Antimicrobial activity, foaming properties, and interacting mechanism of rhamnolipids in presence of silk fibroin through spectroscopy, molecular docking, and microbiological experiments.

As a type of biosurfactant, rhamnolipids (RLs) are multifunctional skin-care ingredients, and the molecular interaction of RLs with silk fibroin (SF) is a more complicated process than has long been believed. The interaction and functional properties of them, and their potential as fungicidal agents for agricultural products and as organic preservatives for cosmetics were assessed in this paper. The SF addition makes the RLs aggregation easier through the complexes formation, which decreases the applied concentration of surfactant. The results of spectroscopic analyses and molecular docking suggest that hydrogen bonding and van der Waals forces are significant contributed to the binding mechanism between the two substances. The addition of SF notably enhances the foaming capacity and stability of RLs. The certain antibacterial and antifungal properties of RLs are basically not affected by the SF addition, even the SF-RLS system demonstrates an unobvious synergistic inhibitory impact on Glomerella cingulate (GC). The results offer a theoretical framework for the utilization of RLs as natural fungicides and preservatives in presence of nutritional components, considering the properties of RLs as nontoxic, biodegradable, environmentally friendly, and good compatibility.

Mechanisms of conjugative transfer of antibiotic resistance genes induced by extracellular polymeric substances: Insights into molecular diversities and electron transfer properties.

Dissemination of antibiotic resistance genes (ARGs) has become a critical threat to public health. Activated sludge, rich in extracellular polymeric substances (EPS), is an important pool of ARGs. In this study, mechanisms of conjugation transfer of ARGs induced by EPS, including tightly bound EPS (TBEPS), soluble EPS (SEPS), and loosely bound EPS (LBEPS), were explored in terms of molecular diversities and electron transfer properties of EPS. Conjugation transfer frequency was increased by 9.98-folds (SEPS), 4.21-folds (LBEPS), and 15.75-folds (TBEPS) versus the control, respectively. Conjugation-related core genes involving SOS responses (9 genes), membrane permeability (18 genes), intercellular contact (17 genes), and energy metabolism pathways (13 genes) were all upregulated, especially in the presence of TBEPS. Carbohydrates and aliphatic substances in SEPS and LBEPS were contributors to ARG transfer, via influencing reactive oxygen species (ROS) formation (SEPS) and ROS and adenosine triphosphate (ATP) production (LBEPS). TBEPS had the highest redox potential and greatest lability and facilitated electron transfer and alternated respiration between cells, thus promoting ARG transfer by producing ATP. Generally, the chemical molecular characteristics and redox properties of EPS facilitated ARG transfer mainly by influencing lipid peroxidation and ATP, respectively.

No genetic link between Parkinson's disease and SARS-CoV-2 infection: a two-sample Mendelian randomization study.

Objective: Existing literature has not clearly elucidated whether SARS-CoV-2 infection increases the incidence of Parkinson's disease or if Parkinson's disease patients are more susceptible to the effects of SARS-CoV-2 infection. To clarify the issue, this study employs a genetic epidemiological approach to investigate the association. Methods: This study utilizes a two-sample Mendelian randomization analysis. The primary analysis employs the inverse variance-weighted (IVW) method, supplemented by secondary analyses including MR-Egger regression, weighted median, IVW radial method, and weighted mode, to evaluate the bidirectional causal relationship between Parkinson's disease and SARS-CoV-2 infection. Results: IVW results showed no genetic causality between SARS-CoV-2 susceptibility, hospitalization rate and severity and Parkinson's disease. (IVW method: p = 0.408 OR = 1.10 95% CI: 0.87 ~ 1.39; p = 0.744 OR = 1.11 95% CI: 0.94 ~ 1.09; p = 0.436 OR = 1.05 95% CI: 0.93 ~ 1.17). Parkinson's disease was not genetically associated with susceptibility to new crown infections, hospitalization rates, and severity (IVW method: p = 0.173 OR = 1.01 95% CI: 0.99 ~ 1.03; p = 0.109 OR = 1.05 95% CI: 0.99 ~ 1.12; p = 0.209 OR = 1.03 95% CI: 0.99 ~ 1.07). MR-Egger regression, weighted median, IVW radial method, and weighted mode results are consistent with the results of the IVW method. Conclusion: This study does not support a genetic link between Parkinson's disease and SARS-CoV-2 infection, and the association observed in previous cohort studies and observational studies may be due to other confounding factors.

[Immunological mechanism of Ermiao Powder improving inflammation in rats with collagen-induced arthritis through α7nAChR-JAK2/STAT3 pathway].

This study investigated the immunological mechanisms of Ermiao powder in the treatment of rheumatoid arthritis rats through the alpha 7 nicotinic acetylcholine receptor(α7nAChR)-Janus kinases 2(JAK2)/signal transducer and activator of transcription 3(STAT3) signaling pathway. A total of 56 female Wistar rats were randomly divided into the normal group(HG, n=8), collagen-induced arthritis(CIA) model group(CM, n=8), vagotomy group(VA, n=8), sham group(SH, n=8), Ermiao Powder treatment model group(EM, n=8), Ermiao Powder treatment for vagotomy group(EV, n=8) and Ermiao Powder treatment for sham group(ES, n=8). Following the establishment of CIA models in all groups except the HG group, the rats underwent unilateral vagotomy and sham operation(only the vagus nerve was separated). Drug treatment was started 7 days after surgery and continued for 35 days. The body weight and joints of rats were recorded, the pathological changes of the spleen of rats were observed, the contents of interleukin-6(IL-6), interleukin-1ß(IL-1ß) and tumor necrosis factor-α(TNF-α) in serum were detected by enzyme-linked immunosorbent assay(ELISA), and the mRNA and protein expression of α7nAChR-JAK2/STAT3 pathway core genes in spleen were detected by qRT-PCR, Western blot and immunohistochemistry. RESULTS:: showed that CM group(compared with HG group) and VA group(compared with CM group and SH group) had significantly decreased body weight(P<0.05, P<0.01), increased arthritis score(P<0.05, P<0.01), swollen ankle joints with deformity, and increased and enlarged lymph nodes in the spleen. There were also notable increases in the serum levels of IL-6, IL-1ß and TNF-α(P<0.05, P<0.01), and in the mRNA expressions of JAK2 and STAT3 in the spleen(P<0.05, P<0.01). The protein levels of phosphorylated JAK2(p-JAK2)/JAK2 and phospho-STAT3(p-STAT3)/STAT3 were significantly increased(P<0.05, P<0.01), and the number of JAK2, p-JAK2, STAT3 and p-STAT3 cells increased(P<0.05, P<0.01). EM group(compared with CM group) and ES group(compared with SH group) exhibited significantly increased body weight(P<0.01), decreased arthritis scores(P<0.05, P<0.01), reduced swelling of ankle joint, and decreased number and volume of lymph nodes in the spleen. Furthermore, serum levels of IL-6, IL-1ß, and TNF-α decreased(P<0.05, P<0.01), the mRNA expression of JAK2 and STAT3 in spleen decreased(P<0.05, P<0.01), the protein levels of p-JAK2/JAK2 and p-STAT3/STAT3 decreased(P<0.05, P<0.01), and the number of JAK2, p-JAK2, STAT3 and p-STAT3 cells decreased(P<0.05, P<0.01), whereas the mRNA and protein expressions of α7nAChR were significantly increased(P<0.01). Compared with the VA group, there was no significant differences in weight gain and arthritis scores in the EV group. The number of lymph nodes in the spleen was not significantly reduced and the volume was still large, suggesting the inflammation was not significantly improved. The serum levels of IL-6, IL-1ß and TNF-α were not significantly different, and there were no significant differences in α7nAChR, JAK2, and STAT3 mRNA expression in the spleen. The protein expression levels of p-JAK2/JAK2 and α7nAChR in spleen were lower(P<0.05, P<0.01), while p-STAT3/STAT3 protein expression was not significantly different. Besides, the two groups had no significant difference in the number of JAK2, p-JAK2, STAT3, and p-STAT3 cells. The results suggested that unilateral vagotomy promoted the increase of phosphorylated JAK2 and STAT3 expressions and exacerbated inflammation. In contrast, Ermiao Powder alleviated the inflammation in rheumatoid arthritis rats by activating the α7nAChR-mediated JAK2/STAT3 pathway through the vagus nerve, suggesting that the α7nAchR-JAK2/STAT3 pathway may be a potential target for the treatment of rheumatoid arthritis.

Electron stochastic acceleration in laboratory-produced kinetic turbulent plasmas.

The origin of energetic charged particles in universe remains an unresolved issue. Astronomical observations combined with simulations have provided insights into particle acceleration mechanisms, including magnetic reconnection acceleration, shock acceleration, and stochastic acceleration. Recent experiments have also confirmed that electrons can be accelerated through processes such as magnetic reconnection and collisionless shock formation. However, laboratory identifying stochastic acceleration as a feasible mechanism is still a challenge, particularly in the creation of collision-free turbulent plasmas. Here, we present experimental results demonstrating kinetic turbulence with a typical spectrum k-2.9 originating from Weibel instability. Energetic electrons exhibiting a power-law distribution are clearly observed. Simulations further reveal that thermal electrons undergo stochastic acceleration through collisions with multiple magnetic islands-like structures within the turbulent region. This study sheds light on a critical transition period during supernova explosion, where kinetic turbulences originating from Weibel instability emerge prior to collisionless shock formation. Our results suggest that electrons undergo stochastic acceleration during this transition phase.

PKM2 aggregation drives metabolism reprograming during aging process.

While protein aggregation's association with aging and age-related diseases is well-established, the specific proteins involved and whether dissolving them could alleviate aging remain unclear. Our research addresses this gap by uncovering the role of PKM2 aggregates in aging. We find that PKM2 forms aggregates in senescent cells and organs from aged mice, impairing its enzymatic activity and glycolytic flux, thereby driving cells into senescence. Through a rigorous two-step small molecule library screening, we identify two compounds, K35 and its analog K27, capable of dissolving PKM2 aggregates and alleviating senescence. Further experiments show that treatment with K35 and K27 not only alleviate aging-associated signatures but also extend the lifespan of naturally and prematurely aged mice. These findings provide compelling evidence for the involvement of PKM2 aggregates in inducing cellular senescence and aging phenotypes, and suggest that targeting these aggregates could be a promising strategy for anti-aging drug discovery.

SNX5-Rab11a protects against cardiac hypertrophy through regulating LRP6 membrane translocation.

BACKGROUNDS: Pathological cardiac hypertrophy is considered one of the independent risk factors for heart failure, with a rather complex pathogenic machinery. Sorting nexins (SNXs), denoting a diverse family of cytoplasmic- and membrane-associated phosphoinositide-binding proteins, act as a pharmacological target against specific cardiovascular diseases including heart failure. Family member SNX5 was reported to play a pivotal role in a variety of biological processes. However, contribution of SNX5 to the development of cardiac hypertrophy, remains unclear. METHODS: Mice underwent transverse aortic constriction (TAC) to induce cardiac hypertrophy and simulate pathological conditions. TAC model was validated using echocardiography and histological staining. Expression of SNX5 was assessed by western blotting. Then, SNX5 was delivered through intravenous administration of an adeno-associated virus serotype 9 carrying cTnT promoter (AAV9-cTnT-SNX5) to achieve SNX5 cardiac-specific overexpression. To assess the impact of SNX5, morphological analysis, echocardiography, histological staining, hypertrophic biomarkers, and cardiomyocyte contraction were evaluated. To unravel potential molecular events associated with SNX5, interactome analysis, fluorescence co-localization, and membrane protein profile were evaluated. RESULTS: Our results revealed significant downregulated protein level of SNX5 in TAC-induced hypertrophic hearts in mice. Interestingly, cardiac-specific overexpression of SNX5 improved cardiac function, with enhanced left ventricular ejection fraction, fraction shortening, as well as reduced cardiac fibrosis. Mechanistically, SNX5 directly bound to Rab11a, increasing membrane accumulation of Rab11a (a Rab GTPase). Afterwards, this intricate molecular interaction upregulated the membrane content of low-density lipoprotein receptor-related protein 6 (LRP6), a key regulator against cardiac hypertrophy. Our comprehensive assessment of siRab11a expression in HL-1 cells revealed its role in antagonism of LRP6 membrane accumulation under SNX5 overexpression. CONCLUSIONS: This study revealed that binding of SNX5 with LRP6 triggers their membrane translocation through Rab11a assisting, defending against cardiac remodeling and cardiac dysfunction under pressure overload. These findings provide new insights into the previously unrecognized role of SNX5 in the progression of cardiac hypertrophy.

High Prevalence of Antibiotic Resistance in Traditionally Fermented Foods as a Critical Risk Factor for Host Gut Antibiotic Resistome.

This study aimed to assess the suitability of fermented food interventions to replenish damaged gut microbiota. Metagenomic assessment of published sequencing data found that fermented food interventions led to a significant increase in the gut antibiotic resistome in healthy human subjects. Antibiotic resistome and viable antibiotic-resistant (AR) bacteria were further highly prevalent in retail kimchi and artisan cheeses by metagenomic and culture analyses. Representative AR pathogens of importance in nosocomial infections, such as Klebsiella pneumoniae, Serratia marcescens, and vancomycin-resistant Enterococcus (VRE), as well as commensals and lactic acid bacteria, were characterized; some exhibited an extremely high minimum inhibitory concentration (MIC) against antibiotics of clinical significance. Exposing fermented food microbiota to representative antibiotics further led to a boost of the corresponding antibiotic and multidrug-resistance gene pools, as well as disturbed microbiota, including the rise of previously undetectable pathogens. These results revealed an underestimated public health risk associated with fermented food intervention at the current stage, particularly for susceptible populations with compromised gut integrity and immune functions seeking gut microbiota rescue. The findings call for productive intervention of foodborne AR via technology innovation and strategic movements to mitigate unnecessary, massive damages to the host gut microbiota due to orally administered or biliary excreted antibiotics.

Harmonization of Longitudinal Diffusion Tensor Imaging Data of the Pediatric Cervical and Thoracic Spinal Cord at 3T Using Longitudinal ComBat.

Diffusion tensor imaging (DTI) of the spinal cord has been extensively used to identify biomarkers for spinal cord pathology. Previously, the longitudinal ComBat (longComBat) technique was examined to reduce scanner effects in multi-site, multi-scanner spinal cord DTI data. This study aimed to assess its effectiveness on longitudinal scans using a single-scanner pediatric dataset, including healthy and spinal cord injury (SCI) subjects. Two identical datasets were collected from 42 healthy and 27 SCI subjects with a 2-hour interval between scans on a 3T Siemens MRI scanner. Axial DTI images of the entire cervical and thoracic spinal cord were obtained, and various average diffusion tensor metrics (FA, MD, RD, & AD) were measured at each vertebral level. Pearson correlation and intraclass correlation coefficients were used to evaluate inter- and intra-subject agreement pre- and post-harmonization. Minimal improvement in agreement was observed with the mean square residual (MSR) model, while the restricted maximum likelihood estimator (REML) model showed reduced intra-subject agreement in all the tensor metrics. The significant variability between longitudinal DTI scans within a single scanner was likely due to physiological motion rather than scanner effects. Post-harmonization using the longComBat MSR model showed limited improvement in agreement.

Transcriptomic and Physiological Analysis Reveals the Possible Mechanism of Inhibiting Strawberry Aroma Changes by Ultrasound after Harvest.

The volatile compounds in strawberries play a significant role in the formation of strawberry aroma. However, these compounds undergo continual changes during storage, resulting in a decline in quality. In this study, a total of 67 volatile organic compounds (VOCs) were identified in strawberries through quantitative analysis. At the end of the storage period, the VOC content in the ultrasonic group was 119.02 µg/kg higher than that in the control group. The results demonstrated that the ultrasonic treatment increased the contents of terpenes and esters at the end of storage. Among these, linalool increased from 67.09 to 91.41 µg/kg, while ethyl cinnamate increased from 92.22 to 106.79 µg/kg. Additionally, the expression of the key metabolic genes closely related to these substances was significantly up-regulated. The expression of the FaNES gene, related to terpene metabolism, was up-regulated by 2.8 times in the second day, while the expression of the FaAAT gene, related to ester metabolism, was up-regulated by 1.5 times. In summary, this study provides a theoretical basis for exploring the mechanism of ultrasonic effect on strawberry flavor and quality after harvest.

Current landscape of fecal microbiota transplantation in treating depression.

Depression, projected to be the predominant contributor to the global disease burden, is a complex condition with diverse symptoms including mood disturbances and cognitive impairments. Traditional treatments such as medication and psychotherapy often fall short, prompting the pursuit of alternative interventions. Recent research has highlighted the significant role of gut microbiota in mental health, influencing emotional and neural regulation. Fecal microbiota transplantation (FMT), the infusion of fecal matter from a healthy donor into the gut of a patient, emerges as a promising strategy to ameliorate depressive symptoms by restoring gut microbial balance. The microbial-gut-brain (MGB) axis represents a critical pathway through which to potentially rectify dysbiosis and modulate neuropsychiatric outcomes. Preclinical studies reveal that FMT can enhance neurochemicals and reduce inflammatory markers, thereby alleviating depressive behaviors. Moreover, FMT has shown promise in clinical settings, improving gastrointestinal symptoms and overall quality of life in patients with depression. The review highlights the role of the gut-brain axis in depression and the need for further research to validate the long-term safety and efficacy of FMT, identify specific therapeutic microbial strains, and develop targeted microbial modulation strategies. Advancing our understanding of FMT could revolutionize depression treatment, shifting the paradigm toward microbiome-targeting therapies.

Nano co-delivery of doxorubicin and plumbagin achieves synergistic chemotherapy of hepatocellular carcinoma.

Doxorubicin (DOX) is a chemotherapy drug used for hepatocellular carcinoma (HCC) treatment, but its effectiveness can be dramatically dampened by cancer cell chemoresistance. Signal transducer and activator of transcription 3 (STAT3) is implicated with drug resistance in a range of cancers (e.g., HCC), and the STAT3 inhibition can reverse the resistance of cancer cells to chemotherapeutic drugs. In the present study, a combination regimen to improve the efficiency of DOX was provided via the STAT3 blockade using plumbagin (PLB). A poly(lactic-co-glycolic acid) decorated by polyethylene glycol and aminoethyl anisamide was produced in the present study with the hope of generating the nanoparticles for co-delivery of DOX and PLB. The resulting co-formulation suppressed the STAT3 activity and achieved the synergistic chemotherapy, which led to tumor inhibition in the mice with subcutaneous DOX-resistant HCC, without causing any toxicity. The present study reveals the synergism of DOX and PLB, and demonstrates a promising combinatorial approach for treating HCC.

Interaction mechanism and compatibility studies of silk protein peptide (SPP) with the common surfactants SDS and DTAB.

The molecular interaction of low-molecular-weight SPP with common surfactants (SDS and DTAB) is a more complicated process than has been long believed. In this work, the interaction mechanism between SDS/DTAB and SPP was proposed using multiple methods including conductivity measurements, ST, UV-vis, FT-IR, DLS, fluorescence spectroscopy, and molecular docking simulations. Moreover, the foaming properties of the mixed systems were studied, and they were evaluated as cosmetics preservatives. The effects of various surfactant and protein concentrations and ratios on compatibility and functionality were studied. Based on the results, the mechanism of complex formation was identified as a cooperative van der Waals interaction followed by hydrophobic interaction and hydrogen bonding. A simpler head group leads to easier aggregation and interaction with the SPP, the formation of smaller-sized complexes, and a weaker impact on the fluorescence intensity. Thus, SDS monomers easily aggregate on SPP chains, leading to a stronger influence on the final secondary structure of SPP. This was confirmed by multiple spectroscopy methods. Comparing its single surfactant system, the SDS-SPP solution demonstrates better foaming power and the DTAB-SPP solution shows higher bacteriostatic activity. The good compatibility between SDS/DTAB and SPP can improve the functional properties of SDS or DTAB as well as lower the optimal concentration of each component. These results provide data and theoretical support for the design of cosmetic product formulas.

Dual-Temperature/pH-Sensitive Hydrogels with Excellent Strength and Toughness Crosslinked Using Three Crosslinking Methods.

Hydrogels are widely used as excellent drug carriers in the field of biomedicine. However, their application in medicine is limited by their poor mechanical properties and softness. To improve the mechanical properties of hydrogels, a novel triple-network amphiphilic hydrogel with three overlapping crosslinking methods using a one-pot free-radical polymerization was synthesized in this study. Temperature-sensitive and pH-sensitive monomers were incorporated into the hydrogel to confer stimulus responsiveness, making the hydrogel stimuli-responsive. The successful synthesis of the hydrogel was confirmed using techniques, such as proton nuclear magnetic resonance spectroscopy (1H NMR), Fourier-transform infrared spectroscopy (FT-IR), and X-ray diffraction (XRD). In order to compare and analyze the properties of physically crosslinked hydrogels, physically-chemically double-crosslinked hydrogels, and physically-chemically clicked triple-crosslinked hydrogels, various tests were conducted on the gels' morphology, swelling behavior, thermal stability, mechanical properties, and drug loading capacity. The results indicate that the triple-crosslinked hydrogel maintains low swelling, high mechanical strength, and good thermal stability while not significantly compromising its drug delivery capability.

Asian Screening Array and Next-Generation Sequencing Based Panels Applied to Preimplantation Genetic Testing for Monogenic Disorders Preclinical Workup in 294 Families: A Retrospective Analysis.

OBJECTIVE: Currently, the most commonly used methods for linkage analysis of pre-implantation genetic testing for monogenic disorders (PGT-M) are next generation sequencing (NGS) and SNP array. We aim to investigate whether the application efficacy of Asian screening array (ASA) in PGT-M preclinical workup for the Chinese population is superior to NGS based single nucleotide polymorphism (SNP) panels. METHODS: We conducted a retrospective analysis by reviewing 294 couples from a single center over the past 4 years and compared the detection results between NGS-based SNP panels and ASA. Using the numbers of informative SNPs upstream and downstream flanking of variants, we assessed the detection efficiency of both methods in monogenic diseases, chromosomal microdeletion syndrome and males with de novo variants, among other scenarios. RESULTS: Results indicate that ASA offers a greater number of informative SNPs compared with NGS-based SNP panels. Additionally, data analysis for ASA is generally more straightforward and may require less computational resources. While ASA can address most PGT-M challenges, we have also identified certain genes in previous tests that are not suitable for PGT-M using ASA. CONCLUSION: The application of ASA in PGT-M preclinical workup for Chinese populations has good practical value as it can perform linkage analysis for most genetic variants. However, for certain variants, NGS or other testing methods, such as mutated allele revealed by sequencing with aneuploidy and linkage analysis (MARSALA), may still be necessary for completion.

Organosiloxane-Modified Auricularia Polysaccharide (Si-AP): Improved High-Temperature Resistance and Lubrication Performance in WBDFs.

This study introduces a novel organosilicon-modified polysaccharide (Si-AP) synthesized via grafting and comprehensively evaluates its performance in water-based drilling fluids (WBDFs). The molecular structure of Si-AP was characterized using Fourier-transform infrared spectroscopy (FTIR) and 1H-NMR experiments. Thermalgravimetric analysis (TGA) confirmed the good thermal stability of Si-AP up to 235 °C. Si-AP significantly improves the rheological properties and fluid loss performance of WBDFs. With increasing Si-AP concentration, system viscosity increases, API filtration rate decreases, clay expansion is inhibited, and drilling cuttings hydration dispersion is suppressed, especially under high-temperature conditions. Additionally, mechanistic analysis indicates that the introduction of siloxane groups can effectively inhibit the thermal degradation of AP chains and enhance their high-temperature resistance. Si-AP can form a lubricating film by adsorbing on the surface of clay particles, improving mud cake quality, reducing the friction coefficient, and significantly enhancing the lubricating performance of WBDFs. Overall, Si-AP exhibits a higher temperature-resistance limit compared to AP and more effectively optimizes the lubrication, inhibition, and control of the filtration rate of WBDFs under high-temperature conditions. While meeting the requirements of drilling fluid systems under high temperatures, Si-AP also addresses environmental concerns and holds promise as an efficient solution for the exploitation of deep-seated oil and gas resources.

Multimodal and hemispheric graph-theoretical brain network predictors of learning efficacy for frontal alpha asymmetry neurofeedback.

EEG neurofeedback using frontal alpha asymmetry (FAA) has been widely used for emotion regulation, but its effectiveness is controversial. Studies indicated that individual differences in neurofeedback training can be traced to neuroanatomical and neurofunctional features. However, they only focused on regional brain structure or function and overlooked possible neural correlates of the brain network. Besides, no neuroimaging predictors for FAA neurofeedback protocol have been reported so far. We designed a single-blind pseudo-controlled FAA neurofeedback experiment and collected multimodal neuroimaging data from healthy participants before training. We assessed the learning performance for evoked EEG modulations during training (L1) and at rest (L2), and investigated performance-related predictors based on a combined analysis of multimodal brain networks and graph-theoretical features. The main findings of this study are described below. First, both real and sham groups could increase their FAA during training, but only the real group showed a significant increase in FAA at rest. Second, the predictors during training blocks and at rests were different: L1 was correlated with the graph-theoretical metrics (clustering coefficient and local efficiency) of the right hemispheric gray matter and functional networks, while L2 was correlated with the graph-theoretical metrics (local and global efficiency) of the whole-brain and left the hemispheric functional network. Therefore, the individual differences in FAA neurofeedback learning could be explained by individual variations in structural/functional architecture, and the correlated graph-theoretical metrics of learning performance indices showed different laterality of hemispheric networks. These results provided insight into the neural correlates of inter-individual differences in neurofeedback learning. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-023-09939-x.

Gut microbiome and metabolome alterations in traditional Chinese medicine damp-heat constitution following treatment with a Chinese patent medicine and lifestyle intervention.

BACKGROUND: The gut microbiota is crucial in human health and diseases. Traditional Chinese Medicine Constitution (TCMC) divides people into those with a balanced constitution (Ping-he [PH]) and those with an unbalanced constitution. Dampness-heat constitution (Shi-re [SR]) is a common unbalanced constitution in the Chinese population and is susceptible to diseases. However, unbalanced constitutions can be regulated by Chinese medicine and lifestyle interventions in clinical practice. Ermiao Pill (EMP) is a Chinese medicine known for clearing heat and draining dampness and improving SR. However, the efficacy and mechanism of EMP are unclear. HYPOTHESIS/PURPOSE: To determine alterations in the gut microbiota and metabolome in SR and any changes after EMP treatment combined with lifestyle intervention. STUDY DESIGN: Randomized clinical trial. METHODS: We enrolled 112 healthy SR individuals and evaluated the efficacy of EMP along with lifestyle interventions. We further assessed serum cytokine levels, serum and urinary metabolomes, and the gut microbiota by 16S rRNA gene sequencing analysis before and after the EMP and lifestyle interventions. RESULTS: 107 SR individuals (55 in the intervention group and 52 in the control group) completed the 1-month-intervention and 1-year-follow-up. The intervention group significantly improved their health status within 1 month, with a reduced SR symptom score, and the efficacy lasted to the 1-year follow-up. The control group needed a further 6 months to reduce the SR symptom score. The gut microbiota of PH individuals was more diverse and had significantly higher proportions of many bacterial species than the SR. Microbiota co-occurrence network analysis showed that SR enriches metabolites correlating with microbial community structure, consistent with traits of healthy SR-enriched microbiota. CONCLUSION: EMP combined with lifestyle intervention produced health benefits in SR individuals. Our study indicates a pivotal role of gut microbiota and metabolome alterations in distinguishing between healthy SR and PH. Furthermore, the study reveals structural changes of gut microbiota and metabolites induced by EMP and lifestyle intervention. The treatment enriched the number of beneficial bacteria, such as Akkermansia muciniphila and Lactobacillus in the gut. Our findings provide a strong indication that several metabolite factors are associated with the gut microbiota. Moreover, the gut microbiome and metabolome might be powerful tools for TCMC diagnosis and personalized therapy.

Cytotoxic xanthanolide sesquiterpenes from the fruits of Xanthium italicum Moretti.

One previously undescribed xanthanolide sesquiterpene dimer pungiolide P (1), possessing an unprecedented scaffold with a 5/7/5/7/5 ring system skeleton and its intermediate pungiolide Q (2), ten xanthanolide sesquiterpenes (3-12), two eudesmene sesquiterpene derivatives (13-14), one phenylpropionic acid derivative (15), together with eleven known compounds (16-26) were obtained from the fruits of Xanthium italicum Moretti. A possible biosynthetic pathway for pungiolide P (1) was also proposed, which was supported by its bio-synthetic intermediate (2). Compounds 1, 4-5, 18-21, and 25 exhibited cytotoxic activity against a variety of human cancer cell lines. Furthermore, compounds 1, 4-5, could cause blockage of the cell cycle in the G2/M phase and induce apoptosis in H460 cells. Notably, pungiolide P (1) exhibited significantly superior cytotoxicity compared to previously reported compounds, providing valuable insights for natural anti-tumor sources.

Screening of potential drugs for the treatment of diabetic kidney disease using single-cell transcriptome sequencing and connectivity map data.

OBJECTIVE: To explore the feasibility of screening potential drugs for the treatment of diabetic kidney disease (DKD) using a single-cell transcriptome sequencing dataset and Connectivity Map (CMap) database screening. METHODS: A DKD single-nucleus transcriptome sequencing dataset was analyzed using Seurat 4.0 to obtain specific podocyte subclusters and differentially expressed genes (DEGs) related to DKD. These DEGs were subsequently subjected to a search against the CMap database to screen for drug candidates. Cell and animal experiments were conducted to evaluate the efficacy of the top 3 drug candidates. RESULTS: Initially, we analyzed the DKD single-nucleus transcriptome sequencing dataset to obtain intrinsic renal cells such as podocytes, endothelial cells, mesangial cells, proximal tubular cells, collecting duct cells and immune cells. Podocytes were further divided into four subclusters, among which the proportion of POD_1 podcytes was significantly greater in DKD kidneys than in control kidneys (34.0 % vs. 3.4 %). The CMap database was searched using the identified DEGs in the POD_1 subcluster, and the drugs, including tozasertib, paroxetine, and xylazine, were obtained. Cell-based experiments showed that tozasertib, paroxetine and xylazine had no significant podocyte toxicity in the concentration range of 0.01-50 µM. Tozasertib, paroxetine, and xylazine all reversed the advanced glycation end products (AGEs)-induced decrease in podocyte marker levels, but the effect of paroxetine was more prominent. Animal experiments showed that paroxetine decreased urine ALB/Cr levels in DKD model mice by approximately 51.5 % (115.7 mg/g vs. 238.8 mg/g, P < 0.05). Histopathological assessment revealed that paroxetine attenuated basement membrane thickening, restored the number of foot processes of podocytes, and reduced foot process fusion. In addition, paroxetine also attenuated renal tubular-interstitial fibrosis. Mechanistically, paroxetine inhibited the expression of GRK2 and NLRP3, decreased the phosphorylation level of p65, restored NRF2 expression, and relieved inflammation and oxidative stress. CONCLUSION: This strategy based on single-cell transcriptome sequencing and CMap data can facilitate the identification and aid the rapid development of clinical DKD drugs. Paroxetine, screened by this strategy, has excellent renoprotective effects.