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Due to the challenges of antibiotic resistance to global health, bacteriocins as antimicrobial compounds have received more and more attention. Bacteriocins are biosynthesized by various microbes and are predominantly used as food preservatives to control foodborne pathogens. Now, increasing researches have focused on bacteriocins as potential clinical antimicrobials or immune-modulating agents to fight against the global threat to human health. Given the broad- or narrow-spectrum antimicrobial activity, bacteriocins have been reported to inhibit a wide range of clinically pathogenic and multidrug-resistant bacteria, thus preventing the infections caused by these bacteria in the human body. Otherwise, some bacteriocins also show anticancer, anti-inflammatory, and immune-modulatory activities. Because of the safety and being not easy to cause drug resistance, some bacteriocins appear to have better efficacy and application prospects than existing therapeutic agents do. In this review, we highlight the potential therapeutic activities of bacteriocins and suggest opportunities for their application.

Background Sleep disorders occur frequently among patients with Parkinson’s disease (PD). Neurotransmitters and neurosteroids are known to be involved in various neurophysiological processes, including sleep development. We aimed to assess the associations of peripheral neurotransmitter and neurosteroid levels with various sleep disorders in early-stage PD. Methods Fifty-nine patients with early-stage PD and 30 healthy controls were enrolled. Demographic and clinical data were collected, and sleep conditions were comprehensively assessed with clinical questionnaires and polysomnography. Blood samples were obtained from all participants at 1:00 AM and 9:00 AM. The concentrations of plasma neurotransmitters and neurohormones were detected via high-performance liquid chromatography tandem mass spectrometry. Results Sleep disorders were common nonmotor symptoms (81.4%) and coexisted in approximately half of the patients. Dysautonomia was significantly associated with the presence of multiple sleep disorders. RBD was associated with dysautonomia and was negatively correlated with the plasma melatonin concentration at 1:00 AM (r = − 0.40, p  = 0.002) in early-stage PD patients. The RLS group had higher PSQI scores, and RLS was negatively associated with the 5-hydroxytryptamine levels (r = − 0.40, p  = 0.002) at 1:00 AM and glutamine levels (r = − 0.39, p  = 0.002) at 9:00 AM. SDB was associated with cognitive impairment, a greater body mass index, and lower plasma acetylcholine concentrations at 1:00 AM. Conclusion Combined sleep disturbances are common in early-stage PD. Dysautonomia is closely related to various sleep disorders, including RBD, EDS, and insomnia. Changes in peripheral neurotransmitter and neurohormone levels may be involved in the development of sleep disorders. Plain English Summary Many people with Parkinson’s disease (PD) experience sleep problems. Chemicals in the body called neurotransmitters and neurosteroids play a role in sleep regulation. This study looked at how levels of these chemicals in the blood might be linked to sleep disorders in people with early-stage PD. We found that sleep problems were very common in PD patients (81.4%), and about half had multiple sleep issues. Dysautonomia was linked to multiple sleep disorders. REM sleep behavior disorder (RBD) was linked to dysautonomia and lower levels of melatonin at 1:00 AM, restless legs syndrome (RLS) was associated with poorer sleep quality and lower levels of serotonin and glutamine at different times. Sleep-disordered breathing (SDB) was linked to memory problems, higher body weight, and lower levels of acetylcholine at 1:00 AM. Understanding these links could help improve sleep treatments for PD patients.

This study mimics the metabolic environment of metabolic dysfunction-associated steatotic liver disease (MASLD) and diabetic mellitus (DM) to investigate the function of BRCA1 in regulating glucose and lipid metabolism in hepatocytes under high glucose (HG) settings. MASLD and DM-related datasets (GSE89632, GSE95849) were screened for overlapping genes, Protein-Protein Interaction (PPI) network and enrichment analyses were performed. Then, quantitative real-time polymerase chain reaction (qRT-PCR), Western Blotting (WB), and enzymatic colorimetric assays to examine the expression changes of BRCA1 in mouse primary hepatocytes under HG conditions and the impact of the combined PI3K/Akt signaling pathway on key metabolic markers of gluconeogenesis and lipid metabolism. Our study identified seven key overlapping genes (AURKA, BRCA1, ISG15, NUSAP1, OAS1, RSAD2, TLR7) between MASLD and DM. Experiments found that when BRCA1 was overexpressed in mouse primary hepatocytes, intracellular triglyceride content and lipid metabolism-related biomarkers (such as PEPCK, SREBP-1c, G6Pase, and FAS) were significantly increased in HG circumstances. However, the knockdown of BRCA1 reduced the expression of these indicators. Besides, we also observed that under HG conditions, the expression of proteins linked to the PI3K/Akt signaling pathway was negatively regulated by BRCA1 expression. Moreover, TG content and expression of lipid metabolism markers are also regulated by BRCA1 and PI3K/Akt pathway inhibitor Ly294002. As a key regulator of hepatocyte metabolism under HG conditions, BRCA1 can participate in regulating glucose and lipid metabolism in mouse primary hepatocytes through the PI3K/AKT signaling pathway, which be able to become a possible remedy strategy for DM with MASLD.

Background Accurately forecasting the prognosis could improve cervical cancer management, however, the currently used clinical features are difficult to provide enough information. The aim of this study is to improve forecasting capability by developing a miRNAs-based machine learning survival prediction model. Results The expression characteristics of miRNAs were chosen as features for model development. The cervical cancer miRNA expression data was obtained from The Cancer Genome Atlas database. Preprocessing, including unquantified data removal, missing value imputation, samples normalization, log transformation, and feature scaling, was performed. In total, 42 survival-related miRNAs were identified by Cox Proportional-Hazards analysis. The patients were optimally clustered into four groups with three different 5-years survival outcome (≥ 90%, ≈ 65%, ≤ 40%) by K-means clustering algorithm base on top 10 survival-related miRNAs. According to the K-means clustering result, a prediction model with high performance was established. The pathways analysis indicated that the miRNAs used play roles involved in the regulation of cancer stem cells. Conclusion A miRNAs-based machine learning cervical cancer survival prediction model was developed that robustly stratifies cervical cancer patients into high survival rate (5-years survival rate ≥ 90%), moderate survival rate (5-years survival rate ≈ 65%), and low survival rate (5-years survival rate ≤ 40%).

Objective The aim of this study is to evaluate an AAV vector that can selectively target breast cancer cells and to investigate its specificity and anti-tumor effects on breast cancer cells both in vitro and in vivo, offering a new therapeutic approach for the treatment of EpCAM-positive breast cancer. Methods In this study, a modified AAV2 viral vector was used, in which EpCAM-specific DARPin EC1 was fused to the VP2 protein of AAV2, creating a viral vector that can target breast cancer cells. The targeting ability and anti-tumor effects of this viral vector were evaluated through in vitro and in vivo experiments. Results The experimental results showed that the AAV2M EC1 virus could specifically infect EpCAM-positive breast cancer cells and accurately deliver the suicide gene HSV-TK to tumor tissue in mice, significantly inhibiting tumor growth. Compared to the traditional AAV2 viral vector, the AAV2M EC1 virus exhibited reduced accumulation in liver tissue and had no impact on tumor growth. Conclusion This study demonstrates that AAV2M EC1 is a gene delivery vector capable of targeting breast cancer cells and achieving selective targeting in mice. The findings offer a potential gene delivery system and strategies for gene therapy targeting EpCAM-positive breast cancer and other tumor types.

Long noncoding RNAs are widely implicated in diverse disease processes. Nonetheless, their regulatory roles in bone resorption are undefined. Here, we identify lncRNA Nron as a critical suppressor of bone resorption. We demonstrate that osteoclastic Nron knockout mice exhibit an osteopenia phenotype with elevated bone resorption activity. Conversely, osteoclastic Nron transgenic mice exhibit lower bone resorption and higher bone mass. Furthermore, the pharmacological overexpression of Nron inhibits bone resorption, while caused apparent side effects in mice. To minimize the side effects, we further identify a functional motif of Nron. The delivery of Nron functional motif to osteoclasts effectively reverses bone loss without obvious side effects. Mechanistically, the functional motif of Nron interacts with E3 ubiquitin ligase CUL4B to regulate ERα stability. These results indicate that Nron is a key bone resorption suppressor, and the lncRNA functional motif could potentially be utilized to treat diseases with less risk of side effects. LncRNAs are implicated in the pathogenesis of a number of diseases. Here, the authors show that the lncRNA Nron suppresses bone resorption, and show that delivery of a functional motif of Nron increases bone mass in mouse models of osteoporosis.

[This corrects the article DOI: 10.1371/journal.pone.0083132.].

The Yiqi Qubai (YQ) formula is a hospital preparation for treating vitiligo in China that has had reliable efficacy for decades. The formula consists of four herbs; however, the extraction process to produce the formula is obsolete and the active ingredients and mechanisms remain unknown. Therefore, in this paper, fingerprints were combined with the chemometrics method to screen high-quality herbs for the preparation of the YQ standard decoction (YQD). Then, the YQD preparation procedure was optimized using response surface methodology. A total of 44 chemical constituents, as well as 36 absorption components (in rat plasma) of YQD, were identified via UPLC-Q-TOF/MS. Based on the ingredients, the quality control system of YQD was optimized by establishing the SPE-UPLC-Q-TOF/MS identification method and the HPLC quantification method. Network pharmacological analysis and molecular docking showed that carasinaurone, calycosin-7-O-β-d-glucoside, methylnissolin-3-O-glucoside, genkwanin, akebia saponin D, formononetin, akebia saponin B, and apigenin may be the key active components for treating vitiligo; the core targets associated with them were AKT1, MAPK1, and mTOR, whereas the related pathways were the PI3K-Akt, MAPK, and FoxO signaling pathways. Cellular assays showed that YQD could promote melanogenesis and tyrosinase activity, as well as the transcription and expression of tyrosinase-associated proteins (i.e., TRP-1) in B16F10 cells. In addition, YQD also increased extracellular tyrosinase activity. Further efficacy validation showed that YQD significantly promotes melanin production in zebrafish. These may be the mechanisms by which YQD improves the symptoms of vitiligo. This is the first systematic study of the YQ formula that has optimized the standard decoction preparation method and investigated the active ingredients, quality control, efficacy, and mechanisms of YQD. The results of this study lay the foundations for the clinical application and further development of the YQ formula.

Summary Uncovering the mechanisms underlying stress‐resistant traits in xerophytes thriving in harsh environments can aid the genetic improvement of crops. The xerophyte Zygophyllum xanthoxylum features high Na+ accumulation in leaves, mediated by the vacuolar antiporter ZxNHX1. Co‐expression of ZxNHX1 and vacuolar H+‐PPase gene ZxVP1‐1 has been demonstrated to enhance the stress resistance and biomass of alfalfa. However, it remains unknown if ZxNHX1 outperforms its homologues from the Na+‐excluding and stress‐sensitive glycophytes such as Arabidopsis in enhancing plant stress resistance and yield. Here, we found that expression of ZxNHX1 conferred superior growth under salt stress in alfalfa, compared to the Arabidopsis homologue AtNHX1. When expressed in yeast, ZxNHX1 displays stronger Na+/H+ but weaker K+/H+ exchange activity than AtNHX1. Under both K+ sufficient and deficient conditions, an Arabidopsis atnhx1‐1 mutant expressing ZxNHX1 accumulated higher Na+ and lower K+ concentrations, with more Na+ being sequestered into vacuoles and a larger proportion of K+ retained in the cytosol. This optimized cellular ion distribution ensures energy‐conserving osmotic adjustment, leading to stronger stress resistance and higher biomass than plants expressing AtNHX1. Moreover, ZxNHX1 governed the root uptake and root‐to‐leaf transport of Na+ at the whole‐plant level, whereas AtNHX1 acted mainly in K+ transport processes. We also identified a polar residue Thr265 in a membrane‐spanning region of ZxNHX1 that influences its Na+ and K+ selectivity. These findings reveal a new energy‐conserving, Na+‐based osmotic adjustment mechanism that can enhance crop stress resistance without sacrificing yield, providing an effective way for utilizing saline soils to expand crop production into marginal lands.

Background Pyroptosis is a form of programmed cell death involved in the pathophysiological progression of hypoxic pulmonary hypertension (HPH). Emerging evidence suggests that N6-methyladenosine (m6A)-modified transcripts of long noncoding RNAs (lncRNAs) are important regulators that participate in many diseases. However, whether m6A modified transcripts of lncRNAs can regulate pyroptosis in HPH progression remains unexplored. Methods The expression levels of FENDRR in hypoxic pulmonary artery endothelial cells (HPAECs) were detected by using quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH). Western blot, Lactate dehydrogenase (LDH) release assay, Annexin V-FITC/PI double staining, Hoechst 33342/PI fluorescence staining and Caspase-1 activity assay were used to detect the role of FENDRR in HPAEC pyroptosis. The relationship between FENDRR and dynamin-related protein 1 (DRP1) was explored using bioinformatics analysis, Chromatin Isolation by RNA Purification (CHIRP), Electrophoretic mobility shift assay (EMSA) and Methylation-Specific PCR (MSP) assays. RNA immunoprecipitation (RIP) and m6A dot blot were used to detect the m6A modification levels of FENDRR. A hypoxia-induced mouse model of pulmonary hypertension (PH) was used to test preventive effect of conserved fragment TFO2 of FENDRR. Results We found that FENDRR was significantly downregulated in the nucleus of hypoxic HPAECs. FENDRR overexpression inhibited hypoxia-induced HPAEC pyroptosis. Additionally, DRP1 is a downstream target gene of FENDRR, and FENDRR formed an RNA–DNA triplex with the promoter of DRP1, which led to an increase in DRP1 promoter methylation that decreased the transcriptional level of DRP1. Notably, we illustrated that the m6A reader YTHDC1 plays an important role in m6A-modified FENDRR degradation. Additionally, conserved fragment TFO2 of FENDEE overexpression prevented HPH in vivo. Conclusion In summary, our results demonstrated that m6A-induced decay of FENDRR promotes HPAEC pyroptosis by regulating DRP1 promoter methylation and thereby provides a novel potential target for HPH therapy.