Relationship between rumen microbiota and pregnancy toxemia in ewes.

Introduction: Pregnancy toxemia (PT) is a nutritional metabolic disease of ewes in late pregnancy. This study aimed to reveal the relationship between rumen microbiota and PT. Methods: We selected 10 healthy ewes (CON) and 10 pregnancy toxemia ewes (PT) at 135 days of gestation according to the blood ß-hydroxybutyrate (BHBA), glucose (Glu) concentrations and clinical symptoms. Blood and rumen fluid were collected before morning feeding to determine serum biochemical indices and rumen fermentation parameters. Total DNA of rumen fluid was extracted and the V3-V4 regions of 16S rRNA were amplified by PCR for high-throughput sequencing. Results: The results showed that the serum concentrations of Glu, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), uric acid (UA), creatinine (Cr), acetate, propionate, butyrate, and microbial crude protein (MCP) were decreased (p < 0.05) and the concentrations of BHBA, aspartate aminotransferase (AST), acetate to propionate ratio (A/P), and ammonia nitrogen (NH3-N)were higher (p < 0.05) in PT ewes than those in CON ewes. 16S rRNA analysis showed the differences of ß-diversity were observed in rumen microbiota between CON and PT ewes. At the phylum level, the relative abundance of Bacteroidota and Proteobacteria were higher (p < 0.01), while Firmicutes was lower (p < 0.01) in PT ewes. At the genus level, the relative Prevotella, Butyrivibrio, Ruminococcus, Lachnospiraceae_AC2044_group, Lachnospiraceae_XPB1014_group, Lachnospiraceae_ND3007_group, and Oribacterium were lower (p < 0.01) in PT ewes. Meanwhile, the relative abundance of Oribacterium, Butyrivibrio, Ruminococcus, and Lachnospiraceae_AC2044_group were positively correlated (p < 0.01) with Glu, INS, acetate, propionate, and butyrate, and negatively correlated (p < 0.01) with BHBA, P, GC, AST, and A/P. Discussion: In conclusion, the decrease of Oribacterium, Butyrivibrio, Ruminococcus, and Lachnospiraceae_AC2044_group in the rumen of PT ewes reduced the concentrations of volatile fatty acids (acetate, propionate, and butyrate) and serum Glu, and increased BHBA concentration, indicating that the differences in rumen bacteria genera were related to pregnancy toxemia of ewes.

Comparison of resting-state brain activity between insomnia and generalized anxiety disorder: A coordinate-based meta-analysis.

Patients with insomnia disorder (ID) usually experience a greater burden of comorbid anxiety symptoms. However, the neural mechanism under the mutual relationship between ID and anxiety remains largely unclear. The meta-analysis aimed to explore the concordance and distinction of regional brain functional activity in patients with ID and those with generalized anxiety disorder (GAD) using coordinate-based activation likelihood estimation approach. Studies using resting-state regional homogeneity, amplitude of low-frequency fluctuations (ALFF), or fractional ALFF in patients with ID or GAD were included by searching multiple databases up to May 24, 2024. Using meta-analytic approach, 21 studies of ID vs. healthy controls (HC) and 16 studies of GAD vs. HC were included to illuminate the common and distinct patterns between the two disorders. Results showed that ID and GAD shared increased brain activities in the left posterior cingulate cortex and left precuneus, as well as decreased brain activity in the left medial prefrontal cortex. Additionally, compared with ID, GAD showed greater increased activities in the left superior frontal gyrus. Our study reveals both common and different activation patterns between ID and GAD, which may provide novel insights for understanding the neural basis of the two disorders and enlighten the possibility of the development of more targeted treatment strategies for ID and GAD.

Continuous therapy in HHV-8 negative Multicentric Castleman Disease and prolonged progression-free survival.

The optimal treatment endpoints and duration of continuous therapy for multicentric Castleman disease (MCD) remain controversial. We retrospectively analyzed data from 123 patients with Human Herpesvirus (HHV)-8 negative MCD. We demonstrated that continuous therapy significantly enhanced progression-free survival (PFS) in patients who achieved an optimal response after initial treatment. These findings underscore the critical role of continuous therapy in HHV-8 negative MCD. Further studies with larger cohorts are required to validate these findings.

scRNA-seq reveals the landscape of immune repertoire of PBMNCs in iMCD.

The etiology of idiopathic multicentric Castleman disease (iMCD) is poorly understood, and the identification of targetable disease mediators remains an unmet clinical need. Thus, we firstly employed single-cell RNA sequencing (scRNA-seq) to elucidate the landscape of the immune repertoire of peripheral blood mononuclear cells (PBMNCs) in iMCD and to identify additional driver cytokines/cells/pathways to address IL-6 blockade-refractory cases. We revealed that the inflammatory cytokine storm observed in iMCD was a significant phenomenon pervasive across all immune cells. B-plasma cell subsets was the main source of IL-6. The IL-6 signaling pathway was significantly activated across a spectrum of immune cells. Systemic upregulation of CXCL13 is mainly driven by peripheral helper T (Tph) and regulatory T (Treg) cells. Notably, a significant positive interaction was observed between CXCL13-expressing T cells and IL-6 signaling-activated B cells. This study provides an immune perspective on PBMNCs in iMCD at the single-cell level, unveiling pathways or targets characterized by atypical inflammatory expression that could potentially serve as promising candidates for therapeutic intervention in iMCD.

Acupuncture modulates emotional network resting-state functional connectivity in patients with insomnia disorder: a randomized controlled trial and fMRI study.

BACKGROUND: Insomnia disorder (ID) is one of the most common sleep problems, usually accompanied by anxiety and depression symptoms. Functional magnetic resonance imaging (fMRI) study suggests that both poor sleep quality and negative emotion are linked to the dysregulation of brain network related to emotion processing in ID patients. Acupuncture therapy has been proven effective in improving sleep quality and mood of ID patients, but the involved neurobiological mechanism remains unclear. We aimed to investigate the modulation effect of acupuncture on resting-state functional connectivity (rsFC) of the emotional network (EN) in patients experiencing insomnia. METHODS: A total of 30 healthy controls (HCs) and 60 ID patients were enrolled in this study. Sixty ID patients were randomly assigned to real and sham acupuncture groups and attended resting-state fMRI scans before and after 4 weeks of acupuncture treatment. HCs completed an MRI/fMRI scan at baseline. The rsFC values within EN were calculated, and Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Pittsburgh Sleep Quality Index (PSQI), Hyperarousal Scale (HAS), and actigraphy data were collected for clinical efficacy evaluation. RESULTS: Resting-state FC analysis showed abnormalities in rsFC centered on the thalamus and dorsolateral prefrontal cortex within EN of ID patients compared to HCs. After real acupuncture treatment, rsFC of the anterior cingulate cortex, hippocampus, and amygdala were increased compared with the sham acupuncture group (p < 0.05, FDR corrected). In real acupuncture group, the rsFC value was decreased between left amygdala and left thalamus after 4 weeks of treatment compared with baseline. A trend of correlation was found that the increased rsFC value between the right amygdala and left hippocampus was positively correlated with the decreased HAMA scores across all ID patients, and the decreased left amygdala rsFC value with the left thalamus was negatively correlated with the increased sleep efficiency in the real acupuncture group. CONCLUSION: Our findings showed that real acupuncture could produce a positive effect on modulating rsFC within network related to emotion processing in ID patients, which may illustrate the central mechanism underlying acupuncture for insomnia in improving sleep quality and emotion regulation. TRIAL REGISTRATION: http://www.chictr.org.cn ., ChiCTR1800015282, 20/03/2018.

Dynamic Changes in the Nutrient Digestibility, Rumen Fermentation, Serum Parameters of Perinatal Ewes and Their Relationship with Rumen Microbiota.

Changes in physiological and biochemical parameters are crucial for the reproductive performance and health of perinatal ewes. This study investigated the temporal variations in feed intake, nutrient digestibility, serum parameters, and ruminal fermentation on days 21, 14, and 7 before lambing (Q21, Q14, and Q7) and days 3, 7, and 14 after lambing (H3, H7, and H14). The results showed that dry matter intake (DMI) and glucose (Glu) gradually decreased (p < 0.05) before lambing and increased (p < 0.05) after lambing. The digestibility of dry matter (DMD), crude protein (CPD), and acid detergent fiber (ADFD) increased (p < 0.05) before lambing, then decreased (p < 0.05) on day H3, and then increased (p < 0.05) on day H14. The rumen pH, NH3-N, and triglycerides (TG) gradually increased (p < 0.05) before lambing and were higher (p < 0.05) on day Q7 than after lambing. The concentrations of acetate, butyrate, and total volatile fatty acids (T-VFA) were lower (p < 0.05) on day Q7 than those on days Q21 and Q14, then increased (p < 0.05) after lambing. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) concentrations gradually decreased (p < 0.05) in perinatal ewes. BHBA and NEFA concentrations were lower (p < 0.05) on day Q21 than those from days Q14 to H14. The rumen microbiota compositions were different (p < 0.05) in perinatal ewes, and g_Anaerovibrio, g_Lachnobacterium, and g_Schwartzia were positively correlated (p < 0.05) with DMI, Glu, acetate, propionate, and T-VFA, and negatively correlated (p < 0.05) with LDL-C. g_Bacillus was negatively correlated (p < 0.05) with DMI, Glu, acetate, propionate, butyrate, and T-VFA, but positively correlated (p < 0.05) with rumen pH and LDL-C. In summary, the DMI, nutrient digestibility, rumen fermentation, and serum parameters changed during the perinatal period of ewes, and the changes in DMI, serum glucose, acetate, propionate, and T-VFA were related to the rumen bacteria.

Sample-Specific MS/MS Methods in High-Throughput Mass Spectrometry.

The drug discovery process increasingly relies on high-throughput sample analysis to accelerate the identification of viable drug candidates. Recently, chromatographic-free high-throughput mass spectrometry (HT-MS) technologies have emerged, significantly increasing sample readout speed and enabling the analysis of large sample sets. These HT-MS platforms continuously acquire data from various samples into a single data file, presenting challenges in applying distinctive data acquisition methods to specific samples. This study introduces a novel approach that integrates real-time sample loading status to activate sample-specific MS/MS data acquisition methods on the high-throughput acoustic ejection mass spectrometry platform. Effective method switching and high signal reproducibility were demonstrated across different data acquisition window durations in multiple reaction monitoring (MRM), high-resolution MRM (MRMHR), and information-dependent acquisition modes. This advancement provides a user-friendly and robust solution to the method-setting challenges of HT-MS, expanding the implementation of HT-MS platforms in drug discovery and other high-throughput analytical applications.

Effects of Replacing Soybean Meal with Cottonseed Meal, Peanut Meal, Rapeseed Meal, or Distillers' Dried Grains with Solubles on the Growth Performance, Nutrient Digestibility, Serum Parameters, and Rumen Fermentation in Growing Lambs.

Considering the frequently large price fluctuations for soybean meal, an alternative is the increased use of locally produced high-protein ingredients. The objective of this study was to evaluate the effects of the total replacement of soybean meal with different sources of protein on the growth performance, nutrient digestibility, serum parameters, rumen fermentation parameters, and bacterial communities in growing lambs. Sixty sheep with similar body weights (38.46 ± 0.71 kg) were distributed to one of five treatments: soybean meal (SBM); cottonseed meal (COM); peanut meal (PEM); rapeseed meal (RAM); and distillers' dried grains with solubles (DDGS). The experiment lasted 62 days with a 10-day adaptation period and a 52-day growing period. The results indicated that the body weight and average daily gain were not affected by different protein sources (p > 0.05), but the dry matter intake of the SBM group was lower than that of the other groups (p < 0.05); otherwise, the feed efficiency was higher (p < 0.05). The digestion of dry matter was higher in the SBM, COM, and RAM groups than in the DDGS and PEM groups (p < 0.05). Meanwhile, compared to the other groups, the SBM group had the highest digestion of gross energy and crude protein (p < 0.05). In addition, the concentration of glutathione peroxidase was highest in the SBM group (p < 0.05). Regarding the rumen fermentation, the SBM group had the highest concentration of NH3-N (p < 0.05). The rumen bacterial community was not affected by treatments (p > 0.05). In conclusion, the total replacement of soybean meal with cottonseed, peanut, rapeseed, or DDGS reduced digestibility but did not impact the body weight or average daily gain of growing lambs and had no effect on the immune function and rumen bacterial community; thus, they can be used to substitute the soybean meal.

Inhibition of Prolactin Affects Epididymal Morphology by Decreasing the Secretion of Estradiol in Cashmere Bucks.

Yanshan Cashmere bucks are seasonal breeding animals and an important national genetic resource. This study aimed to investigate the involvement of prolactin (PRL) in the epididymal function of bucks. Twenty eleven-month-old Cashmere bucks were randomly divided into a control (CON) group and a bromocriptine (BCR, a prolactin inhibitor, 0.06 mg/kg body weight (BW)) treatment group. The experiment was conducted from September to October 2020 in Qinhuangdao City, China, and lasted for 30 days. Blood was collected on the last day before the BCR treatment (day 0) and on the 15th and 30th days after the BCR treatment (days 15 and 30). On the 30th day, all bucks were transported to the local slaughterhouse, where epididymal samples were collected immediately after slaughter. The left epididymis was preserved in 4% paraformaldehyde for histological observation, and the right epididymis was immediately preserved in liquid nitrogen for RNA sequencing (RNA-seq). The results show that the PRL inhibitor reduced the serum PRL and estradiol (E2) concentrations (p < 0.05) and tended to decrease luteinizing hormone (LH) concentrations (p = 0.052) by the 30th day, but no differences (p > 0.05) occurred by either day 0 or 15. There were no differences (p > 0.05) observed in the follicle-stimulating hormone (FSH), testosterone (T), and dihydrotestosterone (DHT) concentrations between the two groups. The PRL receptor (PRLR) protein was mainly located in the cytoplasm and intercellular substance of the epididymal epithelial cells. The PRL inhibitor decreased (p < 0.05) the expression of the PRLR protein in the epididymis. In the BCR group, the height of the epididymal epithelium in the caput and cauda increased, as did the diameter of the epididymal duct in the caput (p < 0.05). However, the diameter of the cauda epididymal duct decreased (p < 0.05). Thereafter, a total of 358 differentially expressed genes (DEGs) were identified in the epididymal tissues, among which 191 were upregulated and 167 were downregulated. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that ESR2, MAPK10, JUN, ACTL7A, and CALML4 were mainly enriched in the estrogen signaling pathway, steroid binding, calcium ion binding, the GnRH signaling pathway, the cAMP signaling pathway, and the chemical carcinogenesis-reactive oxygen species pathway, which are related to epididymal function. In conclusion, the inhibition of PRL may affect the structure of the epididymis by reducing the expression of the PRLR protein and the secretion of E2. ESR2, MAPK10, JUN, ACTL7A, and CALML4 could be the key genes of PRL in its regulation of epididymal reproductive function.

The Enhanced Performance of NiCuOOH/NiCu(OH)2 Electrode Using Pre-Conversion Treatment for the Electrochemical Oxidation of Ammonia.

Electrochemical oxidation of ammonia is an attractive process for wastewater treatment, hydrogen production, and ammonia fuel cells. However, the sluggish kinetics of the anode reaction has limited its applications, leading to a high demand for novel electrocatalysts. Herein, the electrode with the in situ growth of NiCu(OH)2 was partially transformed into the NiCuOOH phase by a pre-treatment using highly oxidative solutions. As revealed by SEM, XPS, and electrochemical analysis, such a strategy maintained the 3D structure, while inducing more active sites before the in situ generation of oxyhydroxide sites during the electrochemical reaction. The optimized NiCuOOH-1 sample exhibited the current density of 6.06 mA cm-2 at 0.5 V, which is 1.67 times higher than that of NiCu(OH)2 (3.63 mA cm-2). Moreover, the sample with a higher crystalline degree of the NiCuOOH phase exhibited lower performance, demonstrating the importance of a moderate treatment condition. In addition, the NiCuOOH-1 sample presented low selectivity (<20%) towards NO2- and stable activity during the long-term operation. The findings of this study would provide valuable insights into the development of transition metal electrocatalysts for ammonia oxidation.

High-Throughput Acoustic Ejection Mass Spectrometry with Adjustable Signal Durations.

High-throughput mass spectrometry (MS) has witnessed rapid advancements and has found extensive applications across various disciplines. It enables the fast and accurate analysis of large sample sets, delivering a 10-fold or greater enhancement in analytical throughput when compared to conventional LC-MS methods. However, the signal duration in these high-throughput MS technologies is typically confined to a narrow range, presenting challenges for workflows demanding prolonged signal durations. In this study, we introduce a method that enables precise modulation of the signal duration on an acoustic ejection mass spectrometry (AEMS) system while ensuring high signal reproducibility. This flexibility allows for simultaneous and precise analysis of a significantly greater number of MS/MS transitions in high-throughput MS environments. Additionally, it offers a unique approach for parameter optimization and method development with minimal sample volume requirements. This advancement enhances the efficiency of MS-based analyses across diverse applications and facilitates broader utilization of MS technologies in high-throughput settings, including data-dependent acquisition (DDA) and data-independent acquisition (DIA).

Ethanol extract of Eclipta prostrata induces multiple myeloma ferroptosis via Keap1/Nrf2/HO-1 axis.

BACKGROUND: Multiple myeloma (MM) is an incurable hematological malignancy with limited therapeutic efficacy. Eclipta prostrata is a traditional Chinese medicinal plant reported to possess antitumor properties. However, the effects of E. prostrata in MM have not been explored. PURPOSE: The aim of this study was to define the mechanism of the ethanol extract of E. prostrata (EEEP) in treating MM and identify its major components. METHODS: The pro-ferroptotic effects of EEEP on cell death, cell proliferation, iron accumulation, lipid peroxidation, and mitochondrial morphology were determined in RPMI-8226 and U266 cells. The expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), kelch-like ECH-associated protein 1 (Keap1), heme oxygenase-1 (HO-1), glutathione peroxidase 4 (GPX4), and 4-hydroxynonenal (4HNE) were detected using western blotting during EEEP-mediated ferroptosis regulation. The RPMI-8226 and U266 xenograft mouse models were used to explore the in vivo anticancer effects of EEEP. Finally, high performance liquid chromatography (HPLC) and ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry system (UPLC-Q/TOF-MS) were used to identify the major constituents of EEEP. RESULTS: EEEP inhibited MM cell growth and induced cell death in vitro and in vivo. By promoting malondialdehyde and Fe2+ accumulation, lipid peroxidation, and GSH suppression, EEEP triggers ferroptosis in MM. Mechanistically, EEEP regulates the Keap1/Nrf2/HO-1 axis and stimulates ferroptosis. EEEP-induced lipid peroxidation and malondialdehyde accumulation were blocked by the Nrf2 activator NK-252. In addition, HPLC and UPLC-Q/TOF-MS analysis elucidated the main components of EEEP, including demethylwedelolactone, wedelolactone, chlorogenic acid and apigenin, which may play important roles in the anti-tumor function of EEEP. CONCLUSION: In summary, EEEP exerts its anti-MM function by inducing MM cell death and inhibiting tumor growth in mice. We also showed that EEEP can induce lipid peroxidation and accumulation of ferrous irons in MM cells both in vivo and in vitro, leading to ferroptosis. In addition, this anti-tumor function may be achieved by the EEEP activation of Keap1/Nrf2/HO-1 axis. This is the first study to reveal that EEEP exerts anti-MM activity through the Keap1/Nrf2/HO-1-dependent ferroptosis regulatory axis, making it a promising candidate for MM treatment.

Increased functional connectivity within the salience network in patients with insomnia.

BACKGROUND: Insomnia is a common sleep disorder with significant negative impacts on emotional states; however, the underlying mechanism of insomnia with comorbid emotional dysregulation remains largely unknown. The salience network (SN) plays an important role in both sleep and emotional regulation. The study aimed to explore the specific alterations in functional connectivity (FC) within the SN in insomnia patients. METHODS: A total of 30 eligible patients with insomnia disorder (ID group) and 30 healthy controls (HC group) underwent resting-state functional magnetic resonance imaging (fMRI) scanning and psychometric assessments. Differences in FC within the SN were examined using seed-based region-to-region connectivity analysis. RESULTS: Compared with healthy controls, patients with insomnia showed increased FC within the SN, mainly between the anterior cingulate cortex (ACC) and right superior frontal gyrus (SFG), the right SFG and right supramarginal gyrus (SMG), and between the right insular (INS) and left SMG (P<0.05). Additionally, significant correlations were observed between increased FC and the Hamilton Depression Rating Scale (HAMD), Pittsburgh Sleep Quality Index (PSQI), and Hamilton Anxiety Rating Scale (HAMA) scores (P<0.05, after Bonferroni correction). CONCLUSIONS: These results suggest that increased FC within the SN may be related to poor sleep quality and negative emotions, highlighting the importance of the SN in the pathophysiological mechanisms of insomnia with comorbid emotional dysregulation.

When idiopathic multicentric Castleman disease meets COVID-19: a multicenter retrospective study from China.

Idiopathic multicentric Castleman disease (iMCD) is a rare and cytokine storm-driven inflammatory disorder. The exact cause of iMCD is still unknown, although several hypotheses have been proposed. However, regardless of the underlying cause, the ultimate result is the activation of the inflammatory pathway, which can lead to damage in multiple organs. Currently, there have been several reports highlighting the intricate link between coronavirus disease 2019 (COVID-19) and iMCD. To better understand the impact of COVID-19-induced immune storm on iMCD, we conducted a multicenter retrospective study in three hospitals in China. A total of 28 patients with iMCD were included, among whom 25 had confirmed COVID-19 infection, and we presented 4 cases that showed different disease progression after the infection of COVID-19, including 2 who did not receive any treatment for Castleman disease before. Our findings underscore the necessity of carefully monitoring iMCD patients with COVID-19 and promptly intervening to address any changes in their condition. Besides, this study also summarized the shared cytokines between COVID-19 and iMCD. Recent studies have shown promising results in treating severe COVID-19 and iMCD using tocilizumab, an interleukin-6 receptor antagonist. Therefore, it suggests that other potential cytokine storm therapy targets that have been effective in COVID-19 may also be explored for the treatment of iMCD.

Abnormal alterations of regional spontaneous neuronal activity and functional connectivity in insomnia patients with difficulty falling asleep: a resting-state fMRI study.

BACKGROUND: Insomnia disorder (ID) seriously affects people's daily life. Difficulty falling asleep is the most commonly reported complaint in patients with ID. However, the mechanism of prolonged sleep latency (SL) is still obscure. The aim of our present study was to investigate the relationship between prolonged SL and alterations in spontaneous neural activity and brain functional connectivity (FC) in ID patients using functional magnetic resonance imaging (fMRI). METHODS: A total of 52 insomniacs with difficulty falling asleep and 30 matched healthy controls (HCs) underwent resting-state fMRI. The amplitude of low-frequency fluctuation (ALFF) was measured and group differences were compared. The peak areas with significantly different ALFF values were identified as the seed regions to calculate FC to the whole brain. SL was assessed by a wrist actigraphy device in ID patients. The Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Rating Scale (HAMA), and Hyperarousal Scale (HAS) were evaluated in both ID patients and HCs. Finally, correlation analyses were performed between the clinical features and FC/ALFF values. RESULTS: ID patients showed higher PSQI, HAMA, HAS scores than HCs. The functional MRI results indicated increased ALFF value in the left insula and right amygdala and decreased ALFF value in the right superior parietal lobe (SPL) in ID patients. The seed-based FC analysis demonstrated increased FC between the left insula and the bilateral precentral gyrus and FC between the right amygdala and the left posterior cingulate cortex (PCC) in patients with ID. Correlation analysis indicated that the increased FC value of the right amygdala-left PCC was positively correlated with SL measured by actigraphy. CONCLUSION: This study revealed abnormal regional spontaneous fluctuations in the right amygdala, left insula, and right SPL, as well as increased FC in the left insula-precentral and right amygdala-left PCC. Moreover, the prolonged SL was positively correlated with the abnormal FC in the right amygdala-left PCC in ID patients. The current study showed the correlation between prolonged SL and the abnormal function of emotion-related brain regions in ID patients, which may contribute to a better understanding of the neural mechanisms underlying difficulty falling asleep in patients with ID. CLINICAL TRIAL REGISTRATION: http://www.chictr.org.cn ., ChiCTR1800015282. Registered on 20th March 2018.

Bispecific antibody treatment of multiple myeloma: latest updates from the 2022 ASH annual meeting.

Background: Effective novel therapies for multiple myeloma (MM) patients who are unresponsive to conventional treatments (triple-class refractory) are an urgent need. Bispecific antibodies (BsAbs) offer a promising new approach to stimulate T cells and induce tumor cell death by targeting molecules on the surface of malignant plasma cells and CD3 on the surface of T cells. Objectives: Addressing the issue of improving the prognosis of triple-class refractory MM patients has become a significant clinical challenge. Design: This is a brief report. Methods: This article summarizes the latest updates of BsAbs treatment of MM from the 2022 ASH annual meeting. Results: BsAbs that target B-cell maturation antigen and G protein-coupled receptor family C group 5 memberD have demonstrated remarkable clinical activity and favorable safety profiles. Many potential targets for myeloma cells are currently undergoing phase I/II clinical trials, and these off-the-shelf bispecific molecules are likely to become a critical part of the MM treatment landscape. Conclusion: This article provides an overview of the latest advances in BsAbs immunotherapy for refractory and relapsed MM and highlights significant findings from the 2022 ASH annual meeting.

Prolactin inhibitor changes testosterone production, testicular morphology, and related genes expression in cashmere goats.

Prolactin has multifaceted roles in lactation, growth, metabolism, osmoregulation, behavior, and the reproduction of animals. This study aimed to investigate the involvement of prolactin in testicular function in cashmere goats. Twenty cashmere goats were randomly assigned to either the control group (CON) or the bromocriptine treatment group (BCR, bromocriptine, prolactin inhibitor). Blood and testis samples collected for analysis after 30 days of treatment. The results indicated that, compared with the CON group, BCR significantly decreased (p < 0.05) the serum concentrations of prolactin, and significantly increased (p < 0.05) the levels of testosterone and luteinizing hormone (LH) on day 30. The serum level of the follicle-stimulating hormone (FSH) was not affected (p > 0.05) by the treatment. The mean seminiferous tubule diameter and spermatogenic epithelium thickness were increased (p < 0.05) in the BCR group. Subsequently, we performed RNA sequencing and bioinformatics analysis to identify the key genes and pathways associated with the regulation of spermatogenesis or testosterone secretion function. A total of 142 differentially expressed genes (DEGs) were identified (91 were upregulated, 51 were downregulated). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed that the DEGs were mainly involved in the extracellular matrix (ECM), hippo, and steroid hormone biosynthesis, which are related to testicular function. The expression of the genes SULT2B1, CYP3A24, and CYP3A74 in the steroid hormone biosynthesis pathway significantly increased (p < 0.05) in the BCR group, which was validated by qRT-PCR. These results provide a basis for understanding the mechanisms underlying the regulation of testicular function by prolactin in cashmere goats.

[Apelin-13 promotes mitochondrial autophagy and improves rat myocardial ischemia-reperfusion injury by blocking PINK1/parkin signaling pathway].

Objective To investigate the effect of adipocytokine Apelin-13 (AP13) on mitochondrial autophagy in myocardial ischemia reperfusion injury (MIRI) and its mechanism. Methods MIRI model was established by ligating the coronary artery branches of rats. The rats are divided into sham group, AP13-treated sham group, MIRI group and AP13-treated MIRI group. 24 h after the establishment of MIRI model, serum creatine kinase (CK), lactate dehydrogenase (LDH) and cardiac troponin I (cTnI) levels were detected by ELISA, and the size of myocardial infarction was detected by 2, 3, 5-triphenyltetrazole chloride (TTC) staining. Terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL) was used to detect the apoptosis of myocardial cells in MIRI myocardium, and transmission electron microscopy (TEM) was employed to observe the mitochondrial damage of myocardial cells and the formation of autophagosomes in the damaged myocardium. Western blot analysis was used to detect the microtubule-associated protein 1 light chain 3 II (LC3 II)/LC3 I ratio and protein expression level of the ubiquitin-binding protein (P62), phosphatase and tensin homologous (PTEN)-induced kinase 1 (PINK1), E3 ubiquitin ligase parkin and cleaved-caspase-3(c-caspase-3)in myocardial infarction tissues of rats in each group. The myocardial cells isolated from myocardial infarction area of rats were infected with adenovirus carrying GFP-LC3, and the co-localization of translocase of outer mitochondrial membrane 20 (TOM20) and LC3 was observed by immunofluorescence cytochemical staining. Results Compared with sham operation group or AP13-treated sham group, serum CK, LDH, cTnI, myocardial infarction area and apoptosis rate of MIRI group or AP13-treated MIRI rats were significantly increased, and there was no significant difference between the first two groups. Compared with MIRI group, the above changes were significantly decreased in AP13-treated MIRI rats. The integrity of mitochondrial structure in cardiomyocytes was significantly damaged, and a large number of autophagosomes enclosing mitochondria appeared in MIRI group and AP13-treated MIRI group compared with the sham group or AP13-treated sham group. However, compared with MIRI group, mitochondrial damage of myocardial cells in AP13-treated MIRI group was significantly reduced, and the number of autophagosomes was significantly increased. LC3 II/LC3 I ratio, PINK1, parkin and c-caspase-3 protein expression were significantly increased, while the expression level of P62 was significantly decreased in MIRI group or AP13-treated MIRI group compared with the other two groups. The change trend of above protein levels in AP13-treated MIRI group was significantly decreased compared with MIRI group. LC3 and TOM20 were co-located in the mitochondria of cardiomyocytes after MIRI modeling, and the expression intensity of LC3 in AP13-treated MIRI group was significantly increased compared with that in MIRI group. Conclusion Aplein-13 may promote the level of mitochondrial autophagy through PINK1/parkin signaling pathway, which can effectively reduce the size of myocardial infarction caused by I/R and reduce the rate of apoptosis.

[Tiaoshen acupuncture for primary insomnia: a pilot randomized controlled trial].

OBJECTIVE: To observe the effects of Tiaoshen (regulating the spirit) acupuncture on cognitive function and sleep quality in patients with primary insomnia (PI). METHODS: Sixty patients with PI were randomly divided into an observation group (30 cases, 2 cases dropped off) and a control group (30 cases, 2 cases dropped off, 1 case was excluded). The patients in the observation group were treated with acupuncture at Baihui (GV 20), Shenting (GV 24), Sishencong (EX-HN 1), and bilateral Benshen (GB 13), Shenmen (HT 7), Neiguan (PC 6), Sanyinjiao (SP 6). The patients in the control group were treated with shallow needling at non-effective points. Each treatment was provided for 30 min, once every other day, 3 treatments per week for 4 weeks. The Montreal cognitive assessment (MoCA), digit span test (DST), trail making test (TMT)-A, Pittsburgh sleep quality index (PSQI), and fatigue scale-14 (FS-14) were used to assess cognitive function and sleep quality before and after treatment, as well as in follow-up of 4-week after treatment completion. Correlation analysis was conducted between the differences in PSQI scores and differences in MoCA scores before and after treatment in the observation group. RESULTS: Compared with before treatment, the total score, visuospatial and executive function score and delayed memory score of MoCA as well as DST backward score were increased (P<0.01), while TMT-A time, PSQI and FS-14 scores were significantly reduced (P<0.01) after treatment and in follow-up in the observation group. Compared with before treatment, the PSQI score in the control group was reduced (P<0.01, P<0.05). After treatment and in follow-up, the observation group had significantly higher total score, visuospatial and executive function score, delayed memory score of MoCA, and DST backward score compared to the control group (P<0.05, P<0.01). In the observation group, the TMT-A time was significantly shorter than that in the control group (P<0.05, P<0.01), and the PSQI and FS-14 scores were significantly lower than those in the control group (P<0.01). In the observation group, there was a negative correlation between the difference in PSQI scores (post-treatment minus pre-treatment) and the difference in MoCA scores (post-treatment minus pre-treatment) (r=-0.481, P<0.01). A similar negative correlation was found between the difference in PSQI scores (follow-up minus pre-treatment) and the difference in MoCA scores (follow-up minus pre-treatment) (r=-0.282, P<0.05). CONCLUSION: Tiaoshen acupuncture could improve cognitive function, enhance sleep quality, and alleviate daytime fatigue in patients with PI. The improvement in cognitive function in patients with PI is correlated with the improvement in sleep quality.

MALAT1 regulates network of microRNA-15a/16-VEGFA to promote tumorigenesis and angiogenesis in multiple myeloma.

MALAT1 is one of the most hopeful members implicated in angiogenesis in a variety of non-malignant diseases. In multiple myeloma (MM), MALAT1 is recognized as the most highly expressed long non-coding RNA. However, the functional roles of MALAT1 in angiogenesis and the responsible mechanisms have not yet been explored. Herein, we discovered a novel regulatory network dependent on MALAT1 in relation to MM tumorigenesis and angiogenesis. We observed that MALAT1 was upregulated in MM and significantly associated with poor overall survival. MALAT1 knockdown suppressed MM cell proliferation and promoted apoptosis, while restricting endothelial cells angiogenesis. Moreover, MALAT1 directly targeted microRNA-15a/16, and microRNA-15a/16 suppression partly reverted the effects of MALAT1 deletion on MM cells in vitro as well as tumor growth and angiogenesis in vivo. In addition, further study indicated that MALAT1 functioned as a competing endogenous RNA for microRNA-15a/16 to regulate vascular endothelial growth factor A (VEGFA) expression. Our results suggest that MALAT1 plays an important role in the regulatory axis of microRNA-15a/16-VEGFA to promote tumorigenicity and angiogenesis in MM. Consequently, MALAT1 could serve as a novel promising biomarker and a potential antiangiogenic target against MM.