Effect of reactive oxygen species (ROS) produced by pyridine and quinoline on NH4+-N removal under phenol stress: The shift of nitrification pathway and its potential mechanisms.

Pyridine and quinoline are typical nitrogenous heterocyclic compounds with different structures that are found in coking wastewater. However, neither the corresponding mechanism nor its effect on the degradation of NH4+-N under phenol stress is known. In this study, the effects of pyridine and quinoline degradation on NH4+-N removal under phenol stress were evaluated using three lab-scale sequencing batch reactors. The average NH4+-N removal efficiencies of the reactors were 99.46 %, 88.86 %, and 98.64 %. With the increased concentration of pyridine and quinoline, NH4+-N and NO3--N accumulated to 58.37 mg/L and 141.37 mg/L, respectively, due to the lack of an electron donor and anaerobic environment. The addition of pyridine and quinoline significantly improved antioxidant response and altered the nitrification pathway. The nitrification process shifted from the mediation of amo and hao to the mediation of Ncd2 due to oxidative stress induced by pyridine and quinoline. Furthermore, oxidative stress interferes with the metabolism of carbon sources, resulting in decreased biomass. These results provide a new perspective for coking wastewater treatment processes.

Sensory-motor neuropathy in Mfn2 T105M knock-in mice and its reversal by a novel piperine-derived mitofusin activator.

Mitochondrial dysfunction is a hallmark of many genetic neurodegenerative diseases, but therapeutic options to reverse mitochondrial dysfunction are limited. While recent studies support the possibility of improving mitochondrial fusion/fission dynamics and motility to correct mitochondrial dysfunction and resulting neurodegeneration in Charcot-Marie-Tooth disease (CMT) and other neuropathies, the clinical utility of reported compounds and relevance of pre-clinical models are uncertain. Here, we describe motor and sensory neuron dysfunction characteristic of clinical CMT type 2A in a CRISPR/Casp-engineered Mfn2 Thr105Met (T105M) mutant knock-in mouse. We further demonstrate that daily oral treatment with a novel mitofusin activator derived from the natural product piperine can reverse these neurological phenotypes. Piperine derivative 8015 promoted mitochondrial fusion and motility in Mfn2-deficient cells in a mitofusin-dependent manner, and reversed mitochondrial dysfunction in cultured fibroblasts and reprogrammed motor neurons from a human CMT2A patient carrying the MFN2 T105M mutation. Like previous mitofusin activators, 8015 exhibited stereospecific functionality, but the more active stereoisomer, 8015-P2, is unique in that it has sub-nanomolar potency and undergoes entero-hepatic recirculation which extends its in vivo half-life. Daily administration of 8015-P2 to Mfn2 T105M knock-in mice for 6 weeks normalized neuromuscular and sensory dysfunction and corrected histological/ultrastructural neurodegeneration and neurogenic myoatrophy. These studies describe a more clinically relevant mouse model of CMT2A and an improved mitofusin activator derived from piperine. We posit that 8015-P2 and other piperine derivatives may benefit CMT2A or other neurodegenerative conditions wherein mitochondrial dysdynamism plays a contributory role. Significance Statement Mitochondrial dysfunction is widespread and broadly contributory in neurodegeneration, but difficult to target therapeutically. Here, we describe 8015-P2, a new small molecule mitofusin activator with ~10-fold greater potency and improved in vivo pharmacokinetics vs comparators, and demonstrate its rapid reversal of sensory and motor neuron dysfunction in an Mfn2 T105M knock-in mouse model of Charcot-Marie-Tooth disease type 2A. These findings further support the therapeutic approach of targeting mitochondrial dysdynamism in neurodegeneration.

Investigating Neuroplasticity Changes Reflected by BDNF Levels in Astrocyte-Derived Extracellular Vesicles in Patients with Depression.

Purpose: To investigate the neuroplasticity hypothesis of depression by measuring brain-derived neurotrophic factor (BDNF) levels in plasma astrocyte-derived extracellular vesicles (ADEVs) and to evaluate their potential as biomarkers for depression compared with plasma BDNF levels. Patients and Methods: Thirty-five patients with major depressive disorder (MDD) and 35 matched healthy controls (HCs) were enrolled. Plasma ADEVs were isolated using a combination of ultracentrifugation and immunoaffinity capture. Isolated ADEVs were validated using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. BDNF levels were quantified in both ADEVs and plasma. ALG-2-interacting protein X (Alix) and cluster of differentiation 81 (CD81) levels, two established extracellular vesicle markers, were measured in ADEVs. Results: After false discovery rate correction, patients with MDD exhibited higher CD81 levels (P FDR = 0.040) and lower BDNF levels (P FDR = 0.043) in ADEVs than HCs at baseline. BDNF levels in ADEVs normalized to CD81 (P FDR = 0.002) and Alix (P FDR = 0.040) remained consistent with this finding. Following four weeks of selective serotonin reuptake inhibitor treatment (n=10), CD81 levels in ADEVs decreased (P FDR = 0.046), while BDNF levels normalized to CD81 increased (P FDR = 0.022). BDNF levels in ADEVs were more stable than in plasma. Exploratory analysis revealed no correlation between BDNF levels in ADEVs and plasma (ρ=0.117, P = 0.334). Conclusion: This study provides human in vivo evidence supporting the neuroplasticity hypothesis of depression by demonstrating altered BDNF levels in ADEVs. ADEVs may be more suitable for developing biomarkers of depression than plasma-derived biomarkers.

Hyperkalemia burden and treatment patterns in Chinese patients on hemodialysis: final analysis of a prospective multicenter cohort study (PRECEDE-K).

OBJECTIVES: Patients with end-stage renal disease (ESRD) on hemodialysis (HD) are at risk for hyperkalemia (HK), associated with cardiac arrhythmia and sudden death. Data on the burden of HK and management techniques among HD patients in China are still scarce. This study assessed the treatment modalities, recurrence, and prevalence of HK in Chinese HD patients. METHODS: In this prospective cohort study conducted from May 2021 to July 2022, patients aged ≥18 years who had ESRD and were on HD were enrolled from 15 centers in China (up to 6 months). RESULTS: Overall, 600 patients were enrolled. At the baseline visit, mean (± standard deviation) urea reduction ratio was 68.0% ± 9.70 and Kt/V was 1.45 ± 0.496. Over 6 months, 453 (75.5%) patients experienced HK, of whom 356 (78.6%) recurred. Within 1, 2, 3, 4, 5, and 6 months, 203 (44.8%), 262 (57.8%), 300 (66.2%), 326 (72.0%), 347 (76.6%), and 356 (78.6%) patients had at least one HK recurrence event, respectively. The proportions of patients with ≥1, 2, 3, 4, 5, or 6 HK recurrence events were 356 (78.6%), 306 (67.5%), 250 (55.2%), 208 (45.9%), 161 (35.5%), and 110 (24.3%), respectively. Among the 453 patients who experienced HK, only 24 (5.3%) were treated with potassium binders: seven (1.5%) with sodium polystyrene sulfonate, 13 (2.9%) with calcium polystyrene sulfonate, and six (1.3%) with sodium zirconium cyclosilicate. CONCLUSION: Since HK is a chronic illness, long-term care is necessary. Patients on HD should have effective potassium management on non-dialysis days, yet our real-world population rarely used potassium binders. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04799067.

Quercetin ameliorates oxidative stress-induced apoptosis of granulosa cells in dairy cow follicular cysts by activating autophagy via the SIRT1/ROS/AMPK signaling pathway.

BACKGROUND: Follicular cysts contribute significantly to reproductive loss in high-yield dairy cows. This results from the death of follicular granulosa cells (GCs) caused by oxidative stress. Quercetin is known to have significant antioxidant and anti-apoptotic effects. However, the effect of quercetin on follicular cysts has yet been elucidated. Therefore, this study aimed to explore the anti-oxidant and anti-apoptosis effects and potential molecular mechanisms of quercetin in H2O2-induced primary cow GCs and 3-nitropropionic acid (3-NPA)-induced mouse model of oxidative stress and thus treat ovarian cysts in dairy cows. RESULTS: In this study, compared with estrus cows, cows with follicular cysts showed heightened levels of oxidative stress and increased follicular cell apoptosis, while autophagy levels were reduced. A model of oxidative stress was induced in vitro by H2O2 and showed significant increases in apoptosis together with reduced autophagy. These effects were significantly ameliorated by quercetin. Effects similar to those of quercetin were observed after treatment of cells with the reactive oxygen species (ROS) inhibitor N-acetylcysteine (NAC). Further investigations using chloroquine (autophagy inhibitor), rapamycin (autophagy activator), selisistat (SIRT1 inhibitor), and compound C (AMPK inhibitor) showed that chloroquine counteracted the effects of quercetin on oxidative stress-induced apoptosis, while rapamycin had the same effect as quercetin. In addition, the SIRT1/AMPK pathway inhibitors antagonized quercetin-mediated mitigation of the effects of oxidative stress on increased apoptosis and reduced autophagy. Consistent with the results in vitro, in mouse ovarian oxidative stress model induced by 3-NPA, quercetin activated autophagy through the SIRT1/AMPK signaling pathway, while alleviating oxidative stress damage and inhibiting apoptosis in mouse ovaries. CONCLUSIONS: These findings indicate that quercetin can inhibit apoptosis in GCs and restore ovarian function by activating autophagy through the SIRT1/ROS/AMPK signaling pathway, suggesting a new direction for the treatment of ovarian follicular cysts in high-yield dairy cows.

In vivo evidence of increased vascular endothelial growth factor in patients with major depressive disorder.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a candidate mediator of blood-brain barrier (BBB) disruption in depression. However, previous studies have mainly focused on peripheral blood VEGF levels, and the results are heterogeneous. Here we use astrocyte-derived extracellular vesicles (ADEVs) isolated from plasma to explore the in vivo changes of VEGF levels in patients with major depressive disorder (MDD). METHODS: Thirty-five unmedicated patients with MDD and 35 healthy controls (HCs) were enrolled, and plasma ADEVs were isolated from each participant. VEGF levels in ADEVs and glial fibrillary acidic protein (GFAP) in plasma were measured. Additionally, Alix and CD81, two established extracellular vesicle markers, were quantified in ADEVs. RESULTS: At baseline, MDD patients exhibited significantly increased levels of VEGF in ADEVs and GFAP in plasma. Following four weeks of selective serotonin reuptake inhibitor treatment, these target protein levels did not significantly change. ROC curve analysis revealed an AUC of 0.711 for VEGF in ADEVs. In exploratory analysis, VEGF levels in ADEVs were positively correlated with Alix and CD81. LIMITATIONS: Multiple factors regulate BBB permeability. This study focused solely on VEGF and the sample size for longitudinal analysis was relatively small. CONCLUSION: Our study is the first to confirm increased ADEV-derived VEGF levels in patients with MDD, thereby providing preliminary evidence supporting the hypothesis that the BBB is disrupted in depression.

Occurrence, sources and transport of triazine herbicides in the Antarctic marginal seas.

The extensively applied triazine herbicides are easily transported by ocean currents over long distances. This study analyzed ten triazine herbicides in the Antarctic marginal seas and the Southern Indian Ocean during the austral summer for the first time, addressing their largely unexplored behavior in remote marine environments. The total triazine herbicides showed great spatial heterogeneity, with a range of 20-790 pg/L and an average of 31 ± 66 pg/L. The waterborne transport of triazine herbicides in the Antarctic was affected by hydrological processes, especially the blocking and accumulation effect of the polar front. Variations in sea ice extent and temperature were also important influencing factors, resulting in elevated triazine herbicides in surface seawater of East Antarctica, but reduced levels in West Antarctica. Furthermore, the source apportionment results indicated that approximately 55 % of the herbicides originated from sugarcane cultivation, 28 % from algaecide use, and 16 % from corn and sorghum farming.

Comparative Genomics of Limosilactobacillus reuteri YLR001 Reveals Genetic Diversity and Probiotic Properties.

To gain deeper insights into the genomic characteristics of Limosilactobacillus reuteri (L. reuteri) YLR001 and uncover its probiotic properties, in the current study, a comprehensive analysis of its whole genome was conducted, explicitly exploring the genetic variations associated with different host organisms. The genome of YLR001 consisted of a circular 2,242,943 bp chromosome with a GC content of 38.84%, along with three circular plasmids (24,864, 38, 926, and 132,625 bp). Among the 2183 protein-coding sequences (CDSs), the specific genes associated with genetic adaptation and stress resistance were identified. We predicted the function of COG protein genes and analyzed the KEGG pathways. Comparative genome analysis revealed that the pan-genome contained 5207 gene families, including 475 core gene families and 941 strain-specific genes. Phylogenetic analysis revealed distinct host specificity among 20 strains of L. reuteri, highlighting substantial genetic diversity across different hosts. This study enhanced our comprehension of the genetic diversity of L. reuteri YLR001, demonstrated its potential probiotic characteristics, and established more solid groundwork for future applications.

Changes in the Microbiome in Yak Mastitis: Insights Based on Full-Length 16S rRNA Sequencing.

Mastitis is an inflammation of the mammary gland that can be caused by various factors, including biological, chemical, mechanical, or physical. Microbiological culture, DNA techniques, and high-throughput next-generation sequencing have been used to identify mastitis-causing pathogens in various animal species. However, little is known about microbiota and microbiome changes linked to yak milk mastitis. This study aimed to characterize the milk microbiota of healthy and mastitis-infected yaks using full-length 16S rRNA sequencing. The results showed that the bacterial microbiota comprises 7 phyla, 9 classes, 20 orders, 39 families, 59 genera, and 72 species. Proteobacteria and Firmicutes were the predominant microbial communities, with lower abundances of Bacteroidota, Actinobacteriota, Acidobacteriota, and other minor groupings also observed. Proteobacteria dominated the clinical and subclinical mastitis groups (95.36% and 89.32%, respectively), in contrast to the healthy group (60.17%). Conversely, Firmicutes were more common in the healthy group (39.7%) than in the subclinical and clinical mastitis groups (10.49% and 2.92%, respectively). The predominant organisms found in the healthy group were Leuconostoc mesenteroides, Lactococcus piscium, Carnobacterium maltaromaticum, and Lactococcus raffinolactis. Low abundances of Staphylococcus aureus species were found in both subclinical and clinical mastitis groups, with Moraxella osloensis and Psychrobacter cibarius dominating the subclinical mastitis group and Pseudomonas fluorescens dominating the clinical mastitis group. An alpha diversity study revealed that the healthy group had a higher microbial diversity than the clinical and subclinical mastitis groups. According to beta-diversity analysis, the principal coordinate analysis identified that mastitis-infected samples significantly differed from healthy ones. The milk microbiota of healthy yaks is more varied, and specific prominent taxa within various groups can act as marker microorganisms for mastitis risk. The genera Leuconostoc and Lactococcus are promising candidates for creating probiotics.

Classical swine fever virus inhibits serine metabolism-mediated antiviral immunity by deacetylating modified PHGDH.

Classical swine fever virus (CSFV), an obligate intracellular pathogen, hijacks cellular metabolism to evade immune surveillance and facilitate its replication. The precise mechanisms by which CSFV modulates immune metabolism remain largely unknown. Our study reveals that CSFV infection disrupts serine metabolism, which plays a crucial role in antiviral immunity. Notably, we discovered that CSFV infection leads to the deacetylation of PHGDH, a key enzyme in serine metabolism, resulting in autophagic degradation. This deacetylation impairs PHGDH's enzymatic activity, reduces serine biosynthesis, weakens innate immunity, and promotes viral proliferation. Molecularly, CSFV infection induces the association of HDAC3 with PHGDH, leading to deacetylation at the K364 site. This modification attracts the E3 ubiquitin ligase RNF125, which facilitates the addition of K63-linked ubiquitin chains to PHGDH-K364R. Subsequently, PHGDH is targeted for lysosomal degradation by p62 and NDP52. Furthermore, the deacetylation of PHGDH disrupts its interaction with the NAD+ substrate, destabilizing the PHGDH-NAD complex, impeding the active site, and thereby inhibiting de novo serine synthesis. Additionally, our research indicates that deacetylated PHGDH suppresses the mitochondria-MAVS-IRF3 pathway through its regulatory effect on serine metabolism, leading to decreased IFN-ß production and enhanced viral replication. Overall, our findings elucidate the complex interplay between CSFV and serine metabolism, revealing a novel aspect of viral immune evasion through the lens of immune metabolism. IMPORTANCE: Classical swine fever (CSF) seriously restricts the healthy development of China's aquaculture industry, and the unclear pathogenic mechanism and pathogenesis of classical swine fever virus (CSFV) are the main obstacle to CSF prevention, control, and purification. Therefore, it is of great significance to explore the molecular mechanism of CSFV and host interplay, to search for the key signaling pathways and target molecules in the host that regulate the replication of CSFV infection, and to elucidate the mechanism of action of host immune dysfunction and immune escape due to CSFV infection for the development of novel CSFV vaccines and drugs. This study reveals the mechanism of serine metabolizing enzyme post-translational modifications and antiviral signaling proteins in the replication of CSFV and enriches the knowledge of CSFV infection and immune metabolism.

Effectiveness, safety, and treatment pattern of sodium zirconium cyclosilicate in Chinese patients with hyperkalemia: interim analysis from a multicenter, prospective, real-world study (Actualize Study).

Introduction: Sodium zirconium cyclosilicate (SZC) is a nonabsorbed cation-exchanger approved in China for the treatment of hyperkalemia [HK; serum potassium (sK+) levels >5.0 mmol/L]. This is the first real-world study aimed to assess the effectiveness, safety, and treatment patterns of SZC in Chinese patients with HK. Here we present the results of the first interim analysis. Methods: This multicenter, prospective, cohort study included patients aged ≥18 years with documented HK within 1-year before study enrollment day. These patients were followed up for 6 months from the enrollment day after initiating SZC treatment. The treatment was categorized into correction phase (FAS-P1) and maintenance phase (FAS-P2 new and ongoing users). Subgroup analysis was performed in patients on hemodialysis (FAS-H). The primary objective was evaluation of safety profile of SZC; secondary objectives included assessment of treatment patterns of SZC and its effectiveness. Results: Of 421 screened patients, 193, 354, and 162 patients were enrolled in the FAS-P1, FAS-P2, and FAS-H groups, respectively. sK+ levels were reduced significantly from 5.9 mmol/L to 5.0 mmol/L after the correction phase. For the maintenance phase, the mean sK+ levels were maintained at 5.2 mmol/L and 5.0 mmol/L in the FAS-P2 new and ongoing user, respectively, and 5.3 mmol/L in the FAS-H subgroup. A considerable proportion of patients showed normokalemia after 48 h of SZC treatment (FAS-P1:51.3%) which was maintained up to 6 months in the maintenance phase (FAS-P2:44%). SZC was well-tolerated. Conclusion: SZC was effective and safe for the treatment of HK in real-world clinical practice in China.

Expression of Tshb and Tshr in the ricefield eel Monopterus albus: Potential paracrine/autocrine roles in gonads.

Thyroid stimulating hormone (TSH), a glycoprotein synthesized and secreted from thyrotrophs of the pituitary gland, is composed of a glycoprotein hormone common alpha subunit (CGA) and a specific beta subunit (TSHB). The major biological function of TSH is to stimulate thyroidal follicles to synthesize and secrete thyroid hormones through activating its cognate receptor, the thyroid stimulating hormone receptor (TSHR). In the present study, polyclonal antisera against ricefield eel Tshb and Tshr were generated respectively, and the expression of Tshb and Tshr was examined at mRNA and protein levels. RT-PCR analysis showed that tshb mRNA was expressed mainly in the pituitary as well as in some extrapituitary tissues including the ovary and testis. Tshr mRNA was also expressed in a tissue-specific manner, with transcripts detected in tissues including the kidney, ovary, and testis. The immunoreactive Tshb signals in the pituitary were shown to be localized to the inner areas of adenohypophysis which are close to the neurohypophysis of adult ricefield eels. Tshb-immunoreatvie cells in the pituitary of ricefield eel larvae were firstly observed at hatching. The expression of immunoreactive Tshb and Cga was also detected in ricefield eel ovary and testis together with Tshr. In the ovary, immunoreactive Tshb, Cga, and Tshr were observed in oocytes and granulosa cells. In the testis, immunoreactive Tshb was mainly observed in Sertoli cells while immunoreactive Cga and Tshr were detected in germ cells as well as somatic cells. Results of the present study suggest that Tsh may be synthesized both in the ovary and testis locally, which may play paracrine and/or autocrine roles in gonadal development in ricefield eels.

Non-diabetes status after diagnosis of impaired glucose tolerance and risk of long-term death and vascular complications: A post hoc analysis of the Da Qing Diabetes Prevention Outcome Study.

BACKGROUND: The association between years of non-diabetes status after diagnosis of impaired glucose tolerance (IGT) and the risk of long-term death and cardiovascular outcomes needed to be clarified. METHODS AND FINDINGS: In this post hoc analysis, we included 540 individuals with IGT who participated in the original Da Qing Diabetes Prevention Study (DQDPS). In the DQDPS, all participants were diagnosed with IGT by a 75 g oral glucose tolerance test and randomized to intervention or control groups with a 6-year lifestyle intervention trial. After the completion of the trial, death, cardiovascular events, and microvascular complications were monitored over a 30-year follow-up. In this post hoc analysis, the Cox analysis assessed the extended risk of these outcomes in individuals who either remained non-diabetes status or progressed to diabetes at the end of 2, 4, and 6 years after diagnosis of IGT. In all participants, the difference in the cumulative incidence rate of the outcomes between the diabetes and non-diabetes group gradually increased over 30 years. Compared with the diabetes group, a significantly lower risk of all-cause death (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.57 to 0.97, p = 0.026), cardiovascular events (HR: 0.63; 95% CI: 0.49 to 0.82, p < 0.001), and microvascular complications (HR: 0.62; 95% CI: 0.45 to 0.86, p = 0.004) first emerged in individuals who remained non-diabetes at the 4 years visit, whereas the significant risk reduction in cardiovascular death was first observed at the end of 6 years (HR: 0.56; 95% CI: 0.39 to 0.81, p = 0.002) after adjustment for age, sex, smoking status, BMI, systolic blood pressure, blood glucose, total cholesterol, intervention, and medications (including insulin plus oral hypoglycaemics, antihypertensives, and lipid-lowering agents). The results in the original intervention group alone were similar to the whole group. The main limitations of our study are the limited number of participants and the sole ethnicity of the Chinese population. CONCLUSIONS: In this study, we observed that maintaining several years of non-diabetes status after IGT diagnosis was associated with a significant reduction in long-term risk of death and vascular complications, and for most of these outcomes, maintaining at least 4 years of non-diabetes status may be needed to achieve a significant risk reduction.

A Case of False Decrease of Plasma D-Dimer.

BACKGROUND: D-dimer, a specific product of cross-linked fibrin degradation, is of great clinical value in the early diagnosis of thrombotic diseases and in monitoring the efficacy of thrombolysis; therefore, the accuracy of D-dimer test results is crucial. METHODS: This article reports a case of a patient with disseminated intravascular coagulation (DIC) who experienced a false decrease in D-dimer due to the hook effect. RESULTS: The three D-dimer test results for DIC patients were 1.09 mg/L, 0.93 mg/L, and 1.43 mg/L. After sample dilution, the results were: first time (1:128) 842.24 mg/L, second time (1:128) 1,505.28 mg/L, third time (1:32) 415.68 mg/L. There was a significant difference in the three test results before and after dilution, because the D-dimer concentration was too high, exceeding the detection range and causing the hook effect, which falsely lowered the D-dimer value. CONCLUSIONS: When the D-dimer value of DIC patients does not match the clinical situation, the possibility of the hook effect should be considered, and the false decrease can be ruled out by the sample dilution method. In this way, accurate clinical results can be obtained to avoid delaying the diagnosis and treatment of DIC patients.

Comparison of Routes of Administration, Frequency, and Duration of Favipiravir Treatment in Mouse and Guinea Pig Models of Ebola Virus Disease.

Favipiravir is a ribonucleoside analogue that has been explored as a therapeutic for the treatment of Ebola Virus Disease (EVD). Promising data from rodent models has informed nonhuman primate trials, as well as evaluation in patients during the 2013-2016 West African EVD outbreak of favipiravir treatment. However, mixed results from these studies hindered regulatory approval of favipiravir for the indication of EVD. This study examined the influence of route of administration, duration of treatment, and treatment schedule of favipiravir in immune competent mouse and guinea pig models using rodent-adapted Zaire ebolavirus (EBOV). A dose of 300 mg/kg/day of favipiravir with an 8-day treatment was found to be fully effective at preventing lethal EVD-like disease in BALB/c mice regardless of route of administration (oral, intraperitoneal, or subcutaneous) or whether it was provided as a once-daily dose or a twice-daily split dose. Preclinical data generated in guinea pigs demonstrates that an 8-day treatment of 300 mg/kg/day of favipiravir reduces mortality following EBOV challenge regardless of route of treatment or duration of treatments for 8, 11, or 15 days. This work supports the future translational development of favipiravir as an EVD therapeutic.

[Effects of acupuncture on fecal short-chain fatty acids and TLR4/MyD88/NF-κB signaling pathway in spontaneously hypertensive rats].

OBJECTIVE: To observe the effects of acupuncture on blood pressure, fecal short-chain fatty acids (SCFAs) and toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway in spontaneously hypertensive rats (SHR), and to explore the mechanism of acupuncture for anti-hypertension. METHODS: Twenty-four male SHR of SPF grade were randomly divided into a model group, a western medication group, an acupuncture group and a sham acupuncture group, with 6 rats in each group, and 6 male Wistar-Kyoto rats were selected as the blank group additionally. Hydrochlorothiazide solution was given by gavage in the western medication group; acupuncture was applied at bilateral "Renying" (ST 9) and "Zusanli" (ST 36) in the acupuncture group, 20 min a time; acupuncture was applied at the non-meridian and non-acupoint points close to bilateral "Renying" (ST 9) and "Zusanli" (ST 36) in the sham acupuncture group, 20 min a time. The intervention was adopted once a day for 4 weeks continuously in each group. The systolic blood pressure (SBP) of the caudal artery was measured before intervention and after 1, 2, 3 and 4 weeks of intervention. After intervention, the morphology of colonic tissue was observed by HE staining; the fecal level of SCFAs was detected by gas chromatography; the serum levels of interleukin (IL)-6, IL-1ßand tumor necrosis factor-α (TNF-α) were detected by ELISA; the protein expression of TLR4, MyD88 and NF-κB p65 in the mesenteric artery was detected by Western blot. RESULTS: Compared with the blank group, in the model group, the SBP was increased (P<0.05), significant pathological changes could be found in the colonic tissue, the fecal SCFAs level was decreased (P<0.05), the serum levels of IL-6, IL-1ß and TNF-α were increased (P<0.05), the protein expression of TLR4, MyD88 and NF-κB p65 in the mesenteric artery was increased (P<0.05). Compared with the model group, the SBP after 2, 3 and 4 weeks of intervention was decreased (P<0.05), the serum levels of IL-6, IL-1ß and TNF-α were decreased (P<0.05) in the acupuncture group and the western medication group; the mucosal epithelium of colonic tissue was intact, the number of intestinal glands was abundant, the fecal SCFAs level was increased (P<0.05), and the protein expression of TLR4, MyD88 and NF-κB p65 in the mesenteric artery was decreased (P<0.05) in the acupuncture group. Compared with the sham acupuncture group, the SBP after 2, 3 and 4 weeks of intervention was decreased (P<0.05), the fecal SCFAs level was increased (P<0.05), the serum levels of IL-6, IL-1ß and TNF-α were decreased (P<0.05), the protein expression of TLR4, MyD88 and NF-κB p65 in the mesenteric artery was decreased (P<0.05) in the acupuncture group. CONCLUSION: Acupuncture at bilateral "Renying" (ST 9) and "Zusanli" (ST 36) can effectively play an anti-hypertensive role in SHR. Its mechanism may be related to regulating fecal SCFAs level and inhibiting the TLR4/MyD88/NF-κB signaling pathway.

Molecular mechanism of the treatment of lung adenocarcinoma by Hedyotis Diffusa: an integrative study with real-world clinical data and experimental validation.

Background: With a variety of active ingredients, Hedyotis Diffusa (H. diffusa) can treat a variety of tumors. The purpose of our study is based on real-world data and experimental level, to double demonstrate the efficacy and possible molecular mechanism of H. diffusa in the treatment of lung adenocarcinom (LUAD). Methods: Phenotype-genotype and herbal-target associations were extracted from the SymMap database. Disease-gene associations were extracted from the MalaCards database. A molecular network-based correlation analysis was further conducted on the collection of genes associated with TCM and the collection of genes associated with diseases and symptoms. Then, the network separation SAB metrics were applied to evaluate the network proximity relationship between TCM and symptoms. Finally, cell apoptosis experiment, Western blot, and Real-time PCR were used for biological experimental level validation analysis. Results: Included in the study were 85,437 electronic medical records (318 patients with LUAD). The proportion of prescriptions containing H. diffusa in the LUAD group was much higher than that in the non-LUAD group (p < 0.005). We counted the symptom relief of patients in the group and the group without the use of H. diffusa: except for symptoms such as fatigue, palpitations, and dizziness, the improvement rate of symptoms in the user group was higher than that in the non-use group. We selected the five most frequently occurring symptoms in the use group, namely, cough, expectoration, fatigue, chest tightness and wheezing. We combined the above five symptom genes into one group. The overlapping genes obtained were CTNNB1, STAT3, CASP8, and APC. The selection of CTNNB1 target for biological experiments showed that the proliferation rate of LUAD A549 cells in the drug intervention group was significantly lower than that in the control group, and it was concentration-dependent. H. diffusa can promote the apoptosis of A549 cells, and the apoptosis rate of the high-concentration drug group is significantly higher than that of the low-concentration drug group. The transcription and expression level of CTNNB1 gene in the drug intervention group were significantly decreased. Conclusion: H. diffusa inhibits the proliferation and promotes apoptosis of LUAD A549 cells, which may be related to the fact that H. diffusa can regulate the expression of CTNNB1.

Recanalization of a long segment occluded superior vena cava by puncturing the remnant calcified fibrin sheath of the internal jugular vein: A case report.

A fibrin sheath with central venous occlusion is a common complication after central venous catheterization, and these patients often experience catheter dysfunction. A calcified fibrin sheath can cause a catheter to be stuck, and typically necessitates catheter removal or replacement. From another point of view, a calcified fibrin sheath can be seen in ultrasound and computed tomography, and the original fibrin sheath channel between the internal jugular vein and the atrium is unusually strong. When central vein occlusion occurs, the remnant calcified fibrin sheath of the internal jugular vein can be punctured under ultrasound guidance, allowing the guidewire to enter the atrium directly through the fibrin sheath. Here, we report a case in which we achieved easy recanalization of a long segment occluded superior vena cava by puncturing the remnant calcified fibrin sheath of the internal jugular vein.

LKB1 inhibits telomerase activity resulting in cellular senescence through histone lactylation in lung adenocarcinoma.

Despite the confirmed role of LKB1 in suppressing lung cancer progression, its precise effect on cellular senescence is unknown. The aim of this research was to clarify the role and mechanism of LKB1 in restraining telomerase activity in lung adenocarcinoma. The results showed that LKB1 induced cellular senescence and apoptosis either in vitro or in vivo. Overexpression of LKB1 in LKB1-deficient A549 cells led to the inhibition of telomerase activity and the induction of telomere dysfunction by regulating telomerase reverse transcriptase (TERT) expression in terms of transcription. As a transcription factor, Sp1 mediated TERT inhibition after LKB1 overexpression. LKB1 induced lactate production and inhibited histone H4 (Lys8) and H4 (Lys16) lactylation, which further altered Sp1-related transcriptional activity. The telomerase inhibitor BIBR1532 was beneficial for achieving the optimum curative effect of traditional chemotherapeutic drugs accompanied by the glycolysis inhibitor 2DG. These data reveal a new mechanism by which LKB1 regulates telomerase activity through lactylation-dependent transcriptional inhibition, and therefore, provide new insights into the effects of LKB1-mediated senescence in lung adenocarcinoma. Our research has opened up new possibilities for the creation of new cancer treatments.