Abnormal Local Brain Activity and Cognitive Impairments in Young Non-Disabled Patients With Intracerebral Hemorrhage: A Resting-State Functional MRI Study.

BACKGROUND: Resting-state functional MRI (rs-fMRI) has identified static changes of local brain activity among patients with intracerebral hemorrhage (ICH). However, the dynamic and concordance-related characteristics of brain activity remain unclear. PURPOSE: To investigate static, dynamic, and concordance-related features of the regional brain activity of young non-disabled ICH patients. STUDY TYPE: Prospective. SUBJECTS: Thirty-three ICH patients (modified Rankin Scale score ≤2, 21% female, 46.36 ± 6.53) and 33 matched healthy controls (HCs) (21% female, 47.64 ± 6.16). FIELD STRENGTH/SEQUENCE: 3-T, rs-fMRI using gradient echo-planar imaging, T1-weighted imaging. ASSESSMENT: Neuropsychological and rs-fMRI data were acquired from all participants. Amplitude of low-frequency fluctuations (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), voxel-mirrored homotopic connectivity, global signal correlation (GSCorr) and degree centrality (DC), and their dynamic and concordance-related changes with sliding window analysis were calculated based on rs-fMRI data at a whole-brain level. The burden of cerebral small vascular diseases (cSVD) was assessed by cSVD scores. All hemorrhage lesions were delineated on normalized T1 images. STATISTICAL TESTS: Multiple regression models, a voxel-level uncorrected P < 0.001, a cluster-level false discovery rate (FDR) corrected q < 0.05, a re-corrected qFDR <0.05 were considered significant. Pearson or Spearman correlation analyses between fMRI data and neurocognitive performance were performed. RESULTS: Compared to HCs, ICH patients showed significant abnormal changes of ALFF, dynamic ALFF, fALFF, ReHo, dynamic ReHo, GSCorr, DC, and voxel-wise concordance in multiple brain regions mainly including the bilateral cerebellar hemispheres, ipsilesional thalamus, and bilateral middle cingulum gyrus. The ALFF in the cerebellar posterior lobe and thalamus were significantly associated with attention (r = -0.481) and executive function (rho = -0.521) in ICH patients. DATA CONCLUSION: Young non-disabled ICH patients exhibit static, dynamic, and concordance-related alterations of local brain activity, part of which shows associations with cognitive functions. These findings may help comprehensively understand the mechanism of cognitive impairment after ICH. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

Effects of different natural products in patients with non-alcoholic fatty liver disease-A network meta-analysis of randomized controlled trials.

Due to a scarcity of appropriate therapeutic approaches capable of ameliorating or eliminating non-alcoholic fatty liver disease (NAFLD), many researchers have come to focus on natural products based on traditional medicine that can be utilized to successfully treat NAFLD. In this study, we aimed to evaluate the effects exerted by seven natural products (curcumin, silymarin, resveratrol, artichoke leaf extract, berberine, catechins, and naringenin) on patients with NAFLD. For this purpose, PubMed, Embase, Cochrane Library, and Web of Science, were searched for randomized controlled trials (RCTs) exclusively. The selected studies were evaluated for methodological quality via the Cochrane bias risk assessment tool, and data analysis software was used to analyze the data accordingly. The RCTs from the earliest available date until September 2022 were collected. This process resulted in 37 RCTs with a total sample size of 2509 patients being included. The results of the network meta-analysis showed that artichoke leaf extract confers a relative advantage in reducing the aspartate aminotransferase (AST) levels (SUCRA: 99.1%), alanine aminotransferase (ALT) levels (SUCRA: 88.2%) and low-density lipoprotein cholesterol (LDL-C) levels (SUCRA: 88.9%). Naringenin conferred an advantage in reducing triglyceride (TG) levels (SUCRA: 97.3%), total cholesterol (TC) levels (SUCRA: 73.9%), and improving high-density lipoprotein cholesterol (HDL-C) levels (SUCRA: 74.9%). High-density catechins significantly reduced body mass index (BMI) levels (SUCRA: 98.5%) compared with the placebo. The Ranking Plot of the Network indicated that artichoke leaf extract and naringenin performed better than the other natural products in facilitating patient recovery. Therefore, we propose that artichoke leaf extract and naringenin may exert a better therapeutic effect on NAFLD. This study may help guide clinicians and lead to further detailed studies.

Synthesis and Characterizations of MoS2 Nanoflowers and Spectroscopic Study of their Interaction with Bovine Serum Albumin.

Molybdenum disulfide nanoflowers (MoS2 NFs) were prepared by hydrothermal method. The prepared MoS2 NFs was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), specific surface areas, Raman and X-ray photoelectron spectroscopy (XPS). The characterization results show that the flower-like spherical MoS2 is composed of many ultra-thin nanosheets with an average diameter of about 300-400 nm. MoS2 NFs also exhibits excellent UV-vis absorption and high fluorescence intensity. In order to explore the biological behavior of MoS2 NFs, the interaction between MoS2 NFs and bovine serum albumin (BSA) was studied by UV-Vis absorption, fluorescence, synchronous fluorescence spectra, and cyclic voltammetry. The results of absorption and fluorescence show that MoS2 NFs and BSA interact strongly through the formation of complexes in the ground state, and the static quenching is the main mechanism. The Stern-Volmer constant and the quenching constant was calculated about 3.79×107 L mol-1 and 3.79×1015 L mol-1 s-1, respectively. The synchronous fluorescence implied that MoS2 in the complex may mainly bind to tryptophan residues of BSA. The cyclic voltammograms indicated that the addition of BSA makes electron reduction of MoS2 NFs more difficult than the corresponding free state. The results show that hydrophobic forces play a major role in the binding interaction between BSA and MoS2 NFs.

[Diosgenin alleviates NAFLD induced by a high-fat diet in rats via mTOR/SREBP-1c/HSP60/MCAD/SCAD signaling pathway].

This study aims to observe the effects of diosgenin on the expression of mammalian target of rapamycin(mTOR), sterol regulatory element-binding protein-1c(SREBP-1c), heat shock protein 60(HSP60), medium-chain acyl-CoA dehydrogenase(MCAD), and short-chain acyl-CoA dehydrogenase(SCAD) in the liver tissue of the rat model of non-alcoholic fatty liver disease(NAFLD) and explore the mechanism of diosgenin in alleviating NAFLD. Forty male SD rats were randomized into five groups: a control group, a model group, low-(150 mg·kg~(-1)·d~(-1)) and high-dose(300 mg·kg~(-1)·d~(-1)) diosgenin groups, and a simvastatin(4 mg·kg~(-1)·d~(-1)) group. The rats in the control group were fed with a normal diet, while those in the other four groups were fed with a high-fat diet. After feeding for 8 weeks, the body weight of rats in the high-fat diet groups increased significantly. After that, the rats were administrated with the corresponding dose of diosgenin or simvastatin by gavage every day for 8 weeks. The levels of triglyceride(TG), total cholesterol(TC), alanine transaminase(ALT), and aspartate transaminase(AST) in the serum were determined by the biochemical method. The levels of TG and TC in the liver were measured by the enzyme method. Oil-red O staining was employed to detect the lipid accumulation, and hematoxylin-eosin(HE) staining to detect the pathological changes in the liver tissue. The mRNA and protein levels of mTOR, SREBP-1c, HSP60, MCAD, and SCAD in the liver tissue of rats were determined by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR) and Western blot, respectively. Compared with the control group, the model group showed increased body weight, food uptake, liver index, TG, TC, ALT, and AST levels in the serum, TG and TC levels in the liver, lipid deposition in the liver, obvious hepatic steatosis, up-regulated mRNA and protein expression levels of mTOR and SREBP-1c, and down-regulated mRNA and protein expression levels of HSP60, MCAD, and SCAD. Compared with the model group, the rats in each treatment group showed obviously decreased body weight, food uptake, liver index, TG, TC, ALT, and AST levels in the serum, TG and TC levels in the liver, lessened lipid deposition in the liver, ameliorated hepatic steatosis, down-regulated mRNA and protein le-vels of mTOR and SREBP-1c, and up-regulated mRNA and protein levels of HSP60, MCAD, and SCAD. The high-dose diosgenin outperformed the low-dose diosgenin and simvastatin. Diosgenin may prevent and treat NAFLD by inhibiting the expression of mTOR and SREBP-1c and promoting the expression of HSP60, MCAD, and SCAD to reduce lipid synthesis, improving mitochondrial function, and promoting fatty acid ß oxidation in the liver.

Application and potential value of curcumin in prostate cancer: a meta-analysis based on animal models.

Introduction: Curcumin is gaining recognition as an agent for cancer chemoprevention and is presently administered to humans. However, the limited number of clinical trials conducted for the treatment of prostate cancer is noteworthy. Animal models serve as valuable tools for enhancing our understanding of disease mechanisms and etiology in humans. The objective of this study was to examine the anti-prostate cancer effects of curcumin in vivo for comprehending its current research status and potential clinical applicability. Methods: Our methodology involved a systematic exploration of animal studies pertaining to curcumin and prostate cancer, as documented in PubMed, Web of Science, Embase, Cochrane Library, CNKI, Wanfang database, Vip database, and SinoMed, up to 03 September 2023. Risk of bias was assessed using the SYRCLE Animal Study Risk of Bias tool. The results were combined using the RevMan 5.3. Results: A comprehensive analysis was conducted on 17 studies encompassing 263 mouse transplantation tumor models. The findings of this meta-analysis demonstrated that curcumin exhibited a superior inhibitory effect on the volume of prostate cancer tumors in mice compared to the control group (standardized mean difference [SMD]: 1.16, 95% confidence interval [CI]: 0.52, 1.80, p < 0.001). Additionally, curcumin displayed a more effective inhibition of mice prostate cancer tumor weight (SMD: -3.27, 95% CI: -4.70, -1.83, p < 0.001). Furthermore, in terms of tumor inhibition rate, curcumin exhibited greater efficacy (SMD: 0.25, 95% CI: 0.23, 0.27, p < 0.001). Moreover, curcumin more effectively inhibited PCNA mRNA (SMD: -3.11, 95% CI: -4.60, -1.63, p < 0.001) and MMP2 mRNA (SMD: -3.19, 95% CI: 5.85, -0.53, p < 0.001). Conclusion: Curcumin exhibited inhibitory properties towards prostate tumor growth and demonstrated a beneficial effect on prostate cancer treatment, thereby offering substantiation for further clinical investigations. It is important to acknowledge that the included animal studies exhibited considerable heterogeneity, primarily because of the limited number of studies included. Consequently, additional randomized controlled trials are required to comprehensively assess the efficacy of curcumin in humans. Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023464661), identifier (CRD42023464661).

Efficacy and safety of Chinese patent medicine in the adjuvant treatment of prostate cancer: A Bayesian network meta-analysis.

BACKGROUND: Prostate cancer is the most common cancer in men. In China, traditional Chinese medicine is used to treat prostate cancer. However, there is a lack of evidence for differences in the effectiveness and safety of different Chinese patent medicines. Therefore, we conducted this Network Meta-analysis to investigate the efficacy and safety of different Chinese patent medicines in the treatment of prostate cancer. METHODS: We systematically search PubMed, Web of Science, Embase, Cochrane library, CNKI database, VIP database, wanfang database, and SinoMed Randomized controlled trials of Chinese patent medicines for the treatment of prostate cancer sores included in the database were retrieved until June 1, 2023. The included studies were assessed for risk of bias using Cochrane randomized controlled trial Bias risk Assessment tool. The main outcome indicators were Efficacy, Prostate Specific Antigen, and adverse reaction. Since different courses of treatment were used in the included studies, we used Bayesian mesh meta-regression to investigate the effects of treatment courses on efficacy and safety. RESULTS: Twenty-seven articles were included, involving 1885 patients. Including 9 kinds of Chinese patent medicine. The results of Network Meta-analysis show that: ① efficacy: compared with androgen antagonists, Bruceolic oil emulsion (relative risk = 1.70, 95% credibility interval [CI] (1.30, 2.29)), Compound Kushen injection (relative risk = 1.39, 95%CI (1.19, 1.70)) had significant advantages. There was no significant difference among all Chinese patent medicines (P > .05). The top 3 Chinese patent medicines were Bruceolic oil emulsion, Zhibodihuang pill, Compound Kushen injection. ② Prostate specific antigen: compared with androgen antagonists, Bruceolic oil emulsion (mean difference [MD] = -10.4, 95%CI [-17.6, -3.21]), Compound Kushen injection (MD = -4.46, 95%CI [-8.80, -1.70]), Shenfu injection (MD = -14.7, 95%CI [-23.4, -6.01]) had significant advantages. The top 3 Chinese patent medicines were Shenfu injection, Bruceolic oil emulsion, Compound Kushen injection. adverse reaction: compared with androgen antagonists, there was no significant difference among all PCM (P > .05). CONCLUSION: Compared with androgen antagonists, Chinese patent medicine has significant difference in effectiveness. The effect of Chinese patent medicine is little affected by the course of treatment and dose. From comprehensive analysis, Bruceolic oil emulsion combined with androgen antagonist is the best intervention measures.

Alleviation of behavioral deficits, amyloid-ß deposition, and mitochondrial structure damage associated with mitophagy upregulation in AD animal models via AAV9-IGF-1 treatment.

By safeguarding the neurological system, insulin-like growth factor 1 (IGF-1) may have a role in the etiology of Alzheimer's disease (AD). The mechanism and signaling route, however, remain unclear. This research aimed to investigate the impact of IGF-1 on AD as well as its possible mechanism and signaling route. In this work, intracerebroventricular AAV9-IGF-1 was delivered to APP/PS1 transgenic mice. Following therapy, the Morris water maze and passive avoidance tests were administered to evaluate spatial learning and memory. The elevated plus maze, the open field test, and the sucrose preference test were used to evaluate anxious-depressive-like behavior. Thioflavin S staining was employed to visualize Aß deposition, and ELISA was used to determine the quantities of soluble Aß1-40 and Aß1-42. Transmission electron microscopy was used to view the mitochondrial structure and mitophagy vesicles. The protein expression levels of PINK1, Parkin, and LC3-II/LC3-I were finally determined by Western blotting. AAV9-IGF-1 therapy enhanced spatial learning and memory, relieved anxious-depressive-like behavior impairments, lowered amyloid-ß deposition, and decreased levels of soluble Aß1-40 and Aß1-42. In addition, AAV9-IGF-1 therapy restored mitochondrial integrity and increased the number of mitophagy in transgenic mice expressing APP/PS1. These results indicate that IGF-1 is protective for APP/PS1 mice. The mechanism of the favorable benefits mediated by IGF-1 was connected to an increase in mitophagy, which might give a novel therapy target in the future.

Detection of intracellular microRNA-21 for cancer diagnosis by a nanosystem containing a ZnO@polydopamine and DNAzyme probe.

MicroRNAs (miRNAs) are a series of single-stranded non-coding ribonucleic acid (RNA) molecules which associated closely with various human diseases. Efficient strategies for detecting miRNAs are of great significance to cancer diagnosis and prognosis. Here we provide a novel nanosystem that can be applied for the detection of miRNAs. The nanosystem consists of a single-stranded deoxyribonucleic acid (DNA) probe and a probe carrier. The DNA probe was designed based on a deoxyribozyme (DNAzyme) with several necessary functional sequences and two fluorescent dyes labeled at proper sites. The ZnO@polydopamine (ZnO@PDA) nanomaterial serves not only as a probe carrier, but also as a supplier of Zn2+ that can activate the DNAzyme. The DNA probe will undergo a conformation alteration induced by miRNA-21, which then trigger the DNAzyme catalyzed self-cleavage reaction with the assist of Zn2+ provided by ZnO decomposition under weak acid environment. A change of fluorescent color will occur due to the interruption of fluorescence resonance energy transfer between the two fluorescent dyes, and the dissociated miRNA-21 can repeatedly induce the above responses to amplify the fluorescence signal. The feasibility of the whole procedure was demonstrated by various experiments. This nanosystem showed a good selectivity towards miRNA-21, and under the optimal incubation time of 2 hours, a good linear relationship was obtained in a concentration range of 0.01-2.0 nM with a detection limit of 3.8 pM. In in vivo detection, an obvious fluorescence color change from red to green can be observed in the presence of miRNA-21. The results proved that this miRNA detection strategy has a broad application prospect in tumor diagnosis and miRNA related biological studies.

GmMATE100 Is Involved in the Import of Soyasaponins A and B into Vacuoles in Soybean Plants (Glycine max L.).

Triterpenoid saponins, synthesized via the mevalonic acid (MVA) pathway in the cytoplasm, provide protection against pathogens and pests in plants and health benefits for humans. However, the mechanisms by which triterpenoid saponins are transported between cellular compartments remain uncharacterized. Here, we characterize a tonoplast localized multidrug and toxic compound extrusion transporter, GmMATE100 (encoded by Glyma.18G143700), from soybean (Glycine max L.). GmMATE100 is co-expressed with soyasaponin biosynthetic genes, and its expression was induced by MeJA treatment, which also led to soyasaponin accumulation in soybean roots. GmMATE100 efficiently transports multiple type-B soyasaponins as well as type-A soyasaponins with low affinity from the cytosol to the vacuole in a yeast system. The GmMATE100 loss-of-function mutant showed a significant decrease in type-A and type-B soyasaponin contents in soybean roots. This study not only characterized the first soybean triterpenoid saponin transporter but also provided new knowledge for the rational engineering of soyasaponin content and composition in soybean plants to modulate their levels within crop environments.

Micheliolide ameliorates lipopolysaccharide-induced acute kidney injury through suppression of NLRP3 activation by promoting mitophagy via Nrf2/PINK1/Parkin axis.

BACKGROUND: Sepsis-associated acute kidney injury (SA-AKI) represents a frequent complication of in critically ill patients. The objective of this study is to illuminate the potential protective activity of Micheliolide (MCL) and its behind mechanism against SA-AKI. METHODS: The protective potential of MCL on SA-AKI was investigated in lipopolysaccharide (LPS) treated HK2 cells and SA-AKI mice model. The mitochondrial damage was determined by detection of reactive oxygen species and membrane potential. The Nrf2 silencing was achieved by transfection of Nrf2-shRNA in HK2 cells, and Nrf2 inhibitor, ML385 was employed in SA-AKI mice. The mechanism of MCL against SA-AKI was evaluated through detecting hallmarks related to inflammation, mitophagy and Nrf2 pathway via western blotting, immunohistochemistry, and enzyme linked immunosorbent assay. RESULTS: MCL enhanced viability, suppressed apoptosis, decreased inflammatory cytokine levels and improved mitochondrial damage in LPS-treated HK2 cells, and ameliorated renal injury in SA-AKI mice. Moreover, MCL could reduce the activation of NLRP3 inflammasome via enhancing mitophagy. Additionally, Nrf2 deficiency reduced the suppression effect of MCL on NLRP3 inflammasome activation and blocked the facilitation effect of MCL on mitophagy in LPS-treated HK2 cells, the consistent is true for ML385 treatment in SA-AKI mice. CONCLUSIONS: MCL might target Nrf2 and further reduce the NLRP3 inflammasome activation via enhancing mitophagy, which alleviated SA-AKI.

Abnormal dynamic functional connectivity in young nondisabling intracerebral hemorrhage patients.

OBJECTIVE: Previous resting-state functional magnetic resonance imaging studies on intracerebral hemorrhage patients have focused more on the static characteristics of brain activity, while the time-varying effects during scanning have received less attention. Therefore, the current study aimed to explore the dynamic functional network connectivity changes of intracerebral hemorrhage patients. METHODS: Using independent component analysis, the sliding window approach, and the k-means clustering analysis method, different dynamic functional network connectivity states were detected from resting-state functional magnetic resonance imaging data of 37 intracerebral hemorrhage patients and 44 healthy controls. The inter-group differences in dynamic functional network connectivity patterns and temporal properties were investigated, followed by correlation analyses between clinical scales and abnormal functional indexes. RESULTS: Ten resting-state networks were identified, and the dynamic functional network connectivity matrices were clustered into four different states. The transition numbers were decreased in the intracerebral hemorrhage patients compared with healthy controls, which was associated with trail making test scores in patients. The cerebellar network and executive control network connectivity in State 1 was reduced in patients, and this abnormal dynamic functional connectivity was positively correlated with the animal fluency test scores of patients. INTERPRETATION: The current study demonstrated the characteristics of dynamic functional network connectivity in intracerebral hemorrhage patients and revealed that abnormal temporal properties and functional connectivity may be related to the performance of different cognitive domains after ictus. These results may provide new insights into exploring the neurocognitive mechanisms of intracerebral hemorrhage.

Effect of Soy Protein Products on Growth and Metabolism of Bacillus subtilis, Streptococcus lactis, and Streptomyces clavuligerus.

Microbial nitrogen sources are promising, and soy protein as a plant-based nitrogen source has absolute advantages in creating microbial culture medium in terms of renewability, eco-friendliness, and greater safety. Soy protein is rich in variety due to different extraction technologies and significantly different in the cell growth and metabolism of microorganisms as nitrogen source. Therefore, different soy proteins (soy meal powder, SMP; soy peptone, SP; soy protein concentrate, SPC; soy protein isolate, SPI; and soy protein hydrolysate, SPH) were used as nitrogen sources to culture Bacillus subtilis, Streptococcus lactis, and Streptomyces clavuligerus to evaluate the suitable soy nitrogen sources of the above strains. The results showed that B. subtilis had the highest bacteria density in SMP medium; S. lactis had the highest bacteria density in SPI medium; and S. clavuligerus had the highest PMV in SPI medium. Nattokinase activity was the highest in SP medium; the bacteriostatic effect of nisin was the best in SPI medium; and the clavulanic acid concentration was the highest in SMP medium. Based on analyzing the correlation between the nutritional composition and growth metabolism of the strains, the results indicated that the protein content and amino acid composition were the key factors influencing the cell growth and metabolism of the strains. These findings present a new, high-value application opportunity for soybean protein.

The Role of JAK/STAT Signaling Pathway and Its Downstream Influencing Factors in the Treatment of Atherosclerosis.

Atherosclerosis is now widely considered to be a chronic inflammatory disease, with increasing evidence suggesting that lipid alone is not the main factor contributing to its development. Rather, atherosclerotic plaques contain a significant amount of inflammatory cells, characterized by the accumulation of monocytes and lymphocytes on the vessel wall. This suggests that inflammation may play a crucial role in the occurrence and progression of atherosclerosis. As research deepens, other pathological factors have also been found to influence the development of the disease. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a recently discovered target of inflammation that has gained attention in recent years. Numerous studies have provided evidence for the causal role of this pathway in atherosclerosis, and its downstream signaling factors play a significant role in this process. This brief review aims to explore the crucial role of the JAK/STAT pathway and its representative downstream signaling factors in the development of atherosclerosis. It provides a new theoretical basis for clinically affecting the development of atherosclerosis by interfering with the JAK/STAT signaling pathway.

Mechanism of Action and Related Natural Regulators of Nrf2 in Nonalcoholic Fatty Liver Disease.

With the acceleration of people's pace of life, non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the world, which greatly threatens people's health and safety. Therefore, there is still an urgent need for higher-quality research and treatment in this area. Nuclear factor Red-2-related factor 2 (Nrf2), as a key transcription factor in the regulation of oxidative stress, plays an important role in inducing the body's antioxidant response. Although there are no approved drugs targeting Nrf2 to treat NAFLD so far, it is still of great significance to target Nrf2 to alleviate NAFLD. In recent years, studies have reported that many natural products treat NAFLD by acting on Nrf2 or Nrf2 pathways. This article reviews the role of Nrf2 in the pathogenesis of NAFLD and summarizes the currently reported natural products targeting Nrf2 or Nrf2 pathway for the treatment of NAFLD, which provides new ideas for the development of new NAFLD-related drugs.

Diosgenin attenuates metabolic-associated fatty liver disease through the hepatic NLRP3 inflammasome-dependent signaling pathway.

Metabolic-associated fatty liver disease (MAFLD) is one of the most common liver diseases worldwide; however, its pathogenesis and treatment methods have not been perfected. NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) is a promising therapeutic target for MAFLD. Diosgenin (DG) is a natural compound that was identified in a traditional Chinese herbal medicine, which has pharmacological effects, such as anti-inflammatory, antioxidant, hepatoprotective, and hypolipidemic activities. In this study, we examined the effects and molecular mechanisms of DG on MAFLD in vitro and in vivo. We established a rat model by administering a high-fat diet (HFD). We also generated an in vitro MAFLD model by treating HepG2 cells with free fatty acids (FFAs). The results indicated that DG attenuated lipid accumulation and liver injury in both in vitro and in vivo models. DG downregulated the expression of NLRP3, apoptosis-associated speckle-like protein (ASC), cysteinyl aspartate specific proteinase-1 (caspase-1), gasdermin D (GSDMD), GSDMD-n, and interleukin-1ß (IL-1ß). In addition, we silenced and overexpressed NLRP3 in vitro to determine the effects of DG on antiMAFLD. Silencing NLRP3 enhanced the effect of DG on the treatment of MAFLD, whereas NLRP3 overexpression reversed its beneficial effects. Taken together, the results show that DG has a favorable effect on attenuating MAFLD through the hepatic NLRP3 inflammasome-dependent signaling pathway. DG represents a natural NLRP3 inhibitor for the MAFLD treatment.

Antibody-drug conjugates for targeted cancer therapy: Recent advances in potential payloads.

Antibody-drug conjugates (ADCs) represent a promising cancer therapy modality which specifically delivers highly toxic payloads to cancer cells through antigen-specific monoclonal antibodies (mAbs). To date, 15 ADCs have been approved and more than 100 ADC candidates have advanced to clinical trials for the treatment of various cancers. Among these ADCs, microtubule-targeting and DNA-damaging agents are at the forefront of payload development. However, several challenges including toxicity and drug resistance limit the potential of this modality. To tackle these issues, multiple innovative payloads such as immunomodulators and proteolysis targeting chimeras (PROTACs) are incorporated into ADCs to enable multimodal cancer therapy. In this review, we describe the mechanism of ADCs, highlight the importance of ADC payloads and summarize recent progresses of conventional and unconventional ADC payloads, trying to provide an insight into payload diversification as a key step in future ADC development.

Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic SIRT1/PGC-1α pathway.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing worldwide in recent years, causing severe economic and social burdens. Therefore, the lack of currently approved drugs for anti-NAFLD has gradually gained attention. SIRT1, as a member of the sirtuins family, is now the most widely studied in the pathophysiology of many metabolic diseases, and has great potential for preventing and treating NAFLD. Natural products such as Diosgenin (DG) have the potential to be developed as clinical drugs for the treatment of NAFLD due to their excellent multi-target therapeutic effects. In this study, we found that DG can activate the SIRT1/PGC-1α pathway and upregulate the expression of its downstream targets nuclear respiratory factor 1 (NRF1), complex IV (COX IV), mitofusin-2 (MFN2), and PPARα (perox-isome proliferator-activated receptor α) in SD rats induced by high-fat diet (HFD) and HepG2 cells caused by free fatty acids (FFAs, sodium oleate: sodium palmitate = 2:1). Conversely, the levels of dynamin-related protein 1 (DRP1) and inflammatory factors, including NF-κB p65, IL6, and TNFα, were downregulated both in vitro and in vivo. This improved mitochondrial dysfunction, fatty acid oxidation (FAO), lipid accumulation, steatosis, oxidative stress, and hepatocyte inflammation. Subsequently, we applied SIRT1 inhibitor EX527 and SIRT1 agonist SRT1720 to confirm further the necessity of activating SIRT1 for DG to exert therapeutic effects on NAFLD. In summary, these results further demonstrate the potential therapeutic role of DG as a SIRT1 natural agonist for NAFLD. (Graphical Abstracts).

Natural variation in SSW1 coordinates seed growth and nitrogen use efficiency in Arabidopsis.

Seed size is controlled not only by intrinsic genetic factors but also by external environmental signals. Here, we report a major quantitative trait locus (QTL) gene for seed size and weight on chromosome 1 (SSW1) in Arabidopsis, and we found SSW1 acts maternally to positively regulate seed size. Natural variation in SSW1 contains three types of alleles. The SSW1Cvi allele produces larger seeds with more amino acid and storage protein contents than the SSW1Ler allele. SSW1Cvi displays higher capacity for amino acid transport than SSW1Ler due to the differences in transport efficiency. Under low nitrogen supply, the SSW1Cvi allele exhibits increased seed yield and nitrogen use efficiency (NUE). Locations of natural variation alleles of SSW1 are associated with local soil nitrogen contents, suggesting that SSW1 might contribute to geographical adaptation in Arabidopsis. Thus, our findings reveal a mechanism that coordinates seed growth and NUE, suggesting a potential target for improving seed yield and NUE in crops.

Investigation of the Seroprevalence of Brucella Antibodies and Characterization of Field Strains in Immunized Dairy Cows by B. abortus A19.

(1) Background: One method of eradicating brucellosis is to cull cattle that test positive for antibodies 12 months after being vaccinated with the 19-strain vaccine. Variations in immunization regimens and feeding practices may contribute to differences in the rate of persistent antibodies. We conducted this study to investigate the real positive rate of Brucella antibody in field strains of Brucella spp. after immunization over 12 months in dairy cows. This research aims to provide data to support the development of strategies for preventing, controlling, and eradicating brucellosis. (2) Method: We employed the baseline sampling method to collect samples from cows immunized with the A19 vaccine for over 12 months in Lingwu City from 2021 to 2023. Serological detection was conducted using the RBPT method. An established PCR method that could distinguish between 19 and non-19 strains of Brucella was utilized to investigate the field strains of Brucella on 10 dairy farms based on six samples mixed into one using the Mathematical Expectation strategy. (3) Results: We analyzed the rates of individual seropositivity and herd seropositive rates in dairy cattle in Lingwu City from 2021 to 2023 and revealed that antibodies induced by the Brucella abortus strain A19 vaccine persist in dairy herds for more than 12 months. We established a PCR method for identifying both Brucella A19 and non-A19 strains, resulting in the detection of 10 field strains of Brucella abortus from 1537 dairy cows. By employing a Mathematical Expectation strategy, we completed testing of 1537 samples after conducting only 306 tests, thereby reducing the workload by 80.1%. (4) Conclusions: There was a certain proportion of cows with a persistent antibody titer, but there was no evidence that all of these cattle were naturally infected with Brucella. The established PCR method for distinguishing between Brucella abortus strain 19 and non-19 strains can be specifically utilized for detecting natural Brucella infection in immunized cattle. We propose that relying solely on the detection of antibodies in cattle immunized with the A19 vaccine more than 12 months previously should not be solely relied upon as a diagnostic basis for brucellosis, and it is essential to complement this approach with PCR analysis to specifically identify field Brucella spp. Brucella abortus was the predominant strain identified in the field during this study. Detection based on the Mathematical Expectation strategy can significantly enhance detection efficiency.

Association between gastroesophageal reflux disease and stroke: a bidirectional Mendelian randomization study.

Objective: Some previous studies have suggested a potential link between stroke and gastroesophageal reflux disease (GERD). We used a two-sample bidirectional Mendelian randomization (MR) method to explore the causal relationship between stroke and GERD. Design: Summary-level data derived from the published genome-wide association studies (GWAS) were employed for analyses. Single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for stroke (n = 446,696) and its common subtypes ischemic stroke (IS) (n = 440,328), large vessel stroke (LVS) (n = 410,484), small vessel stroke (SVS) (n = 198,048), and cardioembolic stroke (CES) (n = 413,304) were obtained from the MEGASTROKE consortium. The data on intracerebral hemorrhage (ICH) (n = 721,135) come from the UK Biobank. Instrumental variables (IVs) for lacunar stroke (LS) (n = 474,348) and GERD (n = 602,604) were screened from publicly available genetic summary data. The inverse variance weighted (IVW) method was used as the main MR method. Pleiotropy was detected by the MR-Egger intercept test, MR pleiotropy residual sum and outlier, and leave-one-out analysis. Cochran Q statistics were used as supplements to detect pleiotropy. Results: We found that GERD can causally increase the risk of stroke [IVW odds ratio (OR): 1.22, 95% confidence interval (CI): 1.13-1.32, p = 1.16 × 10-6] and its common subtypes IS (OR: 1.19, 95% CI: 1.10-1.30, p = 3.22 × 10-5), LVS (OR: 1.49, 95% CI: 1.21-1.84, p = 1.47 × 10-4), and LS (OR: 1.20, 95% CI: 1.001-1.44, p = 0.048). Several important risk factors for stroke have also been implicated in the above causal relationship, including type 2 diabetes, sleep apnea syndrome, high body mass index, high waist-to-hip ratio, and elevated serum triglyceride levels. In reverse MR analysis, we found that overall stroke (OR: 1.09, 95% CI: 1.004-1.19, p = 0.039) and IS (OR: 1.10, 95% CI: 1.03-1.17, p = 0.007) have the causal potential to enhance GERD risk. Conclusion: This MR study provides evidence supporting a causal relationship between GERD and stroke and some of its common subtypes. We need to further explore the interconnected mechanisms between these two common diseases to better prevent and treat them.