Impact of low-to moderate-intensity exercise training on the mRNA expression of purine receptors across various vessels in SHR.

OBJECTIVE: In this study, we developed an exercise training protocol for assessing both blood pressure dynamics and mRNA expression levels of purine receptors in various vascular tissues during physical activity. The objective is to assess the impact of exercise training on blood pressure regulation in spontaneously hypertensive rats (SHR) and purine receptors in vascular tissues. METHODS: Wistar Kyoto (WKY) and SHR rats were randomly allocated into sedentary (Sed) and exercise training (ExT) groups. Rats in the Sed groups were allowed unrestricted movement, whereas those in the ExT groups underwent a 16-week regimen of low- to moderate-intensity treadmill exercise. Throughout the intervention period, blood pressure measurements and body weight recordings were conducted. Additionally, mRNA expressions of purine receptors P2X1, P2Y1, and P2Y2 in renal artery (RA), internal carotid artery (Int), thoracic aorta (Aor), and caudal artery (Cau) tissues were assessed. RESULTS: In the Sed group, body weight of SHR rats was observed to be lower compared to the three other groups. Over the course of the exercise regimen, blood pressure in the ExT group of SHR rats reduced gradually, converging towards levels similar to those observed in WKY rats by the conclusion of the exercise period. Regarding mRNA expression patterns of P2X1 receptors across the four blood vessels, WKY and SHR rats demonstrated similar sequences, consistently displaying the highest expression levels in the Cau. Conversely, mRNA expressions of P2Y1 and P2Y2 receptors exhibited distinct sequences across the four blood vessels in both WKY and SHR rats. Notably, compared to the Sed group of WKY rats, mRNA expression of P2X1 receptor in the Int of SHR rats revealed an increase, while expressions in the Aor of WKY rats and the Cau of SHR rats decreased following exercise. Expression of P2Y1 receptor mRNA decreased across all four types of blood vessels in SHR rats. Post-exercise, P2Y1 receptor mRNA expression increased in the Aor, decreased in the Cau of WKY rats, and increased in the Int and renal artery (RA) of SHR rats. Conversely, expressions of P2Y2 receptor mRNA decreased in the Int and Aor of SHR rats. Except for the Aor of WKY rats, expressions of P2Y2 receptor mRNA increased in the other arteries of both rat types following exercise. CONCLUSION: Differences in the distribution of purine receptor subtypes among distinct arterial segments in both WKY and SHR rats were observed. Exercise training was found to enhance mRNA expression levels of P2Y receptors in these rat models. This finding implies that exercise training might reduce hypertension in SHR rats by bolstering the purinergic relaxation response.

Danggui-Shaoyao-San protects against non-alcoholic steatohepatitis via modulation of hepatic APP protein, Lysosomal CTSB release, and NF-κB activation.

Background: Non-alcoholic steatohepatitis (NASH), an escalating global health concern, is a primary factor behind cirrhosis, liver transplantation, and hepatocellular carcinoma. Effective treatments remain elusive. Danggui-Shaoyao-San (DGSY), a classic famous prescription employed in treating NASH, could hold promise, although its molecular underpinnings are still under investigation. This study undertakes an exploration of the impacts of DGSY on NASH and seeks to illuminate the mechanisms at play. Methods: UHPLC-Q-Orbitrap HRMS was employed to identify compounds within DGSY. Mice underwent a 25-week regimen of HFHC diet and high-sugar water, with 4 weeks of DGSY treatment for efficacy and pathogenic mechanism exploration in vivo. L02 cells were cultured with 0.2 mM FFA for 24 h, exposed to DGSY at 1 mg/ml and 2 mg/ml for efficacy and pathogenic mechanism exploration in vitro. Using online databases, we sought potential targets for NASH treatment, and through PPI networks, identified key targets. Expression levels of genes and proteins were examined by western blotting, RT-PCR, and immunofluorescence staining. Results: Thirty-four compounds were identified within DGSY. DGSY brought about marked reductions in biochemical indicators and yielded significant improvements in NASH mice histological features. Additionally, it mitigated hepatic steatosis and inflammation both in vivo and in vitro. The top 10 targets from two network pharmacology analyses, one focusing on structural prediction and the other on literature mining, identified APOE and APP as potential therapeutic targets for DGSY in NASH treatment. PCR validation confirmed that DGSY reduced APP expression after treatment, and further investigation revealed that DGSY significantly suppressed hepatic APP and Aß expression, indicating its effectiveness in treating NASH. Furthermore, it inhibited Aß-induced Cathepsin B lysosomal release, reducing hepatic inflammation. Conclusion: Danggui-Shaoyao-San has anti-steatohepatitis effects in ameliorating hepatic APP protein expression, reducing hepatic lysosomal CTSB release, and suppressing hepatic NF-κB activation. The study provided a more theoretical basis for the future clinical application of DGSY.

Synergistic impact of plasma albumin and cognitive function on all-cause mortality in Chinese older adults: a prospective cohort study.

Background: Hypoalbuminemia and cognitive impairment (CI) each independently increase the mortality risk in older adults. However, these two geriatric syndromes can occur simultaneously. In community-dwelling older adults, is the combination of hypoalbuminemia and CI linked to a higher mortality risk than either condition alone? Objective: We aimed to investigate the association between plasma albumin, cognitive function, and their synergistic effect on mortality in Chinese community-dwelling older adults. Methods: Data from the Chinese Longitudinal Healthy Longevity Survey (2012) included 1,858 participants aged ≥65. Baseline assessments comprised albumin levels and cognitive status. All-cause mortality was confirmed through 2014-2018 surveys. Cox proportional hazards models assessed associations, and restricted cubic splines explored albumin-mortality relationship. Results: During a median follow-up of 48.85 months, 921 deaths. Albumin≥35 g/L vs < 35g/L [HR: 1.33 (95%CI, 1.10, 1.62)] and CI vs normal cognition [HR: 1.69 (95%CI, 1.43, 1.99)] independently predicted mortality. A dose-response relationship with mortality was observed for albumin quartiles (p < 0.001). Each SD increase in MMSE or albumin correlated with 22% and 15% lower mortality risk, respectively. Combined hypoproteinemia and CI increased the mortality risk by 155%, with a notably higher risk in males, those aged <85 years, and individuals living in rural areas. Interaction effects of albumin and CI on mortality were observed (p < 0.001). In the single CI group, older adults had a 61% increased risk of mortality in the hypoproteinaemia group compared with the albumin-normal group. Restricted cubic spline revealed a reverse J-shaped association, particularly for participants without CI. For individuals with CI, albumin levels were inversely associated with mortality risk. Conclusion: Hypoproteinemia and CI, individually and combined, increased all-cause mortality risk in Chinese older adults, with stronger effects observed in males, younger older adults, and those living in rural areas. These findings emphasize the importance of targeted adjustments and early nutrition programs in health prevention and clinical care for older adults.

Signals from intestinal microbiota mediate the crosstalk between the lung-gut axis in an influenza infection mouse model.

Introduction: Introduction: The influenza virus primarily targets the respiratory tract, yet both the respiratory and intestinal systems suffer damage during infection. The connection between lung and intestinal damage remains unclear. Methods: Our experiment employs 16S rRNA technology and Liquid Chromatography-Mass Spectrometry (LC-MS) to detect the impact of influenza virus infection on the fecal content and metabolites in mice. Additionally, it investigates the effect of influenza virus infection on intestinal damage and its underlying mechanisms through HE staining, Western blot, Q-PCR, and flow cytometry. Results: Our study found that influenza virus infection caused significant damage to both the lungs and intestines, with the virus detected exclusively in the lungs. Antibiotic treatment worsened the severity of lung and intestinal damage. Moreover, mRNA levels of Toll-like receptor 7 (TLR7) and Interferon-b (IFN-b) significantly increased in the lungs post-infection. Analysis of intestinal microbiota revealed notable shifts in composition after influenza infection, including increased Enterobacteriaceae and decreased Lactobacillaceae. Conversely, antibiotic treatment reduced microbial diversity, notably affecting Firmicutes, Proteobacteria, and Bacteroidetes. Metabolomics showed altered amino acid metabolism pathways due to influenza infection and antibiotics. Abnormal expression of indoleamine 2,3-dioxygenase 1 (IDO1) in the colon disrupted the balance between helper T17 cells (Th17) and regulatory T cells (Treg cells) in the intestine. Mice infected with the influenza virus and supplemented with tryptophan and Lactobacillus showed reduced lung and intestinal damage, decreased Enterobacteriaceae levels in the intestine, and decreased IDO1 activity. Discussion: Overall, influenza infection caused damage to lung and intestinal tissues, disrupted intestinal microbiota and metabolites, and affected Th17/Treg balance. Antibiotic treatment exacerbated these effects. Supplementation with tryptophan and Lactobacillus improved lung and intestinal health, highlighting a new understanding of the lung-intestine connection in influenza-induced intestinal disease.

Adeno-Associated Virus Engineering and Load Strategy for Tropism Modification, Immune Evasion and Enhanced Transgene Expression.

Gene therapy aims to add, replace or turn off genes to help treat disease. To date, the US Food and Drug Administration (FDA) has approved 14 gene therapy products. With the increasing interest in gene therapy, feasible gene delivery vectors are necessary for inserting new genes into cells. There are different kinds of gene delivery vectors including viral vectors like lentivirus, adenovirus, retrovirus, adeno-associated virus et al, and non-viral vectors like naked DNA, lipid vectors, polymer nanoparticles, exosomes et al, with viruses being the most commonly used. Among them, the most concerned vector is adeno-associated virus (AAV) because of its safety, natural ability to efficiently deliver gene into cells and sustained transgene expression in multiple tissues. In addition, the AAV genome can be engineered to generate recombinant AAV (rAAV) containing transgene sequences of interest and has been proven to be a safe gene vector. Recently, rAAV vectors have been approved for the treatment of various rare diseases. Despite these approvals, some major limitations of rAAV remain, namely nonspecific tissue targeting and host immune response. Additional problems include neutralizing antibodies that block transgene delivery, a finite transgene packaging capacity, high viral titer used for per dose and high cost. To deal with these challenges, several techniques have been developed. Based on differences in engineering methods, this review proposes three strategies: gene engineering-based capsid modification (capsid modification), capsid surface tethering through chemical conjugation (surface tethering), and other formulations loaded with AAV (virus load). In addition, the major advantages and limitations encountered in rAAV engineering strategies are summarized.

Exploration of ETV6::ABL1-positive AML with concurrent NPM1 and FLT3-ITD mutations.

ETV6::ABL1 is a rare fusion gene that found in MPN, ALL, and AML. It has a complex and diverse formation mechanism due to the reciprocal orientations of the ETV6 and ABL1 genes relative to the centromeres. NPM1 is frequently mutated in adult AML, often accompanied by FLT3-ITD, which suggests molecular synergisms in AML pathogenesis. Previous reports on ETV6::ABL1 mostly focus on FLT3-ITD. In this study, we present a case of AML with ETV6::ABL1, along with NPM1 and FLT3-ITD. The patient showed a rapid increase in primitive cells at the initial stage, along with the presence of immature granulocytes and erythrocytes. Through cytogenetic analysis, fluorescence in situ hybridization (FISH), and RNA-seq, we elucidated the mechanism behind the formation of the ETV6::ABL1 fusion gene. Despite conventional chemotherapy failure and rapid tumor proliferation, we attempted to add FLT3 inhibitor sorafenib to the treatment, along with chemotherapy bridging to haploidentical transplantation. After haplo-HSCT, a combination of sorafenib and dasatinib was administered as maintenance therapy. The patient achieved complete remission (CR) and maintained it for 11 months. The intricate genetic landscape observed in this case presents diagnostic dilemmas and therapeutic challenges, emphasizing the importance of a comprehensive understanding of its implications for disease classification, risk stratification, and treatment selection.

Performances of a novel BAF with ferromanganese oxide modified biochar (FMBC) as the carriers for treating antibiotics, nitrogen and phosphorus in aquaculture wastewater.

In this paper, a biological aerated filter (BAF) based on ferromanganese oxide-biochar (FMBC) was constructed to investigated the removal performance and mechanism for conventional pollutants and four kinds of antibiotic, in contrast of conventional zeolite loaded BAF (BAF-A) and bamboo biochar filled BAF (BAF-B). Results showed that the average removal efficiency of total nitrogen (TN), total phosphorus (TP) and antibiotics in a FMBC-BAF (named by BAF-C) were 52.97 ± 2.27%, 51.58 ± 1.92% and 70.36 ± 1.00% ~ 81.65 ± 0.99% respectively in running period (39-100 d), which were significantly higher than those of BAF-A and BAF-B. In the BAF-C, the expression of denitrification enzyme activities and the secretion of extracellular polymeric substance (EPS) especially polyprotein (PN) were effectively stimulated, as well as accelerated electron transfer activity (ETSA) and lower electrochemical impedance spectroscopy (EIS) were acquired. After 100 days of operation, the abundance of nitrogen, phosphorus and antibiotic removal functional bacteria like Sphingorhabdus (4.52%), Bradyrhizobium (1.98%), Hyphomicrobium (2.49%), Ferruginibacter (7.80%), unclassified_f_Blastoca tellaceae (1.84%), norank_f_JG30-KF-CM45 (6.82%), norank_f_norank_o_SBR1031 (2.43%), Nitrospira (2.58%) norank_f_Caldilineaceae (1.53%) and Micropruina (1.11%) were enriched. Mechanism hypothesis of enhanced performances of nutrients and antibiotics removal pointed that: The phosphorus was removed by adsorption and precipitation, antibiotics removal was mainly achieved through the combined action of adsorption and biodegradation, while nitrogen removal was realized by biologic nitrification and denitrification in a FMBC-BAF for aquaculture wastewater treatment.

Antisense oligonucleotides enhance SLC20A2 expression and suppress brain calcification in a humanized mouse model.

Primary familial brain calcification (PFBC) is a genetic neurological disease, yet no effective treatment is currently available. Here, we identified five novel intronic variants in SLC20A2 gene from six PFBC families. Three of these variants increased aberrant SLC20A2 pre-mRNA splicing by altering the binding affinity of splicing machineries to newly characterized cryptic exons, ultimately causing premature termination of SLC20A2 translation. Inhibiting the cryptic-exon incorporation with splice-switching ASOs increased the expression levels of functional SLC20A2 in cells carrying SLC20A2 mutations. Moreover, by knocking in a humanized SLC20A2 intron 2 sequence carrying a PFBC-associated intronic variant, the SLC20A2-KI mice exhibited increased inorganic phosphate (Pi) levels in cerebrospinal fluid (CSF) and progressive brain calcification. Intracerebroventricular administration of ASOs to these SLC20A2-KI mice reduced CSF Pi levels and suppressed brain calcification. Together, our findings expand the genetic etiology of PFBC and demonstrate ASO-mediated splice modulation as a potential therapy for PFBC patients with SLC20A2 haploinsufficiency.

Effects of H9N2 avian influenza virus infection on metabolite content and gene expression in chick DF1 cells.

After viral infection, the virus relies on the host cell's complex metabolic and biosynthetic machinery for replication. However, the impact of avian influenza virus (AIV) on metabolites and gene expression in poultry cells remains unclear. To investigate this, we infected chicken embryo fibroblasts DF1 cells with H9N2 AIV at an MOI of 3. Our aim was to explore how H9N2 AIV alters DF1 cells metabolic pathways to facilitate its replication. We employed metabolomics and transcriptomics techniques to analyze changes in metabolite content and gene expression. Metabolomics analysis revealed a significant increase in glutathione-related metabolites, including reduced glutathione (GSH), oxidized glutathione (GSSG) and total glutathione (T-GSH) upon H9N2 AIV infection in DF1 cells. Elisa results confirmed elevated levels of GSH, GSSG, and T-GSH consistent with metabolomics findings, noting a pronounced increase in GSSG compared to GSH. Transcriptomics showed significant alterations in genes involved in glutathione synthesis and metabolism post-H9N2 infection. However, adding the glutathione synthesis inhibitor BSO exogenously significantly promoted H9N2 replication in DF1 cells. This was accompanied by increased mRNA levels of pro-inflammatory cytokines (IL-1ß, IFN-γ) and decreased mRNA levels of anti-inflammatory cytokines (TGF-ß, IL-13). BSO also reduced catalase (CAT) gene expression and inhibited its activity, leading to higher reactive oxygen species (ROS) and malondialdehyde (MDA) level in DF1 cells. qPCR results indicated decreased mRNA levels of Nrf2, NQO1, and HO-1 with BSO, ultimately increasing oxidative stress in DF1 cells. Therefore, the above results indicated that H9N2 AIV infection in DF1 cells activated the glutathione metabolic pathway to enhance the cell's self-defense mechanism against H9N2 replication. However, when GSH synthesis is inhibited within the cells, it leads to an elevated oxidative stress level, thereby promoting H9N2 replication within the cells through Nrf2/HO-1 pathway. This study provides a theoretical basis for future rational utilization of the glutathione metabolic pathway to prevent viral replication.

Piperidine-based ionic liquid additive with electrostatic shielding and redox activity enabling advanced lithium-oxygen batteries.

Here, we propose a piperidine-based ionic liquid additive. The electrostatic shielding effect of the piperidine cation (PP13+) effectively inhibits the growth of lithium dendrites. Simultaneously, the redox activity of the bromine anion synergistically reduces the overpotential. This approach significantly improves the cycling performance of lithium-oxygen batteries.

Weiwei Decoction alleviates gastric intestinal metaplasia through the olfactomedin 4/nucleotide-binding oligomerization domain 1/caudal-type homeobox gene 2 signaling pathway.

BACKGROUND: Gastric intestinal metaplasia (IM) is a precancerous lesion that is associated with an elevated risk of gastric carcinogenesis. Weiwei Decoction (WWD) is a promising traditional Chinese herbal formula widely employed in clinical for treating IM. Previous studies suggested the potential involvement of the olfactomedin 4 (OLFM4)/nucleotide-binding oligomerization domain 1 (NOD1)/caudal-type homeobox gene 2 (CDX2) signaling pathway in IM regulation. AIM: To verify the regulation of the OLFM4/NOD1/CDX2 pathway in IM, specifically investigating WWD's effectiveness on IM through this pathway. METHODS: Immunohistochemistry for OLFM4, NOD1, and CDX2 was conducted on tissue microarray. GES-1 cells treated with chenodeoxycholic acid were utilized as IM cell models. OLFM4 short hairpin RNA (shRNA), NOD1 shRNA, and OLFM4 pcDNA were transfected to clarify the pathway regulatory relationships. Protein interactions were validated by co-immunoprecipitation. To explore WWD's pharmacological actions, IM rat models were induced using N-methyl-N'-nitro-N-nitrosoguanidine followed by WWD gavage. Gastric cells were treated with WWD-medicated serum. Cytokines and chemokines content were assessed by enzyme-linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction. RESULTS: The OLFM4/NOD1/CDX2 axis was a characteristic of IM. OLFM4 exhibited direct binding and subsequent down-regulation of NOD1, thereby sustaining the activation of CDX2 and promoting the progression of IM. WWD improved gastric mucosal histological lesions while suppressing intestinal markers KLF transcription factor 4, villin 1, and MUCIN 2 expression in IM rats. Regarding pharmacological actions, WWD suppressed OLFM4 and restored NOD1 expression, consequently reducing CDX2 at the mRNA and protein levels in IM rats. Parallel regulatory mechanisms were observed at the protein level in IM cells treated with WWD-medicated serum. Furthermore, WWD-medicated serum treatment strengthened OLFM4 and NOD1 interaction. In case of anti-inflammatory, WWD restrained interleukin (IL)-6, interferon-gamma, IL-17, macrophage chemoattractant protein-1, macrophage inflammatory protein 1 alpha content in IM rat serum. WWD-medicated serum inhibited tumor necrosis factor alpha, IL-6, IL-8 transcriptions in IM cells. CONCLUSION: The OLFM4/NOD1/CDX2 pathway is involved in the regulation of IM. WWD exerts its therapeutic efficacy on IM through the pathway, additionally attenuating the inflammatory response.

Intense Circularly Polarized Luminescence Induced by Chiral Supramolecular Assembly: The Importance of Intermolecular Electronic Coupling.

Herein we report on circularly polarized luminescence (CPL) emission originating from supramolecular chirality of organic microcrystals with a |glum| value up to 0.11. The microcrystals were prepared from highly emissive difluoroboron ß-diketonate (BF2dbk) dyes R-1 or S-1 with chiral binaphthol (BINOL) skeletons. R-1 and S-1 exhibit undetectable CPL signals in solution but manifest intense CPL emission in their chiral microcrystals. The chiral superstructures induced by BINOL skeletons were confirmed by XRD analysis. Spectral analysis and theoretical calculations indicate that intermolecular electronic coupling, mediated by the asymmetric stacking in the chiral superstructures, effectively alters excited-state electronic structures and facilitates electron transitions perpendicular to BF2bdk planes. The coupling increases cosθµ,m from 0.05 (monomer) to 0.86 (tetramer) and triggers intense optical activity of BF2bdk. The results demonstrate that optical activity of chromophores within assemblies can be regulated by both orientation and extent of intermolecular electronic couplings.

Joint effect of atrial fibrillation and obesity on mortality in critically ill patients.

BACKGROUND: The interplay between atrial fibrillation (AF) and obesity on mortality in critically ill patients warrants detailed exploration, given their individual impacts on patient prognosis. This study aimed to assess the associations between AF, obesity, and 1-year mortality in a critically ill population. METHODS: Utilizing data from the Medical Information Mart for Intensive Care (MIMIC)-IV database, we conducted a retrospective analysis of adult patients admitted to the intensive care unit. The primary endpoint was 1-year mortality, analyzed through Cox regression with hazard ratio (HR) and Kaplan-Meier survival methods. RESULTS: The study included 25,654 patients (median age 67.0 years, 40.6% female), with 39.0% having AF and 36.1% being obese. Multivariate COX regression analysis revealed that AF was associated with a 14.7% increase in the risk of 1-year mortality (p < 0.001), while obesity was linked to a 13.9% reduction in mortality risk (p < 0.001). The protective effect of obesity on mortality was similar in patients with (HR = 0.85) and without AF (HR = 0.86). AF led to a slightly higher risk of mortality in patients without obesity (HR = 1.16) compared to those with obesity (HR = 1.13). Kaplan-Meier survival curves highlighted that non-obese patients with AF had the lowest survival rate, whereas the highest survival was observed in obese patients without AF. CONCLUSIONS: AF significantly increased 1-year mortality risk in critically ill patients, whereas obesity was associated with a decreased mortality risk. The most adverse survival outcomes were identified in non-obese patients with AF.

Lignanamides: A comprehensive review of chemical constituents, biological activities, extraction methods and synthetic pathway.

Lignanamides are a class of compounds containing amide functional groups in lignans. These compounds have excellent anti-inflammatory and neuroprotective, which have shown great potential in terms of food additives, medicine and health supplement. We summarized the recent progress of lignanamides, including chemical constituents, extraction methods, biological activities, and synthetic pathways. The structures were classified according to an updated nomenclature system, can be classified into sixteen types and have certain roles in many respects such as anti-inflammatory, anti-cancer, and antioxidative, which may be important source of materials for functional food. The potential and limitations of different extraction method, chromatographic packing, and synthetic pathway are analyzed. Notably, this review provides an overview of synthesis pathways and applications of lignanamides, further research is needed to improve extraction efficiency and synthesis method, especially in a greener way for better application.

Efficacy and safety of Tianqi Pingchan Granule, a compound Chinese herbal medicine, for levodopa-induced dyskinesia in Parkinson's disease: A randomized double-blind placebo-controlled trial.

BACKGROUND: Patients with Parkinson's disease (PD) undergoing long-term levodopa therapy are prone to develop levodopa-induced dyskinesia (LID). Amantadine is the main drug recommended for the treatment of LID by current guidelines, but it is far from meeting clinical needs. Tianqi Pingchan Granule (TPG), a compound Chinese herbal medicine, has been developed to relieve symptom of LID. OBJECTIVE: This randomized controlled trial evaluated the efficacy and safety of the combination of TPG and amantadine for LID. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This is a randomized double-blind placebo-controlled trial, conducted from January 2020 to August 2021 at 6 sites in Jiangsu, Zhejiang and Shanghai, China. One hundred PD patients with ≥ 0.5 h of LID were randomly assigned to either the TPG plus amantadine group (TPG group) or the placebo plus amantadine group (placebo group), and treated for a period of 12 weeks. To ensure unbiased results, all study participants, investigators and sponsors were unaware of group allocations. Additionally, the data analysts remained blinded until the analysis was finalized. MAIN OUTCOME MEASURES: The primary outcome was assessed using the Unified Dyskinesia Rating Scale (UDysRS) (Range 0-104). The key secondary end point was improvement of motor and non-motor symptoms. Safety analyses included all enrolled patients. RESULTS: One hundred patients were enrolled and randomized into the two treatment groups. The changes in UDysRS at week 12 were -11.02 for the TPG group and -4.19 for the placebo group (treatment difference -6.83 [-10.53 to -3.12]; P = 0.0004). Adverse events were reported for 2 of 50 patients (4.0%) in each of the groups. CONCLUSION: This study indicated that a 12-week treatment of amantadine plus TPG effectively reduced UDysRS scores and was well tolerated, demonstrating the efficacy and safety of TPG for the treatment of LID in PD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04173832. PLEASE CITE THIS ARTICLE AS: Zhang Y, Zhu XB, Zhao Y, Cui GY, Li WT, Yuan CX, Huang JP, Wan Y, Wu N, Song L, Zhao JH, Liang Y, Xu CY, Liu MJ, Gao C, Chen XX, Liu ZG. Efficacy and safety of Tianqi Pingchan Granule, a compound Chinese herbal medicine, for levodopa-induced dyskinesia in Parkinson's disease: A randomized double-blind placebo-controlled trial. J Integr Med. 2024; Epub ahead of print.

Liver involvement with Langerhans cell histiocytosis in adults.

BACKGROUND AND AIMS: Liver involvement portends poor prognosis in adults. We aimed to characterize the clinical features, liver function tests, radiologic findings, molecular profiles, therapeutic approaches and outcomes of adults patients with Langerhans cell histiocytosis (LCH) with liver involvement. METHODS: We conducted a retrospective analysis of all adults with LCH (≥ 18 years) seen at Peking Union Medical College Hospital (Beijing, China) between January 2001 and December 2022. RESULTS: Among the 445 newly diagnosed adults with LCH, 90 patients had liver involvement at diagnosis and 22 patients at relapse. The median age was 32 years (range, 18-66 years). Of 112 evaluable patients, 108 had full liver function testing, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), and total bilirubin and albumin. Elevated ALP was seen in 63.0% and GGT in 86.1%; 14.8% had elevated bilirubin. Next-generation sequencing of 54 patients revealed frequent BRAFN486_P490 (29.6%), BRAFV600E (18.5%), and MAP2K1 (14.8%). OUTCOMES: After a median 40 months' follow-up (range 1-168 months), 3-year progression-free survival (PFS) and overall survival were 49.7% and 86.6% respectively. In multivariable analyses, ≥3 abnormal liver function tests (HR 3.384, 95% CI 1.550-7.388, P = .002) associated with inferior PFS; immunomodulatory drug therapy (HR 0.073, 95% CI, 0.010-0.541, P = .010) correlated with superior PFS versus chemotherapy. CONCLUSIONS: In summary, elevated GGT and ALP were common in adults with LCH liver involvement. Greater than equal to 3 abnormal liver function tests predicted poor outcomes. Immunomodulatory drug therapy was associated with favorable progression-free survival compared to chemotherapy.

New polycyclic polyprenylated acylphloroglucinols with antidepressant activities from Hypericum perforatum L.

Six new polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperidiones A-F (1-6), were obtained from Hypericum perforatum L. Their structures were characterized via extensive spectroscopic analyses, the circular dichroism data of the in situ formed [Mo2(OCOCH3)4] complexes, the nuclear magnetic resonance calculation with DP4 + probability analysis, and the calculated electronic circular dichroism (ECD) spectra. Compounds 1-6 are bicyclic polyprenylated acylphloroglucinols with a major bicyclo[3.3.1]nonane-2,4,9-trione skeleton. Notably, compound 1 is a rare PPAP with a hydroperoxy group, and a plausible biosynthetic pathway for 1 was proposed. Compounds 4 and 6 exhibited significant neuroprotective effects under 10 µM against corticosterone (CORT)-injured SH-SY5Y cells. Furthermore, compound 4 demonstrated a noteworthy antidepressant effect at the dose of 5 mg/kg in the tail suspension test (TST) of mice, which was equivalent to 5 mg/kg of fluoxetine. And it potentially exerted an antidepressant effect through the hypothalamic-pituitary-adrenal (HPA) axis.

Effects of microplastics derived from biodegradable mulch film on different plant species growth and soil properties.

Biodegradable mulch residues contribute significantly to the presence of microplastics in soil ecosystems. The environmental impact of microplastics, especially biodegradable microplastics (bio-MPs), on soil and plants is of increasing concern. In this study, the responses of five crop species potted in soil treated with different mass concentrations of bio-MPs were assessed for one month. The shoot and root biomasses of cabbages and strawberries were inhibited by bio-MPs treatment. There was little variation in the growth indicators of identical plants with the addition of different mass concentrations of bio-MPs; however, a significant difference was observed among different plants with the addition of the same concentration of bio-MPs. The detrimental effects of bio-MPs were more pronounced in strawberries and cabbages than in the other plant species. Moreover, bio-MPs can affect the availability of soil nutrients and enzyme activities. Structural equation modeling showed that changes in soil properties may indirectly affect plant growth and nutrient uptake when exposed to bio-MPs. This study provides a theoretical basis for understanding the ecological effects of biodegradable mulch films.