Liensinine alleviates sepsis-induced acute liver injury by inhibiting the NF-κB and MAPK pathways in an Nrf2-dependent manner.

Sepsis remains a serious public health issue that needs to be addressed globally. Severe liver injury caused by sepsis increases the risk of death in patients with sepsis. Liensinine (Lie) is one of the primary active components in Plumula nelumbinis and has anti-inflammatory and antioxidant effects. Nevertheless, the effects of Lie on septic liver injury are unclear. This research investigated the protective effect of Lie (10, 20 and 40 mg/kg) on liver damage via intraperitoneal administration of LPS (10 mg/kg) to C57BL/6 mice. Lie was given through intraperitoneal injection once a day for five days. Mice were treated with LPS intraperitoneally for 6 h at 1 h after Lie administration on the last day. The results suggested that Lie could decrease AST and ALT levels in serum, ameliorate histopathological changes and inhibit cell apoptosis in mice with LPS-induced septic liver injury. In addition, Lie inhibited increases in the mRNA levels of TNF-α, IL-1ß, iNOS and IL-6. Lie also increased the mRNA level of IL-10. Lie reduced the content of MDA, a marker of lipid peroxidation, and increased the activity of the antioxidant enzymes GSH-Px, CAT and SOD. Our results also showed that Lie could suppress the LPS-activated MAPK and NF-κB pathways and trigger the Nrf2 signaling pathway both in vitro and in vivo. Additionally, an Nrf2 inhibitor (ML385) weakened the suppressive effect of Lie on the MAPK and NF-κB pathways. Our results demonstrated that the suppressive effect of Lie on the MAPK and NF-κB pathways was partially reliant on activation of the Nrf2 pathway. In summary, these results indicate that Lie can improve inflammation and oxidative stress by activating Nrf2, which is a prospective therapeutic drug for alleviating septic liver injury.

CircUGGT2 downregulation by METTL14-dependent m6A modification suppresses gastric cancer progression and cisplatin resistance through interaction with miR-186-3p/MAP3K9 axis.

Chemoresistance is a major therapeutic challenge in advanced gastric cancer (GC). N6-methyladenosine (m6A) RNA modification has been shown to play fundamental roles in cancer progression. However, the underlying mechanisms by which m6A modification of circRNAs contributes to GC and chemoresistance remain unknown. We found that hsa_circ_0030632 (circUGGT2) was a predominant m6A target of METTL14, and METTL14 knockdown (KD) reduced circUGGT2 m6A levels but increased its mRNA levels. The expression of circUGGT2 was markedly increased in cisplatin (DDP)-resistant GC cells. CircUGGT2 KD impaired cell growth, metastasis and DDP-resistance in vitro and in vivo, but circUGGT2 overexpression prompted these effects. Furthermore, circUGGT2 was validated to sponge miR-186-3p and upregulate MAP3K9 and could abolish METTL14-caused miR-186-3p upregulation and MAP3K9 downregulation in GC cells. circUGGT2 negatively correlated with miR-186-3p expression and harbored a poor prognosis in patients with GC. Our findings unveil that METTL14-dependent m6A modification of circUGGT2 inhibits GC progression and DDP resistance by regulating miR-186-3p/MAP3K9 axis.

FOXF1 reverses lung fibroblasts transdifferentiation via inhibiting TGF-ß/SMAD2/3 pathway in silica-induced pulmonary fibrosis.

Silicosis is one of the most common and severe types of pneumoconiosis and is characterized by lung dysfunction, persistent lung inflammation, pulmonary nodule formation, and irreversible pulmonary fibrosis. The transdifferentiation of fibroblasts into myofibroblasts is one of the main reasons for the exacerbation of silicosis. However, the underlying mechanism of transcription factors regulating silicosis fibrosis has not been clarified. The aim of this study was to investigate the potential mechanism of transcription factor FOXF1 in fibroblast transdifferentiation in silica-induced pulmonary fibrosis. Therefore, a silicosis mouse model was established, and we found that FOXF1 expression level was significantly down-regulated in the silicosis group, and after overexpression of FOXF1 by adeno-associated virus (AAV), FOXF1 expression level was up-regulated, and silicosis fibrosis was alleviated. In order to further explore the specific regulatory mechanism of FOXF1 in silicosis, we established a fibroblasts transdifferentiation model induced by TGF-ß in vitro. In the model, the expression levels of SMAD2/3 and P-SMAD2/3 were up-regulated, but the expression levels of SMAD2/3 and P-SMAD2/3 were down-regulated, inhibiting transdifferentiation and accumulation of extracellular matrix after the overexpressed FOXF1 plasmid was constructed. However, after silencing FOXF1, the expression levels of SMAD2/3 and P-SMAD2/3 were further up-regulated, aggravating transdifferentiation and accumulation of extracellular matrix. These results indicate that the activation of FOXF1 in fibroblasts can slow down the progression of silicosis fibrosis by inhibiting TGF-ß/SMAD2/3 classical pathway, which provides a new idea for further exploration of silicosis treatment.

Measles Virus-Based Vaccine Expressing Membrane-Anchored Spike of SARS-CoV-2 Inducing Efficacious Systemic and Mucosal Humoral Immunity in Hamsters.

As SARS-CoV-2 continues to evolve and COVID-19 cases rapidly increase among children and adults, there is an urgent need for a safe and effective vaccine that can elicit systemic and mucosal humoral immunity to limit the emergence of new variants. Using the Chinese Hu191 measles virus (MeV-hu191) vaccine strain as a backbone, we developed MeV chimeras stably expressing the prefusion forms of either membrane-anchored, full-length spike (rMeV-preFS), or its soluble secreted spike trimers with the help of the SP-D trimerization tag (rMeV-S+SPD) of SARS-CoV-2 Omicron BA.2. The two vaccine candidates were administrated in golden Syrian hamsters through the intranasal or subcutaneous routes to determine the optimal immunization route for challenge. The intranasal delivery of rMeV-S+SPD induced a more robust mucosal IgA antibody response than the subcutaneous route. The mucosal IgA antibody induced by rMeV-preFS through the intranasal routine was slightly higher than the subcutaneous route, but there was no significant difference. The rMeV-preFS vaccine stimulated higher mucosal IgA than the rMeV-S+SPD vaccine through intranasal or subcutaneous administration. In hamsters, intranasal administration of the rMeV-preFS vaccine elicited high levels of NAbs, protecting against the SARS-CoV-2 Omicron BA.2 variant challenge by reducing virus loads and diminishing pathological changes in vaccinated animals. Encouragingly, sera collected from the rMeV-preFS group consistently showed robust and significantly high neutralizing titers against the latest variant XBB.1.16. These data suggest that rMeV-preFS is a highly promising COVID-19 candidate vaccine that has great potential to be developed into bivalent vaccines (MeV/SARS-CoV-2).

Tumor microenvironment reprogramming by nanomedicine to enhance the effect of tumor immunotherapy.

With the rapid development of the fields of tumor biology and immunology, tumor immunotherapy has been used in clinical practice and has demonstrated significant therapeutic potential, particularly for treating tumors that do not respond to standard treatment options. Despite its advances, immunotherapy still has limitations, such as poor clinical response rates and differences in individual patient responses, largely because tumor tissues have strong immunosuppressive microenvironments. Many tumors have a tumor microenvironment (TME) that is characterized by hypoxia, low pH, and substantial numbers of immunosuppressive cells, and these are the main factors limiting the efficacy of antitumor immunotherapy. The TME is crucial to the occurrence, growth, and metastasis of tumors. Therefore, numerous studies have been devoted to improving the effects of immunotherapy by remodeling the TME. Effective regulation of the TME and reversal of immunosuppressive conditions are effective strategies for improving tumor immunotherapy. The use of multidrug combinations to improve the TME is an efficient way to enhance antitumor immune efficacy. However, the inability to effectively target drugs decreases therapeutic effects and causes toxic side effects. Nanodrug delivery carriers have the advantageous ability to enhance drug bioavailability and improve drug targeting. Importantly, they can also regulate the TME and deliver large or small therapeutic molecules to decrease the inhibitory effect of the TME on immune cells. Therefore, nanomedicine has great potential for reprogramming immunosuppressive microenvironments and represents a new immunotherapeutic strategy. Therefore, this article reviews strategies for improving the TME and summarizes research on synergistic nanomedicine approaches that enhance the efficacy of tumor immunotherapy.

Simultaneous assessment of absorption and pharmacokinetic characteristics of four active flavonoids from Chimonanthus nitens Leaf Granules using LC-MS determination: in vivo and in vitro.

A sensitive UPLC-HRMS method was developed and validated for simultaneous quantification of four active flavonoids from Chimonanthus nitens Leaf Granules (CNLG) in biological matrix. The method was utilized in pharmacokinetic study of the four flavonoids in rats as well as other evaluation assays in vitro. It was revealed that rutin, nicotiflorin, and astragalin had poor oral bioavailability in rats possibly due to low intestinal permeability and metabolism in intestinal flora. Kaempferol underwent rapid glucuronidation and sulphation in rat plasma with medium permeability coefficient. The results provided valuable data for future research and development of CNLG flavonoids.

Neuroinflammation of Microglial Regulation in Alzheimer's Disease: Therapeutic Approaches.

Alzheimer's disease (AD) is a complex degenerative disease of the central nervous system that is clinically characterized by a progressive decline in memory and cognitive function. The pathogenesis of AD is intricate and not yet fully understood. Neuroinflammation, particularly microglial activation-mediated neuroinflammation, is believed to play a crucial role in increasing the risk, triggering the onset, and hastening the progression of AD. Modulating microglial activation and regulating microglial energy metabolic disorder are seen as promising strategies to intervene in AD. The application of anti-inflammatory drugs and the targeting of microglia for the prevention and treatment of AD has emerged as a new area of research interest. This article provides a comprehensive review of the role of neuroinflammation of microglial regulation in the development of AD, exploring the connection between microglial energy metabolic disorder, neuroinflammation, and AD development. Additionally, the advancements in anti-inflammatory and microglia-regulating therapies for AD are discussed.

A long-term cohort study: the immune evasion and decreasing neutralization dominated the SARS-CoV-2 breakthrough infection.

Most of vaccinees and COVID-19 convalescents can build effective anti-SARS-CoV-2 humoral immunity, which helps preventing infection and alleviating symptoms. However, breakthrough viral infections caused by emerging SARS-CoV-2 variants, especially Omicron subvariants, still pose a serious threat to global health. By monitoring the viral infections and the sera neutralization ability of a long-tracked cohort, we found out that the immune evasion of emerging Omicron subvariants and the decreasing neutralization led to the mini-wave of SARS-CoV-2 breakthrough infections. Meanwhile, no significant difference had been found in the infectivity of tested SARS-CoV-2 variants, even though the affinity between human angiotensin-converting enzyme 2 (hACE2) and receptor-binding domain (RBDs) of tested variants showed an increasing trend. Notably, the immune imprinting of inactivated COVID-19 vaccine can be relieved by infections of BA.5.2 and XBB.1.5 variants sequentially. Our data reveal the rising reinfection risk of immune evasion variants like Omicron JN.1 in China, suggesting the importance of booster with updated vaccines.

Prenatal ultrasound findings and prenatal diagnosis of fetal skeletal dysplasia.

OBJECTIVE: To analyze the value of prenatal ultrasound and molecular testing in diagnosing fetal skeletal dysplasia (SD). METHODS: Clinical data, prenatal ultrasound data, and molecular results of pregnant women with fetal SD were collected in the ultrasound department of our clinic from May 2019 to December 2021. RESULTS: A total of 40 pregnant women with fetal SD were included, with 82.5% exhibiting short limb deformity, followed by 25.0% with central nervous system malformations, 17.50% with facial malformations, 15% with cardiac malformations, and 12.5% with urinary system malformations. The genetic testing positive rate was 70.0% (28/40), with 92.8% (26/28) being single-gene disorders due to mutations in FGFR3, COL1A1, COL1A2, EVC2, FLNB, LBR, and TRPV4 genes. The most common SD subtypes were osteogenesis imperfecta (OI), thanatophoric dysplasia (TD), and achondroplasia (ACH). The gestational age (GA) at initial diagnosis for TD, OI, and ACH was 16.6, 20.9, and 28.3 weeks, respectively (p < 0.05), with no significant difference in femoral shortening between the three groups (p > 0.05). Of the OI cases, 5 out of 12 had a family history. CONCLUSION: Short limb deformity is the most prevalent phenotype of SD. When fetal SD is suspected, detailed ultrasound screening should be conducted, combined with GA at initial diagnosis, family history, and molecular evidence, to facilitate more accurate diagnosis and enhance prenatal counseling and perinatal management.

Detachable string magnetically controlled capsule endoscopy for the noninvasive diagnosis of esophageal diseases: A prospective, blind clinical study.

BACKGROUND: Traditional esophagogastroduodenoscopy (EGD), an invasive examination method, can cause discomfort and pain in patients. In contrast, magnetically controlled capsule endoscopy (MCE), a noninvasive method, is being applied for the detection of stomach and small intestinal diseases, but its application in treating esophageal diseases is not widespread. AIM: To evaluate the safety and efficacy of detachable string MCE (ds-MCE) for the diagnosis of esophageal diseases. METHODS: Fifty patients who had been diagnosed with esophageal diseases were prospectively recruited for this clinical study and underwent ds-MCE and conventional EGD. The primary endpoints included the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of ds-MCE for patients with esophageal diseases. The secondary endpoints consisted of visualizing the esophageal and dentate lines, as well as the subjects' tolerance of the procedure. RESULTS: Using EGD as the gold standard, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of ds-MCE for esophageal disease detection were 85.71%, 86.21%, 81.82%, 89.29%, and 86%, respectively. ds-MCE was more comfortable and convenient than EGD was, with 80% of patients feeling that ds-MCE examination was very comfortable or comfortable and 50% of patients believing that detachable string v examination was very convenient. CONCLUSION: This study revealed that ds-MCE has the same diagnostic effects as traditional EGD for esophageal diseases and is more comfortable and convenient than EGD, providing a novel noninvasive method for treating esophageal diseases.

Oleispirillum naphthae gen. nov., sp. nov., a bacterium isolated from oil sludge, and proposal of Oleispirillaceae fam. nov.

A microaerophilic, Gram-negative, motile, and spiral-shaped bacterium, designated Y-M2T, was isolated from oil sludge of Shengli oil field. The optimal growth condition of strain Y-M2T was at 25 °C, pH 7.0, and in the absence of NaCl. The major polar lipid was phosphatidylethanolamine. The main cellular fatty acid was iso-C17  :  0 3-OH. It contained Q-9 and Q-10 as the predominant quinones. The DNA G+C content was 68.1 mol%. Strain Y-M2T showed the highest 16S rRNA gene sequence similarity to Telmatospirillum siberiense 26-4bT (91.1 %). Phylogenetic analyses based on 16S rRNA gene and genomes showed that strain Y-M2T formed a distinct cluster in the order Rhodospirillales. Genomic analysis showed that Y-M2T possesses a complete nitrogen-fixation cluster which is phylogenetically close to that of methanogene. The nif cluster, encompassing the nitrogenase genes, was found in every N2-fixing strain within the order Rhodospirillales. Phylogeny, phenotype, chemotaxonomy, and genomic results demonstrated that strain Y-M2T represents a novel species of a novel genus in a novel family Oleispirillaceae fam. nov. in the order Rhodospirillales, for which the name Oleispirillum naphthae gen. nov., sp. nov. was proposed. The type strain is Y-M2T (=CCAM 827T=JCM 34765T).

A Direct Comparison of Three Screening Methods for Autism Spectrum Disorder in a High-Likelihood Sibling Population.

Targeted screening of children at increased likelihood of autism is recommended. However, autism screening tools are usually validated for use mainly in low-likelihood populations. This study compared the accuracy of the Modified Checklist for Autism in Toddlers, Revised with Follow-up (M-CHAT-R/F), the ASDetect app, and the Social Attention and Communication Surveillance, Revised (SACS-R). Siblings of autistic children underwent autism screening at 12, 18 and 30 months old. At each visit, caregivers completed the M-CHAT-R/F and ASDetect while trained nurses tested the siblings using the SACS-R. At 36 to 48 months, the siblings underwent an Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) assessment. 189 siblings were screened, 141 completed the study, and 32 were confirmed to have autism. Although not validated for use at 12 months, the M-CHAT-R/F had the best sensitivity among the three tools for this age group, suggesting that early signs are already apparent to caregivers. The M-CHAT-R/F had overall better sensitivity (0.72-0.83) across all age groups, but with overall lower specificity (0.55-0.77). The SACS-R and ASDetect had better positive predictive values at 18 and 30 months (0.60-0.68), while the M-CHAT-R/F was 0.43-0.48. Negative predictive values were generally high across all three tools across all age groups (0.78-0.93). Targeted screening of children at high likelihood of autism yielded a detection rate of 22.7% and should therefore be implemented routinely to facilitate early detection and intervention. The performance of autism screening tools should be examined in higher-likelihood populations for targeted screening of these children.

Capacity of community health centers to treat snakebite envenoming in indigenous territories of the Brazilian Amazon.

INTRODUCTION: The deaths from and morbidities associated with snakebites - amputations, loss of function in the limb, visible scarring or tissue damage - have a vast economic, social, and psychological impact on indigenous communities in the Brazilian Amazon, especially children, and represent a real and pressing health crisis in this population. Snakebite clinical and research experts have therefore proposed expanding antivenom access from only hospitals to include the community health centers (CHC) located near and within indigenous communities. However, there are no studies examining the capacity of CHCs to store, administer, and manage antivenom treatment. In response to this gap, the research team calling for antivenom decentralization developed and validated an expert-based checklist outlining the minimum requirements for a CHC to provide antivenom. METHODS: The objective of this study was thus to survey a sample of CHCs in indigenous territories and evaluate their capacity to provide antivenom treatment according to this accredited checklist. The checklist was administered to nurses and doctors from 16 CHCs, two per indigenous district in Amazonas/Roraima states. RESULTS: Our results can be conceptualized into three central findings: 1) most CHCs have the capacity to provide antivenom treatment, 2) challenges to capacity are human resources and specialized items, and 3) antivenom decentralization is feasible and appropriate in indigenous communities. CONCLUSION: Decentralization would provide culturally and contextually appropriate care accessibility to a historically marginalized and underserved population of the Brazilian Amazon. Future studies should examine optimal resource allocation in indigenous territories and develop an implementation strategy in partnership with indigenous leaders. Beyond the indigenous population, the checklist utilized could be applied to community health centers treating the general population and/or adapted to other low-resource settings.

Analysis of the Risk Factors for Plastic Bronchitis in Children with Severe Adenovirus Pneumonia: A Retrospective Study.

Purpose: Plastic bronchitis (PB), a rare complication of respiratory infection characterized by the formation of casts in the tracheobronchial tree, can lead to airway obstruction and severe condition. Adenovirus is one of the common pathogens of PB caused by infection. This study aimed to evaluate the clinical features and risk factors for PB in children with severe adenovirus pneumonia. Methods: A retrospective study of children with severe adenovirus pneumonia with bronchoscopy results at Guangzhou Women and Children's Hospital between January 2018 and January 2020 was performed. Based on bronchoscopy, we divided children with severe adenovirus pneumonia into two groups: PB and non-PB. Binary logistic regression analysis was used to identify independent risk factors for PB in patients with severe adenovirus pneumonia after univariate analysis. Results: Our study examined 156 patients with severe adenovirus pneumonia with bronchoscopy results in hospital. Among them, 18 developed PB and 138 did not. On multivariate analysis, the independent risk factors of PB in children with severe adenovirus pneumonia were history of allergies (OR 10.147, 95% CI 1.727-59.612; P=0.010), diminished breath sounds (OR 12.856, 95% CI 3.259-50.713; P=0.001), and increased proportion of neutrophils (>70%; OR 8.074, 95% CI 1.991-32.735; P=0.003). Conclusion: Children with severe adenovirus pneumonia with a history of allergies, diminished breath sounds, and increased the proportion of neutrophils >70% may show higher risk of PB.

Urinary proteomics reveals biological processes related to acute kidney injury in Bothrops atrox envenomings.

Acute kidney injury (AKI) is a critical systemic complication caused by Bothrops envenoming, a neglected health problem in the Brazilian Amazon. Understanding the underlying mechanisms leading to AKI is crucial for effectively mitigating the burden of this complication. This study aimed to characterize the urinary protein profile of Bothrops atrox snakebite victims who developed AKI. We analyzed three groups of samples collected on admission: healthy subjects (controls, n = 10), snakebite victims who developed AKI (AKI, n = 10), and those who did not evolve to AKI (No-AKI, n = 10). Using liquid-chromatography tandem mass spectrometry, we identified and quantified (label-free) 1190 proteins. A panel of 65 proteins was identified exclusively in the urine of snakebite victims, with 32 exclusives to the AKI condition. Proteins more abundant or exclusive in AKI's urine were associated with acute phase response, endopeptidase inhibition, complement cascade, and inflammation. Notable proteins include serotransferrin, SERPINA-1, alpha-1B-glycoprotein, and NHL repeat-containing protein 3. Furthermore, evaluating previously reported biomarkers candidates for AKI and renal injury, we found retinol-binding protein, beta-2-microglobulin, cystatin-C, and hepcidin to be significant in cases of AKI induced by Bothrops envenoming. This work sheds light on physiological disturbances caused by Bothrops envenoming, highlighting potential biological processes contributing to AKI. Such insights may aid in better understanding and managing this life-threatening complication.

[Intestinal absorption components and absorption characteristics of Wuwei Qingzhuo San by everted intestinal sac models].

This study investigated the absorption profile of Wuwei Qingzhuo San in different intestinal segments and the absorption characteristics of its alkaloids(piperine, piperanine, piperlonguminine, and dihydropiperlonguminine). The everted gut sac model was established, and the chemical components of Wuwei Qingzhuo San in different intestinal segments were detected by UPLC-Q-TOF-MS. The content of piperine, piperanine, piperlonguminine, and dihydropiperlonguminine in intestinal absorption fluid was determined by UPLC-Q-TRAP-MS and the absorption parameters were calculated. The absorption characteristics in different intestinal segments at different time were analyzed. As a result, 27, 27, 8, and 6 absorbent components from Wuwei Qingzhuo San were detected in the intestinal cyst fluid of jejunum, ileum, duodenum, and colon by UPLC-Q-TOF-MS technology, respectively. It was also found that piperine, piperanine, piperlonguminine, and dihydropiperlonguminine from Wuwei Qingzhuo San showed linear absorption in various intestinal segments, with r values exceeding 0.9. In terms of absorption content, the components were ranked as piperine>piperanine>dihydropiperlonguminine>piperlonguminine in various intestinal segments, but the absorption rate and mechanism of each component varied. The results demonstrate that the absorption of the components of Wuwei Qingzhuo San in different intestinal segments is selective and is not a simple semi-permeable membrane permeation process.

Palmatine alleviates cardiac fibrosis by inhibiting fibroblast activation through the STAT3 pathway.

Cardiac fibrosis, the hallmark of cardiovascular disease, is characterized by excessive deposition of extracellular matrix in the heart. Emerging evidence indicates that cardiac fibroblasts (CFs) play pivotal roles in driving cardiac fibrosis. However, due to incomplete insights into CFs, there are limited effective approaches to prevent or reverse cardiac fibrosis currently. Palmatine, a protoberberine alkaloid extracted from traditional Chinese botanical remedies, possesses diverse biological effects. This study investigated the potential therapeutic value and mechanism of palmatine against cardiac fibrosis. Adult male C57BL/6 mice were treated with vehicle, isoproterenol (ISO), or ISO plus palmatine for one week. After echocardiography assessment, mice hearts were collected for histopathology, real-time polymerase chain reaction, and Western blot analyses. Primary rat CFs were utilized in vitro. Compared to control, ISO-treated mice exhibited cardiac hypertrophy and structural abnormalities; however, treatment with palmatine ameliorated these effects of ISO. Moreover, palmatine treatment mitigated ISO-induced cardiac fibrosis. Network pharmacology and molecular docking analysis showed that palmatine strongly binds the regulators of cardiac fibrosis including signal transducer and activator of transcription 3 (STAT3) and mammalian target of rapamycin. Furthermore, palmatine reduced the elevated fibrotic factor expressions and overactivated STAT3 induced by ISO, Transformed growth factor ß1 (TGF-ß1), or interleukin-6 both in vivo and in vitro. Additionally, blocking STAT3 suppressed the TGF-ß1-induced CF activation. Collectively, these data demonstrated that palmatine attenuated cardiac fibrosis partly by inhibiting fibroblast activation through the STAT3 pathway. This provides an experimental basis for the clinical treatment of cardiac fibrosis with palmatine.

Melatonin alleviates T-2 toxin-induced oxidative damage, inflammatory response, and apoptosis in piglet spleen and thymus.

T-2 toxin, an unavoidable contaminant in animal feeds, can induce oxidative stress and damage immune organs. Melatonin (MT), a natural and potent antioxidant, has shown promise as a detoxifier for various mycotoxins. However, the detoxifying effect of MT on T-2 toxin has not been previously reported. In order to investigate the protective effect of MT added to diets on the immune system of T-2 toxin-exposed piglets, twenty piglets weaned at 28d of age were randomly divided into control, T-2 toxin (1 mg/kg), MT (5 mg/kg), and T-2 toxin (1 mg/kg) + MT (5 mg/kg) groups(n = 5 per group). Our results demonstrated that MT mitigated T-2 toxin-induced histoarchitectural alterations in the spleen and thymus, such as hemorrhage, decreased white pulp size in the spleen, and medullary cell sparing in the thymus. Further research revealed that MT promoted the expression of Nrf2 and increased the activities of antioxidant enzymes CAT and SOD, while reducing the production of the lipid peroxidation product MDA. Moreover, MT inhibited the NF-κB signaling pathway, regulated the expression of downstream cytokines IL-1ß, IL-6, TNF-α, and TGF-ß1. MT also suppressed the activation of caspase-3 while down-regulating the ratio of Bax/Bcl-2 to reduce apoptosis. Additionally, MT ameliorated the T-2 toxin-induced disorders of immune cells and immune molecules in the blood. In conclusion, our findings suggest that MT may effectively protect the immune system of piglets against T-2 toxin-induced damage by inhibiting oxidative stress, inflammatory response, and apoptosis in the spleen and thymus. Therefore, MT holds the potential as an antidote for T-2 toxin poisoning.

Clinical significance of three-dimensional power Doppler combined with two-dimensional Doppler ultrasonography for evaluating fetal growth restriction.

OBJECTIVES: To assess the predictive accuracy of three-dimensional (3D) power Doppler combined with two-dimensional (2D) Doppler ultrasonography in detecting fetal growth restriction (FGR). METHODS: The study was conducted on singleton pregnancies presenting for growth ultrasound examinations between 20 and 40 weeks of gestation. 63 patients with FGR were enrolled and matched 1:1.8 for gestational age with normal fetuses. Both groups were further divided into subgroups, with 32 weeks as the threshold-early-onset and late-onset FGR groups, and corresponding control groups. Conventional 2D Doppler parameters and standardized 3D power Doppler measurements of the placenta, including vascularization index (VI), flow index (FI), and vascularization-flow index (VFI) were obtained for each patient. RESULTS: (1) The average gestational weeks of delivery and birth weight of newborns in early-onset and late-onset FGR case groups were lower than those in control groups, while the incidence of placenta previa and adverse pregnancy outcomes were higher than those in control groups. (2) The biparietal diameter, head circumference, abdominal circumference, femur length, estimated fetal weight, middle cerebral artery systolic/diastolic velocity ratio (S/D), pulsatility index (PI), resistance index (RI), and placental blood perfusion indices of vascular index (VI), flow index (FI), vascular flow index (VFI), and cerebro-placental ratio (CPR) of the early-onset and late-onset FGR case groups were all lower than those of the control group. Moreover, the S/D, PI, and RI of the umbilical and uterine arteries were higher than those of the corresponding control group. (3) For early-onset FGR, the area under the curve (AUC) of the umbilical artery PI was the largest (0.861), exhibiting the highest predictive value. When combined with the placental blood perfusion index, the AUC was 0.789. For late-onset FGR, the AUC of the CPR was 0.861. After integrating the placental blood perfusion index, the AUC increased to 0.877. The positive likelihood ratio (PLR) of combined 2D Doppler indexes (21.938) and negative likelihood ratio (NLR) of VFI (0.565) were the highest in the early-onset FGR group. The PLR of combined 3D Doppler indexes (8.536) and NLR of VFI (0.557) were the highest in the late-onset FGR group. CONCLUSIONS: The combination of 3D Doppler indices with 2D Doppler ultrasonography demonstrated superior predictive value in diagnosing late-onset FGR compared to other conventional indicators. The 3D Dower index, VFI, has a good true-negative predictive value for both early- and late-onset FGR.

Koumine inhibits IL-1ß-induced chondrocyte inflammation and ameliorates extracellular matrix degradation in osteoarthritic cartilage through activation of PINK1/Parkin-mediated mitochondrial autophagy.

Osteoarthritis (OA) is a degenerative joint disease, Increasingly, mitochondrial autophagy has been found to play an important regulatory role in the prevention and treatment of osteoarthritis. Koumine is a bioactive alkaloid extracted from the plant Gelsemium elegans. In previous research, Koumine was found to have potential in improving the progression of OA in rats. However, the specific mechanism of its action has not been fully explained. Therefore, the aim of this study was to investigate whether Koumine can alleviate OA in rats by influencing mitochondrial autophagy. In the in vitro study, rat chondrocytes (RCCS-1) were induced with IL-1ß (10 ng/mL) to induce inflammation, and Koumine (50 µg/mL) was co-treated. In the in vivo study, a rat OA model was established by intra-articular injection of 2% papain, and Koumine was administered orally (1 mg/kg, once daily for two weeks). It was found that Koumine effectively reduced cartilage erosion in rats with osteoarthritis. Additionally, it decreased the levels of inflammatory factors such as IL-1ß, IL-6, and extracellular matrix (ECM) components MMP13 and ADAMTS5 in chondrocytes and articular cartilage tissue, while increasing the level of Collagen II.Koumine inhibited the production of reactive oxygen species (ROS) in cartilage tissue and increased the number of autophagosomes in chondrocytes and articular cartilage tissue. Additionally, it upregulated the expression of mitochondrial autophagy proteins LC3Ⅱ/Ⅰ, PINK1, Parkin, and Drp1. The administration of Mdivi-1 (50 µM) reversed the enhanced effect of Koumine on mitochondrial autophagy, as well as its anti-inflammatory and anti-ECM degradation effects in rats with OA. These findings suggest that Koumine can alleviate chondrocyte inflammation and improve the progression of OA in rats by activating PINK1/Parkin-mediated mitochondrial autophagy.