Antimicrobial sensitisers: Gatekeepers to avoid the development of multidrug-resistant bacteria.

The resistance of multidrug-resistant bacteria to existing antibiotics forces the continued development of new antibiotics and antibacterial agents, but the high costs and long timeframe involved in the development of new agents renders the hope that existing antibiotics may again play a part. The "antibiotic adjuvant" is an indirect antibacterial strategy, but its vague concept has, in the past, limited the development speed of related drugs. In this review article, we put forward an accurate concept of a "non-self-antimicrobial sensitisers (NSAS)", to distinguish it from an "antibiotic adjuvant", and then discuss several scientific methods to restore bacterial sensitivity to antibiotics, and the sources and action mechanism of existing NSAS, in order to guide the development and further research of NSAS.

Mapping the 5-HTergic neural pathways in perimenopausal mice and elucidating the role of oestrogen receptors in 5-HT neurotransmission.

Perimenopausal syndrome (PMS) encompasses neuropsychiatric symptoms, such as hot flashes and depression, which are associated with alterations in the 5-HTergic neural pathway in the brain. However, the specific changes and mechanisms underlying these alterations remain unclear. In this study, ovariectomized mice were used to successfully establish a perimenopause model, and the changes in the expression of 5-HT and its receptors (5-HT1AR and 5-HT2AR) across 72 brain regions in these ovariectomized mice were assessed by immunohistochemistry. Although both 5-HT and 5-HT1AR were widely expressed throughout the brain, only a limited number of regions expressed 5-HT2AR. Notably, decreased expression of 5-HT was observed across almost all brain regions in the ovariectomy (OVX) group compared with the Sham group. Altered expression of both receptors was found within areas related to hot flashes (the preoptic area) or mood disorders (the amygdala). Additionally, reduced oestrogen receptor (ER)α/ß expression was detected in cells in the raphe nucleus (RN), an area known to regulate body temperature. Results showed that ERα/ß positively regulate the transcriptional activity of the enzymes TPH2/MAOA, which are involved in serotonin metabolism during perimenopause. This study revealed the changes in 5-HT neuropathways (5-HT, 5-HT1AR and 5-HT2AR) in perimenopausal mice, mainly in brain regions related to regulation of the body temperature, mood, sleep and memory. This study clarified that the expression of oestrogen receptor decreased in perimenopause, which regulated the transcription levels of TPH2 and MAOA, and ultimately led to the reduction of 5-HT content, providing a new target for clinical diagnosis and treatment of perimenopausal diseases.

Hybrid Edge Results in Narrowed Band Gap: Bottom-up Liquid-Phase Synthesis of Bent N = 6/8 Armchair Graphene Nanoribbons.

Scalable fabrication of graphene nanoribbons with narrow band gaps has been a nontrivial challenge. Here, we have developed a simple approach to access narrow band gaps using hybrid edge structures. Bottom-up liquid-phase synthesis of bent N = 6/8 armchair graphene nanoribbons (AGNRs) has been achieved in high efficiency through copolymerization between an o-terphenyl monomer and a naphthalene-based monomer, followed by Scholl oxidation. An unexpected 1,2-aryl migration has been discovered, which is responsible for introducing kinked structures into the GNR backbones. The N = 6/8 AGNRs have been fully characterized to support the proposed structure and show a narrow band gap and a relatively high electrical conductivity. In addition, their application in efficient gas sensing has also been demonstrated.

Derivatives of the Fungal Natural Product Illudalic Acid Inhibit the Activity of Protein Histidine Phosphatase PHPT1.

PHPT1 is a protein histidine phosphatase that has been implicated in several disease pathways, but the chemical tools necessary to study the biological roles of this enzyme and investigate its utility as a therapeutic target have yet to be developed. To this end, the discovery of PHPT1 inhibitors is an area of significant interest. Here, we report an investigation of illudalic acid and illudalic acid analog-based inhibition of PHPT1 activity. Four of the seven analogs investigated had IC50 values below 5 µM, with the most potent compound (IA1-8H2) exhibiting an IC50 value of 3.4±0.7 µM. Interestingly, these compounds appear to be non-covalent, non-competitive inhibitors of PHPT1 activity, in contrast to other recently reported PHPT1 inhibitors. Mutating the three cysteine residues to alanine has no effect on inhibition, indicating that cysteine is not critical for interactions between inhibitor and enzyme.

Revitalizing Skin Repair: Unveiling the Healing Power of Livisin, a Natural Peptide Calcium Mimetic.

When the skin is damaged, accelerating the repair of skin trauma and promoting the recovery of tissue function are crucial considerations in clinical treatment. Previously, we isolated and identified an active peptide (livisin) from the skin secretion of the frog Odorrana livida. Livisin exhibited strong protease inhibitory activity, water solubility, and stability, yet its wound-healing properties have not yet been studied. In this study, we assessed the impact of livisin on wound healing and investigated the underlying mechanism contributing to its effect. Our findings revealed livisin effectively stimulated the migration of keratinocytes, with the underlying mechanisms involved the activation of CaSR as a peptide calcium mimetic. This activation resulted in the stimulation of the CaSR/E-cadherin/EGFR/ERK signaling pathways. Moreover, the therapeutic effects of livisin were partially reduced by blocking the CaSR/E-cadherin/EGFR/ERK signaling pathway. The interaction between livisin and CaSR was further investigated by molecular docking. Additionally, studies using a mouse full-thickness wound model demonstrated livisin could accelerate skin wound healing by promoting re-epithelialization and collagen deposition. In conclusion, our study provides experimental evidence supporting the use of livisin in skin wound healing, highlighting its potential as an effective therapeutic option.

Glutamatergic and GABAergic neurons in the preoptic area of the hypothalamus play key roles in menopausal hot flashes.

During menopause, when estrogen levels are low, abnormalities in the hypothalamic preoptic area (POA) of the thermoregulatory center can cause hot flashes. However, the involved neural population has not been identified. Proteomics showed that under low estrogen, differentially expressed proteins in the hypothalamus were associated with glutamatergic and GABAergic synapses. RNAscope, Western blotting and qRT-PCR indicated that the number of glutamatergic neurons in the POA was decreased, while the number of GABAergic neurons was increased. Chemogenetics showed that the rat body temperature decreased slowly after glutamatergic neurons were activated and increased quickly after glutamatergic neurons were inhibited, while it increased quickly after GABAergic neurons were activated and decreased slowly after GABAergic neurons were inhibited. RNAscope, immunofluorescence, Western blotting and qRT-PCR further showed that glutamate decarboxylase (GAD) 1 expression in the POA was increased, while GAD2 expression in the POA was decreased; that thermosensitive transient receptor potential protein (ThermoTRP) M (TRPM) 2 expression in glutamatergic neurons was decreased, while TRPM8 expression in GABAergic neurons was increased; and that estrogen receptor (ER) α and ß expression in the POA was decreased, and ERα and ERß expressed in both glutamatergic and GABAergic neurons. Estrogen therapy corrected these abnormalities. In addition, CUT&Tag and Western blot after injection of agonists and inhibitors of ERs showed that ERα and ERß were both transcription factors in glutamatergic and GABAergic synapses. Mechanistically, during menopause, estrogen may regulate the transcription and expression of GADs and ThermoTRPs through ERs, impacting the number and function of glutamatergic and GABAergic neurons, resulting in unbalanced heat dissipation and production in the POA and ultimately triggering hot flashes.

Changes in vesicular glutamate transporter 2 (Vglut2) and vesicular GABA transporter 1 (Vgat1) in the orofacial pain and temperature perception pathway under low estrogen conditions.

OBJECTIVE: To investigate the effects of estrogen on the threshold and temperature of orofacial pain and explore the influence on the function of glutamate and GABA neurons in the orofacial pain temperature perception pathway by observing the expression of vesicular glutamate transporter 2 (Vglut2) and vesicular GABA transporter 1 (Vgat1). METHODS: A total of 24 adult female Sprague-Dawley rats were divided into three groups: sham operation (SHAM), ovariectomized (OVX) and ovariectomized plus estrogen intervention (OVX+E) (n = 8 per group). The threshold of mechanical pain of the orofacial region was assessed with von Frey filaments, and the temperature of the rat orofacial region was monitored by infrared thermography. Changes in the expression of Vglut2 and Vgat1 in glutamatergic and GABAergic neurons in the trigeminal ganglion (TG), spinal trigeminal nucleus (Sp5C), lateral parabrachial nucleus (LPB) and ventral posteromedial nucleus of the thalamus (VPM) were assessed by immunostaining and Western blotting. RESULTS: Under low-estrogen conditions, the mechanical pain threshold of the orofacial region of rats decreased significantly, and the temperature of the orofacial region increased significantly. The expression of Vglut2 and Vgat1 in the TG and Sp5C showed a downward trend, and the decline in Vgat1 was greater than that in Vglut2. Conversely, both proteins were upregulated in the LPB and VPM, and the magnitude of the changes in Vglut2 was greater than that in Vgat1. Estrogen therapy reversed these changes. CONCLUSION: Under low-estrogen conditions, the proportion of glutamate and GABA neurons in the orofacial pain and temperature sensation pathway changes, which leads to the imbalance of neurotransmission function and the enhancement of excitatory transmission of these two kinds of neurons and finally leads to a decrease in the orofacial pain threshold and an increase in temperature.

Inhibitor Screen Identifies Covalent Inhibitors of the Protein Histidine Phosphatase PHPT1.

The protein histidine phosphatase PHPT1 is implicated in a variety of cellular signaling pathways. However, little is known about the precise biological roles of this enzyme and a dearth of chemical tools for studying histidine phosphorylation and dephosphorylation has hampered progress in the field. With the goal of identifying the first inhibitors of PHPT1 activity, we carried out an inhibitor screen using a facile fluorogenic assay for PHPT1 activity recently developed in our laboratory. From a panel of approximately 4000 compounds obtained from the Microsource Spectrum Collection and the NCI Diversity Set IV, we identified several potential hits with significant selectivity for inhibiting PHPT1 activity over other phosphatases. Of these, norstictic acid was the most potent inhibitor of PHPT1 activity with an IC50 value of 7.9 ± 0.8 µM under our assay conditions. Norstictic acid is a time-dependent, covalent inhibitor of PHPT1 activity with K I = 90 ± 20 µM and k inact = 1.7 ± 0.1 min-1.

Effects of Intestinal FXR-Related Molecules on Intestinal Mucosal Barriers in Biliary Tract Obstruction.

Background: The farnesoid X receptor (FXR) is a key factor regulating hepatic bile acid synthesis and enterohepatic circulation. Repression of bile acid synthesis by the FXR is a potential strategy for treating cholestatic liver disease. However, the role of intestinal FXR on the intestinal barrier and intestinal microbiota needs further investigation. Materials: Intestinal tissues were collected from patients with biliary atresia or without hepatobiliary disease. Then, intestinal mRNA levels of FXR-related molecules were determined. To investigate the effect of FXR activation, bile-duct-ligation rats were treated with obeticholic acid [OCA (5 mg/kg/day)] or vehicle (0.5% methyl cellulose) per oral gavage for 14 days. The mRNA levels of intestinal FXR, SHP, TNF-α, FGF15 and bile acid transporter levels were determined. In addition, the intestinal permeability, morphologic changes, and composition of the intestinal microbiota were evaluated. Gut Microbiome was determined by 16S rDNA MiSeq sequencing, and functional profiling of microbial communities was predicted with BugBase and PICRUSt2. Finally, the role of OCA in injured intestinal epithelial cell apoptosis and proliferation was examined by pretreatment with lipopolysaccharide (LPS) in Caco-2 cells. Results: The downstream of the FXR in ileum tissues was inhibited in biliary obstruction. Activation of the FXR signaling pathway by OCA significantly reduced liver fibrosis and intestinal inflammation, improved intestinal microbiota, and protected intestinal mucosa in BDL rats. OCA also altered the functional capacities of ileum microbiota in BDL rats. Significant differences existed between the controls and BDL rats, which were attenuated by OCA in the alpha diversity analysis. Principal coordinates analysis showed that microbial communities in BDL rats clustered separately from controls, and OCA treatment attenuated the distinction. Bugbase and PICRUSt2 analysis showed that OCA changed the composition and structure of the intestinal microbiota and improved the metabolic function of the intestinal microbiota by increasing the relative abundance of beneficial bacteria and reducing the relative abundance of harmful bacteria. Moreover, OCA reduced the apoptosis induced by LPS in Caco-2 cells. Conclusion: The FXR agonist, OCA, activates the intestinal FXR signaling pathway and improves the composition and structure of the intestinal microbiota and intestinal barrier in BDL rats.

Transcriptomic changes in the hypothalamus of ovariectomized mice: Data from RNA-seq analysis.

BACKGROUND: Menopausal symptoms can affect the physical and mental health of females and are often related to abnormal function of the hypothalamus. In this study, we evaluated changes in the hypothalamus transcriptome in ovariectomized mice to identify key mRNAs, and systematically elucidated the possible molecular mechanisms underlying the menopausal syndrome to provide a theoretical basis for clinical diagnosis and treatment. METHODS: Forty-six adult female C57BL/6 J mice were randomly divided into SHAM and OVX groups, 23 mice per group. Eight weeks after the procedure, differentially expressed genes (DEGs) in the hypothalamus were identified through RNA-sequencing. DEGs were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analyses. Key DEGs were then evaluated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical staining. RESULTS: Compared with SHAM group, 7295 genes were upregulated, and 8979 genes were downregulated in the hypothalamus of OVX mice with a fold change of 1.5 (log2 fold change ≥0.585). GO and KEGG analyses suggested these key genes were involved in thermoregulation, food intake, glucose and lipid metabolism, cardiovascular regulation, biological rhythm, and endocrine regulation. CONCLUSIONS: Differential expression of genes in the hypothalamus of OVX mice involved in thermoregulation, eating, sleeping, homeostasis, and endocrine regulation 8 weeks after ovariectomy suggest potential roles in the pathogenesis of climacteric syndrome.

Influence of light-irradiated Noccaea caerulescens on the characteristics of dissolved organic matter in its rhizospheric soil during phytoremediation.

It has been observed that suitable light irradiation can improve the phytoremediation efficiency of various plants by enhancing their growth rate and metal uptake capacity. However, the mechanisms underlying the effects of light irradiation on metal mobilization and translocation in soils have rarely been reported. This experiment was conducted to evaluate the variation in dissolved organic matter (DOM) in the rhizosphere of Noccaea caerulescens (formerly Thlaspi caerulescens J. & C. Presl) when irradiated with different combinations of red (0, 25, 50, 90, and 100% red) and blue light. N. caerulescens was induced to secrete significantly more DOM, relative to the control, into its rhizosphere after being irradiated with pure red light and other red light combinations; this increased the bioavailability of soil Cd. Moreover, the concentrations and proportions of the hydrophilic DOM fractions, particularly hydrophilic acid, which exhibited a high affinity for Cd, increased with increasing ratios of the red light. Furthermore, DOM secreted because of the light irradiation treatments exhibited a significantly higher Cd extraction ability compared with that of the untreated control; this consequently increased the Cd uptake capacity of N. caerulescens. The results demonstrated that the secretion of more DOM, particularly hydrophilic acid, plays a pivotal role in improving the phytoremediation efficiency of N. caerulescens.

Impact of O3 on the phytoremediation effect of Celosia argentea in decontaminating Cd.

Elevated atmospheric O3 can inhibit the growth rate of various plants and increase metal content in their tissues owing to the oxidative damage, thereby affecting their phytoremediation efficiency. In this study, a series of O3 fumigation treatments were designed to evaluate the dry weight, Cd content, and transpiration rate responses of Celosia argentea to different levels of O3 (40, 50, 55, 60, 65, and 80 ppb). The dry weight of C. argentea decreased as the atmospheric O3 level increased, and the Cd concentration of the plant leaves increased until the level of O3 reached 60 ppb before decreasing slightly. The variations in the transpiration rate followed a similar trend to the Cd content under different O3 levels. The phytoremediation efficiency of C. argentea increased with O3 fumigation at low (50 ppb) and moderate (55 and 60 ppb) levels, and significantly decreased at the highest level. The regression curves indicated that the plant species treated with 52 ppb of O3 exhibited the highest Cd accumulation capacity. Overall, the phytoremediation effect of C. argentea cultivated in Cd-polluted soil might be improved under the high-O3 conditions. This result might help to choose suitable plants for soil remediation in future atmospheric environment.

Identification of new dermaseptins with self-assembly tendency: membrane disruption, biofilm eradication, and infected wound healing efficacy.

Severe infections associated with antibiotic-resistant bacteria and biofilms have attracted increasing interest as these diseases are difficult to treat with current antibiotics. Typical cationic antimicrobial peptides dermaseptins are considered to be the most promising next-generation antibiotics because of their broad-spectrum antimicrobial activities and minor side effects. Two new dermaseptin peptides, DMS-PS1 and DMS-PS2, have been identified by "shotgun" molecular cloning of encoding cDNAs in the crude skin secretions of the waxy monkey tree frog, Phyllomedusa sauvagei. The mature peptide sequences predicted from the cloned cDNAs were separated from crude skin secretions and confirmed by mass spectrometry. Chemically synthetic replicates were assessed for various biological activities. Both dermaseptins were potently effective against a broad spectrum of microorganisms including antibiotic-resistant bacteria and displayed significant potency against gram-positive and gram-negative bacterial biofilms with low toxicity towards mammalian red blood cells. Remarkably, DMS-PS2 was effective against infections in murine skin caused by methicillin-resistant Staphylococcus aureus as a result of an induced wound. The actions of DMS-PS2 were with a membrane permeabilization mode. Overall, the data provided convincing evidence for the development of anti-infectious agents and/or biomaterials as a new therapeutic approach against bacterial infections. STATEMENT OF SIGNIFICANCE: Bacterial adhesion to biomaterials remains a major problem. Antimicrobial peptides (AMPs) are well-known components of the innate immune system that can be applied to overcome biofilm-associated infections. Cationic dermaseptin peptides showed significant broad-spectrum antimicrobial activities and activities against bacterial biofilms of persistent infections in association with weak toxicity for mammalian red blood cells. The membrane permeabilizing ability of DMS-PS2 was confirmed, and importantly, it demonstrated potent efficiency of the treatment of MRSA infected murine skin model. Furthermore, beyond our expectation, DMS-PS2 showed a self-aggregating parameter, indicating a promising potential for the use of immobilized AMPs in clinical applications., which makes it also a promising suggestion for infection-proof biomaterial development.

Correlation between FAS single nucleotide polymorphisms and breast carcinoma susceptibility in Asia.

BACKGROUND: FAS cell surface death receptor (FAS) gene has 2 common single nucleotide polymorphisms (SNPs) in its promoter, FAS-1377G > A (rs2234767) and FAS-670A > G (rs1800682). Several studies have investigated the role of these 2 polymorphisms in etiology of breast cancer in Asian population while the outcomes are inconsistent. To derive a more precise assessment of the association between breast cancer susceptibility with FAS gene promoter SNPs, a meta-analysis of published studies was performed. MATERIAL AND METHODS: We systematically searched PubMed, Embase, Web of Science, and the Chinese biomedical database (CBM) for papers published until November 1, 2018. Odds ratio (OR) with 95% confidential interval (95%CI) was conducted to evaluate the associations. Statistical analysis was conducted using Stata13.0 software. A total of 8 studies covering 2564 cases and 2633 controls were included. RESULTS: The integrated results suggest the following: For the FAS-1377G/A polymorphism, we only found significant associations for allele G vs allele A (OR = 1.100, 95%CI = 1.004-1.206, P = .040). After stratification by ethnicity, a significant association was observed only for the AA+GA vs GG genotype in East Asian populations (OR = 1.177, 95% CI = 1.010-1.371, P = .037). The association was not found in West Asian populations. For the FAS -670A/G polymorphism, no association with cancer risk was found in any comparison model. Sensitivity analysis suggests that the meta-analysis results obtained after excluding any single study were similar to the original ones, suggesting that the meta-analysis results were not significantly affected by any single study. CONCLUSION: These results indicated that FAS-1377G/A polymorphism may contribute to the increased breast cancer susceptibility and could be a promising target for cancer risk prediction. Further studies are needed to determine if the FAS gene confers a risk of breast cancer in other ethnic groups, such as Africans and Latin Americans.

Antitumor bioactivity of porphyran extracted from Pyropia yezoensis Chonsoo2 on human cancer cell lines.

BACKGROUND: Pyropia yezoensis, rich in porphyran, is a medicine-edible red alga. In the present study, the physicochemical characteristics, conformational states and antitumor activities of a novel porphyran extracted from the high-yield algal strain Pyropia yezoensis Chonsoo2 and its two degraded derivatives by gamma irradiation were investigated. RESULTS: Pyropia yezoensis porphyran is a water-soluble, triple-helical sulfated hetero-galactopyranose, named PYP. PYP was degraded by gamma irradiation at 20 kGy and 50 kGy, giving two low molecular weight derivatives comprising PYP-20 and PYP-50, respectively. PYP with a higher molecular weight has a solution conformation different from PYP-20 and PYP-50. Three porphyrans had no toxicity in normal human liver cells (HL-7702) and showed antitumor effects on Hep3B, HeLa and MDA-MB-231. They had better antitumor against HeLa cells, exhibiting a similar inhibition ratio compared to 5-fluorouracil, with PYP especially exhibiting a higher inhibition ratio than 5-fluorouracil. With respect to HeLa cells, the different antitumor activities might be related to porphyran molecular weight and solution conformation. Furthermore, the HeLa cell cycle was blocked in the G2/M phase after PYP treatment, leading to cell proliferation inhibition. The induction of cell cycle arrest was related to the changes in the expression of p21, p53, Cyclin B1 and cyclin-dependent kinase 1. CONCLUSION: Pyropia yezoensis porphyran, as applied to medicine and functional food, could potentially be used as a non-toxic natural adjuvant in cancer therapy. © 2019 Society of Chemical Industry.

Rapid Deorphanization of Human Olfactory Receptors in Yeast.

Olfactory receptors are ectopically expressed (exORs) in more than 16 different tissues. Studying the role of exORs is hindered by the lack of known ligands that activate these receptors. Of particular interest are exORs in the colon, the section of the gastrointestinal tract with the greatest diversity of microbiota where ORs may be participating in host-microbiome communication. Here, we leverage a G-protein-coupled receptor (GPCR)-based yeast sensor strain to generate sensors for seven ORs highly expressed in the colon. We screen the seven colon ORs against 57 chemicals likely to bind ORs in olfactory tissue. We successfully deorphanize two colon exORs for the first time, OR2T4 and OR10S1, and find alternative ligands for OR2A7. The same OR deorphanization workflow can be applied to the deorphanization of other ORs and GPCRs in general. Identification of ligands for OR2T4, OR10S1, and OR2A7 will enable the study of these ORs in the colon. Additionally, the colon OR-based sensors will enable the elucidation of endogenous colon metabolites that activate these receptors. Finally, deorphanization of OR2T4 and OR10S1 supports studies of the neuroscience of olfaction.

Sequence specific detection of restriction enzymes at DNA-modified carbon nanotube field effect transistors.

Protein-DNA interactions play a central role in many cellular processes, and their misregulation has been implicated in a number of human diseases. Thus, there is a pressing need for the development of analytical strategies for interrogating the binding of proteins to DNA. Herein, we report the electrical monitoring of a prototypical DNA-binding protein, the PvuII restriction enzyme, at microfluidic-encapsulated, DNA-modified carbon nanotube field effect transistors. Our integrated platform enables the sensitive, sequence specific detection of PvuII at concentrations as low as 0.5 pM in a volume of 0.025 µL (corresponding to ~7500 proteins). These figures of merit compare favorably to state of the art values reported for alternative fluorescent and electrical assays. The overall detection strategy represents a step toward the massively parallel electrical monitoring, identification, and quantification of protein-DNA interactions at arrayed nanoscale devices.

PADI4 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis.

The objective of the study was to investigate the association between peptidylarginine deiminase 4 (PADI4) polymorphism and susceptibility to rheumatoid arthritis (RA). An electronic searching strategy was employed to collect relevant studies on the association between PADI4 polymorphism and susceptibility to RA. The odds ratio (OR) with the 95 % confidence interval (95 % CI) was used to evaluate the RA risk presented by PADI4 polymorphism. Fixed or random effects models were selected based on heterogeneity. Publication bias was assessed using funnel plots, Begg's test, and Egger's test. A total of 27 studies from 21 articles were included. Six gene loci (padi4_94, 104, 92, 90, 89, and 100) were chosen for the meta-analysis. The pooled ORs (95 % CI) for allele 2 versus 1 were 1.08 (1.05-1.12), 1.17 (1.12-1.23), 1.26 (1.18-1.36), 1.17 (1.10-1.24), 1.30 (1.17-1.44), and 1.25 (1.11-1.40), respectively. All six SNPs were significantly associated with RA in Asian populations. Three SNPs (PADI4_104, 90, 89) showed significant associations, while the other three SNPs (PADI4_94, 92, 100) exhibited no associations in the European population. A dose-response relationship between allele 2 of PADI4 and the risk of RA was also identified. In conclusion, this meta-analysis suggests that PADI4 polymorphisms represent a significant risk factor for RA, especially in Asians.