA [(102.1±25.7) mm/1 h vs.(76.5±31.1) mm/1 h; (20.9±6.1) g/L vs. (14.5±6.0) g/L; ( 23.7±5.7) vs.(17.3±4.1), all P<0.05]. The study suggested that there were more severe multi-system damage in the patients with AIHA than in those without AIHA. In the MPA patients with AIHA, six cases received treatment of methylprednisolone combined with immunosuppressant, and two received treatment of methylprednisolone only. Among the eight cases, three were recovered from anemia and four improved. One died of severe lung infection. After 4 years follow-up,in the seven MPA patients with AIHA, three received remission, two died,and two suffered from anemia and abnormal renal function. CONCLUSION: MPA with AIHA is more complicated by multi-system damage and not rare in clinical settings. Glucocorticoid combined with immunosuppressant is beneficial to induce remission for MPA patients with AIHA.

Tedizolid phosphate alleviates DSS-induced ulcerative colitis by inhibiting senescence of cell and colon tissue through activating AMPK signaling pathway.

Ulcerative colitis (UC) is a subtype of inflammatory bowel disease. Previous studies have suggested a link between senescence process and the body's inflammatory reaction, indicating that senescence may exacerbate UC, yet the relation between UC and senescence remains unclear. Tedizolid Phosphate (TED), a novel oxazolidinone antimicrobial, is indicated in acute bacterial skin infections, its impact on senescence is not known. Our research revealed that the UC inducer dextran sulfate sodium (DSS) triggers senescence in both colon epithelial NCM460 cells and colon tissues, and TED that screened from a compound library demonstrated a strong anti-senescence effect on DSS treated NCM460 cells. As an anti-senescence medication identified in this research, TED efficiently alleviated UC and colonic senescence in mice caused by DSS. By proteomic analysis and experimental validation, we found that DSS significantly inhibits the AMPK signaling pathway, while TED counteracts senescence by restoring AMPK activity. This research verified that the development of UC is accompanied with colon tissue senescence, and TED, an anti-senescence medication, can effectively treat UC caused by DSS and alleviate colon senescence. Our work suggests anti-senescence strategy is an effective approach for UC treatment.

FUNDC1-mediated mitophagy triggered by mitochondrial ROS is partially involved in 1-nitropyrene-evoked placental progesterone synthesis inhibition and intrauterine growth retardation in mice.

Intrauterine growth retardation (IUGR) is a major cause of perinatal morbidity and mortality. Previous studies showed that 1-nitropyrene (1-NP), an atmospheric pollutant, induces placental dysfunction and IUGR, but the exact mechanisms remain uncertain. In this research, we aimed to explore the role of mitophagy on 1-NP-evoked placental progesterone (P4) synthesis inhibition and IUGR in a mouse model. As expected, P4 levels were decreased in 1-NP-exposed mouse placentas and maternal sera. Progesterone synthases, CYP11A1 and 3ßHSD1, were correspondingly declined in 1-NP-exposed mouse placentas and JEG-3 cells. Mitophagy, as determined by LC3B-II elevation and TOM20 reduction, was evoked in 1-NP-exposed JEG-3 cells. Mdivi-1, a specific mitophagy inhibitor, relieved 1-NP-evoked downregulation of progesterone synthases in JEG-3 cells. Additional experiments showed that ULK1/FUNDC1 signaling was activated in 1-NP-exposed JEG-3 cells. ULK1 inhibitor or FUNDC1-targeted siRNA blocked 1-NP-induced mitophagy and progesterone synthase downregulation in JEG-3 cells. Further analysis found that mitochondrial reactive oxygen species (ROS) were increased and GCN2 was activated in 1-NP-exposed JEG-3 cells. GCN2iB, a selective GCN2 inhibitor, and MitoQ, a mitochondria-targeted antioxidant, attenuated GCN2 activation, FUNDC1-mediated mitophagy, and downregulation of progesterone synthases in JEG-3 cells. In vivo, gestational MitoQ supplement alleviated 1-NP-evoked reduction of placental P4 synthesis and IUGR. These results suggest that FUNDC1-mediated mitophagy triggered by mitochondrial ROS may contribute partially to 1-NP-induced placental P4 synthesis inhibition and IUGR.

Species Composition of a Small Mammal Community and Prevalence of Echinococcus spp. in the Alpine Pastoral Area of the Eastern Tibetan Plateau.

We aimed to investigate the species composition of a small mammal community and the prevalence of Echinococcus spp. in a typical endemic area of the Tibetan Plateau. One pika and five rodent species were identified based on the morphological characteristics of 1278 small mammal specimens collected during 2014-2019. Detection of Echinococcus DNA in tissue samples from small mammal specimens revealed that Ochotona curzoniae (pika, total prevalence: 6.02%, 26/432), Neodon fuscus (5.91%, 38/643), N. leucurus (2.50%, 3/120), and Alexandromys limnophilus (21.74%, 10/46) were infected by both E. multilocularis and E. shiquicus; Cricetulus longicaudatus (16.67%, 1/6) was infected by E. shiquicus; and no infection was detected in N. irene (0/15). Neodon fuscus and O. curzoniae were the two most abundant small mammal species. There was no significant difference in the prevalence of pika and the overall rodent species assemblage (6.26%, 53/846); however, the larger rodent populations suggested that more attention should be paid to their role in the transmission of echinococcosis in the wildlife reservoir, which has long been underestimated. Moreover, although DNA barcoding provides a more efficient method than traditional morphological methods for identifying large numbers of small mammal samples, commonly used barcodes failed to distinguish the three Neodon species in this study. The close genetic relationships between these species suggest the need to develop more powerful molecular taxonomic tools.

Nicotinamide Suppresses Hyperactivation of Dendritic Cells to Control Autoimmune Disease through PARP Dependent Signaling.

Dendritic cells (DCs) are crucial in initiating and shaping both innate and adaptive immune responses. Clinical studies and experimental models have highlighted their significant involvement in various autoimmune diseases, positioning them as promising therapeutic targets. Nicotinamide (NAM), a form of vitamin B3, with its anti-inflammatory properties, has been suggested, while the involvement of NAM in DCs regulation remains elusive. Here, through analyzing publicly available databases, we observe substantial alterations in NAM levels and NAM metabolic pathways during DCs activation. Furthermore, we discover that NAM, but not Nicotinamide Mononucleotide (NMN), significantly inhibits DCs over-activation in vitro and in vivo. The suppression of DCs hyperactivation effectively alleviates symptoms of psoriasis. Mechanistically, NAM impairs DCs activation through a Poly (ADP-ribose) polymerases (PARPs)-NF-κB dependent manner. Notably, phosphoribosyl transferase (NAMPT) and PARPs are significantly upregulated in lipopolysaccharide (LPS)-stimulated DCs and psoriasis patients; elevated NAMPT and PARPs expression in psoriasis patients correlates with higher psoriasis area and severity index (PASI) scores. In summary, our findings underscore the pivotal role of NAM in modulating DCs functions and autoimmune disorders. Targeting the NAMPT-PARP axis emerges as a promising therapeutic approach for DC-related diseases.

Tauroursodeoxycholic acid targets HSP90 to promote protein homeostasis and extends healthy lifespan.

As the elderly population expands, the pursuit of therapeutics to reduce morbidity and extend lifespan has become increasingly crucial. As an FDA-approved drug for chronic cholestatic liver diseases, tauroursodeoxycholic acid (TUDCA), a natural bile acid, offers additional health benefits beyond liver protection. Here, we show that TUDCA extends the lifespan and healthspan of C. elegans. Importantly, oral supplementation of TUDCA improves fitness in old mice, including clinically relevant phenotypes, exercise capacity and cognitive function. Consistently, TUDCA treatment drives broad transcriptional changes correlated with anti-aging characteristics. Mechanistically, we discover that TUDCA targets the chaperone HSP90 to promote its protein refolding activity. This collaboration further alleviates aging-induced endoplasmic reticulum (ER) stress and facilitates protein homeostasis, thus offering resistance to aging. In summary, our findings uncover new molecular links between an endogenous metabolite and protein homeostasis, and propose a novel anti-aging strategy that could improve both lifespan and healthspan.

[Study on effect of combined application on distribution of gastrodigenin in rats].

To determine the concentration of gastrodigenin in tissue homogenates with high performance liquid chromatography (HPLC) , in order to study the changes of the distribution of gastrodigenin before and after combined application in rat tissues, including heart, liver, spleen, lung, kidney and brain tissues. The study showed that gastrodigenin could be found in kidney, liver, heart, lungs, spleen and brain tissues. After the combined application of Gastrodiae Rhizoma and Ligustici Wallichii Rhizoma, the content of gastrodigenin decreased in kidney and liver to varying degrees, while increasing in lung and brain. This indicated that Ligustici Wallichii Rhizoma had certain impact on the in vivo distribution of gastrodigenin, an active ingredient in Gastrodiae Rhizoma, because it could improve gastrodigenin's distribution in lung and brain tissues. The study provides scientific basis for the combined application of Gastrodiae Rhizoma and Ligustici Wallichii Rhizoma in treating brain diseases.

Inward rectifying Kir4.1 channels regulate oligodendrocyte precursor cell differentiation and CNS myelination in vivo.

The functions of Kir4.1 in oligodendrocyte development have been in controversial. We recently reported that inhibiting Kir4.1 impeded oligodendrocyte precursor cell (OPC) differentiation and oligodendrocyte (OL) maturation, due to Kir4.1 altering intracellular pH of OPCs through Na+/H+ exchangers. However, our conclusion was limited by in vitro observation, thereby it becomes necessary to seek in vivo evidence to determine the roles of Kir4.1 on OPC development and CNS myelination. Here, we used Olig1-Cre to knockout Kir4.1 in OPCs from the early developmental stage. We found that the cell-specific deletion of Kir4.1 significantly impeded OPC differentiation and reduced the number of mature OLs in the cerebral cortex and the corpus callosum. Hence, our in vivo evidence supports that Kir4.1 can regulate OPC differentiation and is essential to CNS myelination.