Insights into multiscale structure and digestive characteristic of starch from two cultivars of chestnut during kernel development.

Multiscale structure and digestive characteristic of starch during kernel development of Castanea henryi ('Jinzhui' (YS) and 'Baiyan No.1' (WS)) were investigated in this study. Structural analysis revealed that the surface of starch granules became smooth, the amylopectin content decreased (from 71.32 % to 70.47 %, from 71.44 % to 68.37 %, respectively), the chain length distribution of amylopectin reduced (the proportion of B1 chain decreased from 52.35 % to 50.60 %, from 52.22 % to 50.59 %, respectively) while the amorphous and semi-crystalline lamellae of starch increased during development, which was consistent with the decreasing relative crystallinity (from 28.79 % to 24.11 %, from 29.57 % to 23.66 %, respectively) and short-range ordering degree. The degradation of ordered structure further resulted in the increase of digestibility, especially in the late developmental stage, supported by a significant decrease of resistant starch content (from 70.21 % to 61.70 % and from 73.58 % to 58.86 %, respectively). Transcriptome analysis and RT-qPCR were performed to explore the possible molecular mechanisms affecting starch structure. The high expression of several key genes including AGPase, GBSS, SBE, SSS, ISA and PUL in late development stage might be the reason of structural changes during development. The results provided valuable information for starch accumulation during kernel development of Castanea henryi.

Environmental pollutants exposure-derived extracellular vesicles: crucial players in respiratory disorders.

BACKGROUND: Individual exposure to environmental pollutants, as one of the most influential drivers of respiratory disorders, has received considerable attention due to its preventability and controllability. Considering that the extracellular vesicle (EV) was an emerging intercellular communication medium, recent studies have highlighted the crucial role of environmental pollutants derived EVs (EPE-EVs) in respiratory disorders. METHODS: PubMed and Web of Science were searched from January 2018 to December 2023 for publications with key words of environmental pollutants, respiratory disorders and EVs. RESULTS: Environmental pollutants could disrupt airway intercellular communication by indirectly stimulating airway barrier cells to secrete endogenous EVs, or directly transmitting exogenous EVs, mainly by biological pollutants. Mechanistically, EPE-EVs transferred specific contents to modulate biological functions of recipient cells, to induce respiratory inflammation and impair tissue and immune function, which consequently contributed to the development of respiratory diseases, such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension, lung cancer and infectious lung diseases. Clinically, EVs could emerged as promising biomarkers and biological agents for respiratory diseases attributed by their specificity, convenience, sensibility and stability. CONCLUSIONS: Further studies of EPE-EVs are helpful to understand the aetiology and pathology of respiratory diseases, and facilitate the precision respiratory medicine in risk screening, early diagnosis, clinical management and biotherapy.

The altered volume of striatum: A neuroimaging marker of treatment in first-episode and drug-naïve schizophrenia.

Although schizophrenia patients exhibit structural abnormalities in the striatum, it remains largely unknown for the role of the striatum subregions in the treatment response of antipsychotic drugs. The purpose of this study was to investigate the associations between the striatal subregions and improved clinical symptoms in first-episode drug-naïve (FEDN) schizophrenia. Forty-two FEDN schizophrenia patients and 29 healthy controls (HCs) were recruited. At baseline, the Positive and Negative Syndrome Scale (PANSS) was used to assess the clinical symptoms of patients, MRI scanner was used to obtain anatomical images of patients and HCs. After 12-week stable doses of risperidone treatment, clinical symptoms were obtained in 38 patients and anatomical images in 26 patients. After 12 weeks of treatment, the left nucleus accumbens volume decreased, whereas the left pallidum volume increased in schizophrenia patients. The decreased left nucleus accumbens volume was positively correlated with cognitive factor improvement measured by PANSS. Intriguingly, greater left nucleus accumbens volume at baseline predicted greater cognitive improvements. Furthermore, the responders who had >50 % improvement in cognitive symptoms exhibited significantly greater baseline left nucleus accumbens volume compared to non-responders. The left striatum volume at baseline and after treatment predicted the cognitive improvements in FEDN schizophrenia, which could be a potential biomarker for the development of precision medicine approaches targeting cognitive function.

Sample Size Requirements of a Pharmaceutical Material Library: A Case in Predicting Direct Compression Tablet Tensile Strength by Latent Variable Modeling.

The material library is an emerging, new data-driven approach for developing pharmaceutical process models. How many materials or samples should be involved in a particular application scenario is unclear, and the impact of sample size on process modeling is worth discussing. In this work, the direct compression process was taken as the research object, and the effects of different sample sizes of material libraries on partial least squares (PLS) modeling in the prediction of tablet tensile strength were investigated. A primary material library comprising 45 materials was built. Then, material subsets containing 5 × i (i = 1, 2, 3, …, 8) materials were sampled from the primary material library. Each subset underwent sampling 1000 times to analyze variations in model fitting performance. Both hierarchical sampling and random sampling were employed and compared, with hierarchical sampling implemented with the help of the tabletability classification index d. For each subset, modeling data were organized, incorporating 18 physical properties and tableting pressure as the independent variables and tablet tensile strength as the dependent variable. A series of chemometric indicators was used to assess model performance and find important materials for model training. It was found that the minimum R2 and RMSE values reached their maximum, and the corresponding values were kept almost unchanged when the sample sizes varied from 20 to 45. When the sample size was smaller than 15, the hierarchical sampling method was more reliable in avoiding low-quality few-shot PLS models than the random sampling method. Two important materials were identified as useful for building an initial material library. Overall, this work demonstrated that as the number of materials increased, the model's reliability improved. It also highlighted the potential for effective few-shot modeling on a small material library by controlling its information richness.

Alleviation of allergic asthma by rosmarinic acid via gut-lung axis.

BACKGROUND: Asthma affects 3% of the global population, leading to over 0.25 million deaths. Due to its complexity, asthma is difficult to cure or prevent, and current therapies have limitations. This has led to a growing demand for alternative asthma treatments. We found rosmarinic acid (RosA) as a potential new drug candidate from natural medicine. However, RosA has poor bioavailability and remains mainly in the gastrointestinal tract after oral administration, suggesting the involvement of gut microbiota in its bioactivity. PURPOSE: To investigate the mechanism of RosA in alleviating allergic asthma by gut-lung axis. METHODS: We used 16S rRNA gene sequencing and metabolites analysis to investigate RosA's modulation of gut microbiota. Techniques of molecular biology and metabolomics were employed to study the pharmacological mechanism of RosA. Cohousing was used to confirm the involvement of gut microbiota in RosA-induced improvement of allergic asthma. RESULTS: RosA decreased cholate levels from spore-forming bacteria, leading to reduced 5-hydroxytryptamine (5-HT) synthesis, bronchoconstriction, vasodilation, and inflammatory cell infiltration. It also increased short-chain fatty acids (SCFAs) levels, facilitating the expression of intestinal tight junction proteins to promote intestinal integrity. SCFAs upregulated intestinal monocarboxylate transporters (MCTs), thereby improving their systemic delivery to reduce Th2/ILC2 mediated inflammatory response and suppress eosinophil influx and mucus production in lung. Additionally, RosA inhibited lipopolysaccharide (LPS) production and translocation, leading to reduced TLR4-NFκB mediated pulmonary inflammation and oxidative stress. CONCLUSIONS: The anti-asthmatic mechanism of oral RosA is primarily driven by modulation of gut microbiota-derived 5-HT, SCFAs, and LPS, achieving a combined synergistic effect. RosA is a safe, effective, and reliable drug candidate that could potentially replace glucocorticoids for asthma treatment.

Hyperinsulinemia impairs decidualization via AKT-NR4A1 signaling: new insight into polycystic ovary syndrome (PCOS)-related infertility.

BACKGROUND: Investigating the underlying molecular mechanisms responsible for endometrial dysfunction in women with PCOS is essential, particularly focusing on the role of hyperinsulinemia. METHODS: We explored the role of insulin in the decidualization process using a synthetic decidualization assay. To dissect the effects of PI3K/AKT-NR4A signaling, we employed small interfering RNAs (siRNAs) targeting the NR4A genes and inhibitors of the PI3K/AKT pathway. We also investigated the disruption of AKT-NR4A1 signaling in the endometrium of PCOS female rats induced with dehydroepiandrosterone (DHEA). Quantitative real-time PCR (qRT-PCR) and Western blot (WB) analyses were utilized to evaluate gene expression regulation. RESULTS: Insulin was found to suppress the expression of decidualization markers in human endometrial stromal cells (hESC) in a dose-dependent manner, concurrently triggering an inappropriate activation of the PI3K/AKT pathway. Members of the NR4A family, as downstream effectors in the PI3K/AKT pathway, were implicated in the insulin-induced disruptions during the decidualization process. Moreover, the endometrium of PCOS models showed significantly elevated levels of phosphorylated (Ser473) AKT, with a corresponding reduction in Nr4a1 protein. CONCLUSIONS: Our research demonstrates that insulin negatively regulates decidualization in hESC via the PI3K/AKT-NR4A pathway. In vivo analysis revealed a significant dysregulation of the AKT-NR4A1 pathway in the endometrium of PCOS rats. These findings offer novel insights into the pathogenesis of infertility and endometrial disorders associated with hyperinsulinemia in PCOS.

Assisted reproductive technology induces different secondary sex ratio: parental and embryonic impacts.

BACKGROUND: Assisted reproduction technology (ART) has advanced significantly, raising concerns regarding its impact on the secondary sex ratio (SSR), which is the sex ratio at birth in offspring. This study aimed to explore factors affecting SSR in singletons, singletons from twin gestation, and twins from twin gestation within the context of ART. METHODS: A retrospective analysis was conducted on data from 8335 births involving 6,223 couples undergoing ART. Binary logistic regression assessed relationships between parental and embryonic factors and SSR in singletons and singletons from twin gestation. Multinomial logistic regression models were utilized to identify factors influencing SSR in twins from twin gestation. RESULTS: Secondary infertility (OR = 1.164, 95% CI: 1.009-1.342), advanced paternal age (OR = 1.261, 95% CI: 1.038-1.534), and blastocyst embryo transfer (OR = 1.339, 95% CI: 1.030-1.742) were associated with an increased SSR, while frozen embryo transfer (FET) showed a negative association with SSR (OR = 0.738, 95% CI: 0.597-0.912) in singletons. A longer duration of gonadotropin (Gn) usage reduced SSR in singletons (OR = 0.961, 95% CI: 0.932-0.990) and singletons from twin gestation (OR = 0.906, 95% CI: 0.838-0.980). In singletons from twin gestation, male-induced infertility (OR = 2.208, 95% CI: 1.120-4.348) and higher Gn dosage (OR = 1.250, 95% CI: 1.010-1.548) were significantly associated with an increased SSR. Women aged > 35 years and intracytoplasmic sperm injection (ICSI) were associated with lower SSR (OR = 0.539, 95% CI: 0.293-0.990 and OR = 0.331, 95% CI: 0.158-0.690, respectively). In twins from twin gestation, paternal age exceeded maternal age (OR = 0.682, 95% CI: 0.492-0.945) and higher Gn dosage (OR = 0.837, 95% CI: 0.715-0.980) were associated with a higher proportion of male twins. Cleavage stage transfer (OR = 1.754, 95% CI: 1.133-2.716) resulted in a higher percentage of boy-girl twins compared to blastocyst transfer. CONCLUSION: This study demonstrates the complex interplay of various factors in determining the SSR in ART, highlighting the importance of considering infertility type, paternal age, fertilization method, embryo transfer stage, and Gn use duration when assessing SSR. Nevertheless, further research with a large sample size is necessary to confirm and expand upon the findings of this study.

Bacterial butyrate mediates the anti-atherosclerotic effect of silybin.

Silybin (SIL) is a versatile bioactive compound used for improving liver damage and lipid disorders and is also thought to be beneficial for atherosclerosis (AS). The goal of this study was to investigate the efficacy of SIL in the treatment of AS in ApoE-/-mice fed a high-fat diet and explore the mechanism underlying treatment outcomes. We found that SIL significantly alleviated AS-related parameters, including the extent of aortic plaque formation, hyperlipidemia, and adhesion molecule secretion in the vascular endothelium. 16 S rRNA gene sequencing analysis, together with the application of antibiotics, showed that intestinal butyrate-producing bacteria mediated the ameliorative effect of SIL on AS. Further analysis revealed that SIL facilitated butyrate production by increasing the level of butyryl-CoA: acetate CoA-transferase (BUT). The increased expression of monocarboxylic acid transporter-1 (MCT1) induced by butyrate and MCT4 induced by SIL in the apical and basolateral membranes of colonocytes, respectively, resulted in enhanced absorption of intestinal butyrate into the circulation, leading to the alleviation of arterial endothelium dysfunction. Moreover, the SIL-mediated increase in intestinal butyrate levels restored gut integrity by upregulating the expression of tight junction proteins and promoting gut immunity, thus inhibiting the AS-induced inflammatory response. This is the first study to show that SIL can alleviate AS by modulating the production of bacterial butyrate and its subsequent absorption.

DNA Nanomachine-Driven Heterogeneous Quadratic Amplification for Sensitive and Programmable miRNA Profiling.

Inspired by the molecular crowding effect in biological systems, a novel heterogeneous quadratic amplification molecular circuit (HEQAC) was developed for sensitive bimodal miRNA profiling (HEQAC-BMP) by combining an MNAzyme-based DNA nanomachine with an entropy-driven catalytic hairpin assembly (E-CHA) autocatalytic circuit. Utilizing ferromagnetic nanomaterials as the substrate for DNA nanomachines, a biomimetic heterogeneous interface was established; thus, a localized molecular crowding system was created that can elevate the local reaction concentration and accelerate the molecular recognition process for a significant threshold signal. Simultaneously, the threshold signal undergoes further amplification by E-CHA and is transformed into a chemical signal, enabling a colorimetric-fluorescence bimodal signal readout. The HEQAC-BMP enables miRNA detection from 10 aM to 10 nM with detection limits of 3.7 aM (colorimetry) and 4.8 aM (fluorometry), respectively. Moreover, the design principle and strategy of HEQAC-BMP can be customized to address other critical viruses or diseases with life-threatening and socioeconomic impacts, enhancing healthcare outcomes for individuals.

Engineered DNAzyme Enables Homogeneous Detection of Cereulide via Polychromic Fluorescence Modality.

Cereulide, the exotoxin of emetic Bacillus cereus, has garnered considerable attention due to its capacity to produce foodborne poisonings and great chemical stability. Herein, a G-quadruplex-hemin DNAzyme-based biosensor was developed to detect cereulide in the homogeneous solution. Due to the special ring structure and high affinity to K+, cereulide can be attracted and intercalated into the G-quadruplex; thus, the properties of the G4 DNAzyme can be altered. The melting temperature (Tm) of the G4 DNAzyme in the presence or absence of cereulide was 58.75 and 50.10 °C, respectively, proving the intercalation of cereulide into the G4 DNAzyme. By using the polychromic fluorescence modality of CdTe quantum dots and o-phenylenediamine to assess the variation in the catalytic activity of the DNAzyme, the intercalation of cereulide had bidirectional effects in G4 DNAzyme-mediated reactions, showing that the fluorescence intensity of CdTe quantum dots displayed a linear relationship with the concentration of cereulide from 0.16 to 40 µg/mL with the limit of detection (LOD) of 0.10 µg/mL, while the fluorescence intensity of DAP exhibited a linear relationship with the concentration of cereulide from 0.02 to 40 µg/mL with the LOD of 0.01 µg/mL. It will be a perspective step of controlling cereulide as a hazardous material in food or the environment.

The contribution of the cingulate cortex: treating depressive symptoms in first-episode drug naïve schizophrenia

Background: Our previous study has shown the cingulate cortex abnormalities in first-episode drug naïve (FEDN) schizophrenia patients with comorbid depressive symptoms. However, it remains largely unknown whether antipsychotics may induce morphometric change in cingulate cortex and its relationship with depressive symptoms. The purpose of this study was to further clarify the important role of cingulate cortex in the treatment on depressive symptoms in FEDN schizophrenia patients. Method: In this study, 42 FEDN schizophrenia patients were assigned into depressed patients group (DP, n = 24) and non-depressed patients group (NDP, n = 18) measured by the 24-item Hamilton Depression Rating Scale (HAMD). Clinical assessments and anatomical images were obtained from all patients before and after 12-week treatment with risperidone. Results: Although risperidone alleviated psychotic symptoms in all patients, depressive symptoms were decreased only in DP. Significant group by time interaction effects were found in the right rostral anterior cingulate cortex (rACC) and other subcortical regions in the left hemisphere. After risperidone treatment, the right rACC were increased in DP. Further, the increasing volume of right rACC was negatively associated with improvement in depressive symptoms. Conclusion: These findings suggested that the abnormality of the rACC is the typical characteristics in schizophrenia with depressive symptoms. It's likely key region contributing to the neural mechanisms underlying the effects of risperidone treatment on depressive symptoms in schizophrenia. (AU)

Effect of excessive gestational weight gain before and after 28 weeks on trial of labor after cesarean stratified by pre-pregnancy body mass index: a retrospective cohort study.

This study aimed to assess the effect of excessive gestational weight gain (GWG) before and after 28 weeks on the mode of delivery in women who attempted a trial of labor after cesarean (TOLAC), stratified by pre-pregnancy BMI. A retrospective analysis of the outcomes of eligible women who attempted trial of labor after cesarean (TOLAC) in a Chinese hospital from January 2016 to October 2022 was performed. GWG before and after 28 weeks was categorized as 'excessive' or 'non-excessive' based on the guideline of Institute of Medicine (IOM). Multivariable logistic regression analyses were used to estimate the effect of excessive GWG before and after 28 weeks on mode of delivery in women who underwent TOLAC, stratified by pre-pregnancy BMI. Of the 512 women who underwent term trial of labor, 71.1% achieved a vaginal birth. No correlation was found between excessive GWG before 28 weeks and the rate of vaginal birth after cesarean (VBAC). Among women with or without excessive GWG before 28 weeks, excessive GWG after 28 weeks was significantly associated with a reduced rate of VBAC. When stratified by pre-pregnancy BMI, women who had excessive gestational weight gain after 28 weeks gestation had lower rates of VBAC than those who did not, regardless of being underweight, normal or overweight (aOR 0.23, 95% CI 0.06-0.88; aOR 0.42, 95% CI 0.25, 0.70; and aOR 0.12, 95% CI 0.04-0.36; respectively). Excessive weight gain after 28 weeks of pregnancy was related to decreased rates of VBAC, irrespective of pre-pregnancy weight status and weight gain before 28 weeks.

Efficient Nanozyme-Triggered Pressure Sensor for Point-of-Care Immunoassay: Visual Sensing and Time Readout Device.

Point-of-care testing (POCT), with its portability and high sensitivity, is an analytical device for rapid on-site sensing and detection. In this study, a POCT device was designed for the portable detection of illegal additives by integrating a coil device that can visually sense color distance and a two-electrode electrochemical system. Real-time monitoring of pressure changes was achieved by driving CeO2@Pt/Au nanoparticle (NP)-labeled antibodies into a competitive immunoreaction, in which CeO2 and Pt/Au synergistically catalyzed the production of large amounts of O2 from H2O2, leading to a significant increase in gas within the closed chamber. Attractively, the coil device converted the pressure stimulus into visually readable change in distance for semi-quantitative detection of the target substance, while the electrical signal output caused by the changes of the solution around the electrodes achieved accurate and reliable quantification of the target. In addition, the proposed dual-mode pressure immunoassay device has acceptable selectivity, stability, and reproducibility. Herein, this portable device, which enables target concentration readings by converting pressure into multiple signals, provides an effective way to visualize POCT assays in resource-limited areas.

Chiral aldehyde catalysis enables direct asymmetric α-substitution reaction of N-unprotected amino acids with halohydrocarbons.

The direct catalytic α-hydrocarbylation of readily available amino acids with halohydrocarbons is one of the most straightforward methods leading to α,α-disubstituted non-proteinogenic α-amino acid compounds. However, all the reported methodologies depend on N-protected amino acids as starting materials. Herein, we report on three highly efficient aldehyde-catalyzed direct α-hydrocarbylations of N-unprotected amino acid esters with aryl-, allyl-, and benzyl halides. By promoting a simple chiral BINOL-aldehyde catalyst or combining catalysts of a chiral aldehyde and Lewis acid ZnCl2, the asymmetric α-arylation, α-allylation, and α-benzylation of amino acid esters with the corresponding halohydrocarbons proceed smoothly, producing α,α-disubstituted α-amino acids in moderate-to-high yields and good-to-excellent enantioselectivities. The asymmetric α-arylation reaction can be applied in the formal synthesis of the clinical candidate compound (+)-AG-041R. Based on the results given by control experiments, three reaction models are proposed to illustrate the stereoselective-control outcomes.

Berberine is a potential alternative for metformin with good regulatory effect on lipids in treating metabolic diseases.

Metformin (MTF) and berberine (BBR) share several therapeutic benefits in treating metabolic-related disorders. However, as the two agents have very different chemical structure and bioavailability in oral route, the goal of this study is to learn their characteristics in treating metabolic disorders. The therapeutic efficacy of BBR and MTF was systemically investigated in the high fat diet feeding hamsters and/or ApoE(-/-) mice; in parallel, gut microbiota related mechanisms were studied for both agents. We discovered that, although both two drugs had almost identical effects on reducing fatty liver, inflammation and atherosclerosis, BBR appeared to be superior over MTF in alleviating hyperlipidemia and obesity, but MTF was more effective than BBR for the control of blood glucose. Association analysis revealed that the modulation of intestinal microenvironment played a crucial role in the pharmacodynamics of both drugs, in which their respective superiority on the regulation of gut microbiota composition and intestinal bile acids might contribute to their own merits on lowering glucose or lipids. This study shows that BBR may be a good alternative for MTF in treating diabetic patients, especially for those complicated with dyslipidemia and obesity.

Case Report: A case of COL1A1-PDGFB fusion uterine sarcoma at cervix and insights into the clinical management of rare uterine sarcoma.

COL1A1-PDGFB gene fusion uterine sarcoma is an especially rare malignant mesenchymal tumor that was previously classified as an undifferentiated uterine sarcoma due to the lack of specific features of differentiation. Till now, only five cases have been reported, and here we presented another case recently diagnosed in a Chinese woman who had vaginal bleeding. She presented with a cervical mass at the anterior lip of the cervix invading the vagina and was treated with laparoscopic total hysterectomy plus bilateral salpingo-oophorectomy (TH+BSO) and partial vaginal wall resection with the final pathology of COL1A1-PDGFB fusion uterine sarcoma. Our aim is to emphasize the importance of differential diagnosis of this rare tumor, as early precise diagnosis may allow patients to benefit from the targeted therapy imatinib. This article also serves as further clinical evidence of this disease, serving to increase clinical awareness of this rare sarcoma to avoid misdiagnosis.

Well-Aligned Track-Accelerated Tripedal DNA Walker for Photoelectrochemical Recognition of Dual-miRNAs Based on Molecular Logic Gates.

Post-transcriptional regulators, microRNAs (miRNAs), are involved in the occurrence and progression of various diseases. However, due to the complexity of disease-related miRNA regulatory networks, the typing and identification of miRNAs have remained challenging. Herein, a linear ladder-like DNA nanoarchitecture (LDN) was constructed to promote the movement efficiency of the tripedal DNA walker (T-walker), which was combined with the DNA-based logic gates and the PTCDA@PDA/CdS/WO3 photoelectrode to develop a novel biosensor for the detection of dual-miRNAs. Two miRNAs, miR-122 and miR-21, were used as targets to operate the logic module, while its output, trigger strands (TSs), initiated a catalytic hairpin assembly (CHA) reaction to form a T-walker. By using LDN as the track, the T-walker efficiently unfolded hairpin 4, which further hybridized with the alkaline phosphatase-modified hairpin 5 (AP-H5). The remaining AP can catalyze the ascorbic acid 2-phosphate (AAP) into ascorbic acid (AA), an ideal electron donor, thus resulting in a photocurrent change. The photocurrent signals of both AND and OR gates displayed a linear relationship with the logarithm of dual-miRNA concentrations with detection limits of 10.1 and 13.6 fM, respectively. Moreover, the intelligent and rational design of DNA tracks gives impetus to create a well-organized sensing interface with wide application in clinical diagnosis and cancer monitoring.

The contribution of the cingulate cortex: treating depressive symptoms in first-episode drug naïve schizophrenia.

Background: Our previous study has shown the cingulate cortex abnormalities in first-episode drug naïve (FEDN) schizophrenia patients with comorbid depressive symptoms. However, it remains largely unknown whether antipsychotics may induce morphometric change in cingulate cortex and its relationship with depressive symptoms. The purpose of this study was to further clarify the important role of cingulate cortex in the treatment on depressive symptoms in FEDN schizophrenia patients. Method: In this study, 42 FEDN schizophrenia patients were assigned into depressed patients group (DP, n = 24) and non-depressed patients group (NDP, n = 18) measured by the 24-item Hamilton Depression Rating Scale (HAMD). Clinical assessments and anatomical images were obtained from all patients before and after 12-week treatment with risperidone. Results: Although risperidone alleviated psychotic symptoms in all patients, depressive symptoms were decreased only in DP. Significant group by time interaction effects were found in the right rostral anterior cingulate cortex (rACC) and other subcortical regions in the left hemisphere. After risperidone treatment, the right rACC were increased in DP. Further, the increasing volume of right rACC was negatively associated with improvement in depressive symptoms. Conclusion: These findings suggested that the abnormality of the rACC is the typical characteristics in schizophrenia with depressive symptoms. It's likely key region contributing to the neural mechanisms underlying the effects of risperidone treatment on depressive symptoms in schizophrenia.

Microbiota-derived short-chain fatty acids mediate the effects of dengzhan shengmai in ameliorating cerebral ischemia via the gut-brain axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Dengzhan shengmai (DZSM) formula, composed of four herbal medicines (Erigeron breviscapus, Panax ginseng, Schisandra chinensis, and Ophiopogon japonicus), is widely used in the recovery period of ischemic cerebrovascular diseases; however, the associated molecular mechanism remains unclear. AIM OF THE STUDY: The purpose of this study was to uncover the links between the microbiota-gut-brain axis and the efficacy of DZSM in ameliorating cerebral ischemic diseases. MATERIALS AND METHODS: The effects of DZSM on the gut microbiota community and bacteria-derived short-chain fatty acid (SCFA) production were evaluated in vivo using a rat model of cerebral ischemia and in vitro through the anaerobic incubation with fresh feces derived from model animals. Subsequently, the mechanism underlying the role of SCFAs in the DZSM-mediated treatment of cerebral ischemia was explored. RESULTS: We found that DZSM treatment significantly altered the composition of the gut microbiota and markedly enhanced SCFA production. The consequent increase in SCFA levels led to the upregulation of the expression of monocarboxylate transporters and facilitated the transportation of intestinal SCFAs into the brain, thereby inhibiting the apoptosis of neurocytes via the regulation of the PI3K/AKT/caspase-3 pathway. The increased intestinal SCFA levels also contributed to the repair of the 2VO-induced disruption of gut barrier integrity and inhibited the translocation of lipopolysaccharide from the intestine to the brain, thus attenuating neuroinflammation. Consequently, cerebral neuropathy and oxidative stress were significantly improved in 2VO model rats, leading to the amelioration of cerebral ischemia-induced cognitive dysfunction. Finally, fecal microbiota transplantation could reproduce the beneficial effects of DZSM on SCFA production and cerebral ischemia. CONCLUSIONS: Our findings suggested that SCFAs mediate the effects of DZSM in ameliorating cerebral ischemia via the gut microbiota-gut-brain axis.

Pharmacology, pharmacokinetics, and toxicity characterization of a novel anti-CD73 therapeutic antibody IBI325 for cancer immunotherapy.

It is an intriguing approach to target the ecto-5'-nucleotidase CD73 to confer synergetic beneficial survival in cancer patients, along with clinically established immunotherapy targets. In this study, a fully human, subnanomolar affinity CD73 antibody IBI325 was developed using the yeast display platform. Compared with Oleclumab, IBI325 was equivalent in hCD73 affinity and more potent in cell-bound and soluble CD73 enzymatic inhibition, and no hook effects were observed. Correspondingly, adenosine monophosphate-mediated immune suppression was reversed by IBI325, and significant T cell proliferation and release of cytokines were observed. Also, IBI325 enhanced the T cell recall response by inducing interferon-γ secretion. The antitumor efficacy of IBI325 was investigated in a hPBMC-reconstituted NOG mouse model, and a hCD73 knock-in mouse model. Consequently, IBI325 induced a significant tumor regression by inducing intratumoral immune cell expansion, and a combo therapy of IBI325 and aPD-1 was superior in efficacy than aCD73 or aPD-1 monotherapy. Additionally, the binding epitopes of CD73 to IBI325 were distinct from previously reported aCD73 therapeutics. IBI325 displayed acceptable pharmacokinetics and sufficient tolerable safety profiles to support clinical development. In conclusion, the pharmacology, pharmacokinetics, and toxicity profiles of IBI325 with complete CD73 inhibition were characterized, and encouraging preclinical outcomes were reported.