Mitochondria-Regulated Information Processing Nanosystem Promoting Immune Cell Communication for Liver Fibrosis Regression.

Liver fibrosis is a coordinated response to tissue injury that is mediated by immune cell interactions. A mitochondria-regulated information-processing (MIP) nanosystem that promotes immune cell communication and interactions to inhibit liver fibrosis is designed. The MIP nanosystem mimics the alkaline amino acid domain of mitochondrial precursor proteins, providing precise targeting of the mitochondria. The MIP nanosystem is driven by light to modulate the mitochondria of hepatic stellate cells, resulting in the release of mitochondrial DNA into the fibrotic microenvironment, as detected by macrophages. By activating the STING signaling pathway, the developed nanosystem-induced macrophage phenotype switches to a reparative subtype (Ly6Clow) and downstream immunostimulatory transcriptional activity, fully restoring the fibrotic liver to its normal tissue state. The MIP nanosystem serves as an advanced information transfer system, allowing precise regulation of trained immunity, and offers a promising approach for effective liver fibrosis immunotherapy with the potential for clinical translation.

Design and Fabrication of Biomass Derived Black Carbon Modified g-C3N4/FeIn2S4 Heterojunction as Highly Efficient Photocatalyst for Wastewater Treatment.

The environmental deterioration caused by dye wastewater discharge has received considerable attention in recent decades. One of the most promising approaches to addressing the aforementioned environmental issue is the development of photocatalysts with high solar energy consumption efficiency for the treatment of dye-contaminated water. In this study, a novel low-cost π-π biomass-derived black carbon modified g-C3N4 coupled FeIn2S4 composite (i.e., FeInS/BC-CN) photocatalyst is successfully designed and fabricated that reveals significantly improved photocatalytic performance for the degradation of Eosin Yellow (EY) dye in aqueous solution. Under dark and subsequent visible light irradiation, the amount optimized composite reveals 99% removal performance for EY dye, almost three-fold compared to that of the pristine FeInS and BC-CN counterparts. Further, it is confirmed by means of the electron spin resonance spectrometry, quenching experiments, and density functional theory (DFT) calculations, that the hydroxyl radicals (•OH) and superoxide radicals (•O2 -) are the dominant oxidation species involved in the degradation process of EY dye. In addition, a systematic photocatalytic degradation route is proposed based on the resultant degradation intermediates detectedduring liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. This work provides an innovative idea for the development of advanced photocatalysts to mitigate water pollution.

Differences in Vertebral Morphology and bone Mineral Density between Grade 1 Vertebral Fracture and Non-Fractured Participants in the Chinese Population.

PURPOSE: To investigate the difference in vertebral morphology and bone mineral density (BMD) between grade 1 VFs and non-fractured participants in the Chinese population to shed light on the clinical significance of grade 1 VFs from various perspectives. METHODS: This retrospective cohort study included patients who received a chest low-dose computed tomography (LDCT) scan for health examination and visited the First Affiliated Hospital of Zhengzhou University, Henan, China, from October 2019 to August 2022. Data were analyzed from March 2023 to July 2023. The main outcome of this study was the difference in morphological parameters and BMD between grade 1 VFs and non-fractured participants. The prevalence of grade 1 VFs in China populations was calculated. The difference in BMD of three fracture types in the Grade 1 group was also evaluated. RESULTS: A total of 3652 participants (1799 males, 54.85 ± 9.02 years, range, 40-92 years; 1853 females, 56.00 ± 9.08 years, range, 40-93 years) were included. The prevalence of grade 2 and 3 increase with age. The prevalence of grade 1 VFs gradually increases ≤ 50y to 60-69y group, but there is a decrease in the ≥ 70 years male group (6.6%) and a rise in the female group (25.5%). There was no significant statistical difference observed in vertebral shape indices (VSI) and BMD between the Grade 1 group and the no-fractured group aged < 50 years old except the wedge index in male. The biconcavity index did not differ between the non-fractured group and the Grade 1 group in men aged 50-59 years, whereas a significant statistical difference was observed in women. Additionally, the results of BMD were consistent with these findings. For the 40-59 years age group, there were significant differences between the compression deformity group and the other groups. CONCLUSIONS: The grade 1 group had higher VSI and lower BMD than the non-fractured group, suggesting an association between the Grade 1 group and osteoporosis in individuals aged over 50 for women and over 60 for men. Different fracture types have significant variations in BMD among middle-aged people. The prevalence of grade 1 VFs exhibits an age-related increase in both genders, with opposite trends observed between older males and females. We suggested VSI can aid physicians in the diagnosis of grade 1 VFs.

Curcumin alleviates zearalenone-induced liver injury in mice by scavenging reactive oxygen species and inhibiting mitochondrial apoptosis pathway.

Curcumin (CUR) is a compound extracted from turmeric that has a variety of functions including antioxidant and anti-inflammatory. As an estrogen-like mycotoxin, zearalenone (ZEN) not only attacks the reproductive system, but also has toxic effects on the liver. However, whether CUR can alleviate ZEN-induced liver injury remains unclear. This paper aims to investigate the protective effect of CUR against ZEN-induced liver injury in mice and explore the molecular mechanism involved. BALB/c mice were randomly divided into control (CON) group, CUR group (200 mg/kg b. w. CUR), ZEN group (40 mg/kg b. w. ZEN) and CUR+ZEN group (200 mg/kg b. w. CUR+40 mg/kg b. w. ZEN). 28 d after ZEN exposure and CUR treatment, blood and liver samples were collected for subsequent testing. The results showed that CUR reversed ZEN-induced hepatocyte swelling and necrosis in mice. It significantly reduced the serum alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in mice (p < 0.05). In addition, CUR significantly reduced hepatic ROS, malondialdehyde, hydrogen peroxide and apoptosis levels in mice (p < 0.05). Quantitative RT-PCR and Western blot results showed that CUR significantly reduced the expression of Bax and Caspase3, and reversed the increase of Nrf2, HO-1 and NQO1 expression in the liver of mice induced by ZEN (p < 0.05). In conclusion, CUR alleviated ZEN-induced liver injury in mice by scavenging ROS and inhibiting the mitochondrial apoptotic pathway.

Synthesis, Thermal Stability and Antifungal Evaluation of Two New Pyrrole Esters.

To develop new chemicals that are stable at high temperatures with biological activity, a pyrrole intermediate was firstly synthesized using glucosamine hydrochloride as raw materials through cyclization and oxidation. Further, two novel pyrrole ester derivatives were prepared via Steglich esterification from pyrrole intermediate with vanillin and ethyl maltol, respectively. Nuclear magnetic resonance (1 H-NMR, 13 C NMR), infrared spectroscopy (IR) and high resolution mass spectrometry (HRMS) were used to confirm the target compounds. Thermal behavior of the compounds was investigated by thermogravimetry (TG), differential scanning calorimeter (DSC) and the pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) methods. The plausible pyrolytic mechanism was proposed. Additionally, their biological activities against the pathogens Fusarium graminearum, Fusarium oxysporum, Fusarium moniliforme, Phytophthora nicotianae, and Rhizoctonia solani were assessed. These target compounds showed outstanding antifungal activities and the highest inhibitor rates of 62.50 % and 68.75 % against R. solani with EC50 values of 0.0296 and 0.0200 mg mL-1 , respectively. SDHI protein sequence was molecularly docked to identify the binding mechanisms in the active pocket and examine the interactions between both the molecules and the SDHI protein.

Effects of Separation and Purification Methods on Antioxidation, Hypoglycemic and DNA Protection Activity of Fenugreek Polysaccharide.

Six low molecular weight fenugreek polysaccharides (FP) were isolated and purified by ethanol stepwise precipitation (EFP-20, EFP-40, and EFP-60) and DEAE-52 cellulose column method (DFP-0, DFP-0.15, and DFP-0.3), respectively. The effects of different separation and purification techniques on the preliminary properties and biological activities of fenugreek polysaccharides were compared. The results showed that the DEAE-52 cellulose-eluted fractions had a higher total sugar content and displayed a looser structure. The molecular weights of all six fractions were in the range of 4-19 kDa, with significant changes in the ratio of galactose to mannose. All six fractions contained α-D-galactopyranose and ß-D-mannopyranose structures. Activity tests showed that all six fractions possessed antioxidant, hypoglycemic and DNA-protective activities. Among them, the DFP-0 fraction showed the highest activity. Overall, different isolation and purification methods lead to changes in the properties and bioactivities of FP, which provides a theoretical basis for the development and application of FP in functional foods and drugs.

Development in Fluorescent OFF-ON Probes Based on Cu2+ Promoted Hydrolysis Reaction of the Picolinate Moiety.

Anions and cations have a key role in our normal life. Cu2+ ion is a crucial trace element accountable for the part of several cellular enzymes and proteins, including cytochrome c oxidase, dopamine monooxygenase, Cu/Zn superoxide dismutase, and ceruloplasmin. WHO has found the extreme acceptable level of Cu2+ ions in drinking water is up to 2.0 ppm. Excess use of Cu2+ ions is associated with various human genetic disorders. Thus, the visualization of Cu2+ ions to avoid its toxic effects in chemical and biological systems is significant. In this review we have summarized sensors based on catalytic hydrolysis of picolinate to detect Cu2+ ions. The sensors based on hydrolysis of picolinate are very selective as compared to the other sensors for Cu2+ ions detection. We have focused on describing the structure, spectral properties, detection limits, and bioimaging model of the sensors.

Hydrogel-potassium humate composite alleviates cadmium toxicity of tobacco by regulating Cd bioavailability.

Cadmium (Cd) removal from soil to reduce Cd accumulation in plants is essential for agroecology, food safety, and human health. Cd enters plants from soil and affects plant growth and development. Hydrogels can easily combine with Cd, thereby altering its bioavailability in soil. However, few studies have evaluated the effects of hydrogel on the complex phytotoxicity caused by Cd uptake in plants and the microbial community structure. Herein, a new poly (acrylic acid)-grafted starch and potassium humate composite (S/K/AA) hydrogel was added to soil to evaluate its impact on tobacco growth and the soil microenvironment. The results indicate that the addition of S/K/AA hydrogel can significantly improve the biomass, chlorophyll (Chl) content, and photosynthetic capacity of tobacco plants during Cd stress conditions, and decrease Cd concentration, probably by affecting Cd absorption through the expression of Cd absorption transporters (e.g., NRAMP5, NRAMP3, and IRT1). Moreover, the application of S/K/AA hydrogel not only reduced the accumulation of reactive oxygen species (ROS), but also reduced the antioxidant activities of peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT), suggesting that S/K/AA hydrogel alleviates Cd toxicity via a non-antioxidant pathway. Notably, we further analyzed the effectiveness of the hydrogel on microbial communities in Cd-contaminated soil and found that it increased the Cd-tolerant microbial community (Arthrobacter, Massilia, Streptomyces), enhancing the remediation ability of Cd-contaminated soil and helping tobacco plants to alleviate Cd toxicity. Overall, our study provides primary insights into how S/K/AA hydrogel affects Cd bioavailability and alleviates Cd toxicity in plants.

Precision Joint RF Measurement of Inter-Satellite Range and Time Difference and Scalable Clock Synchronization for Multi-Microsatellite Formations.

The rapid development of multi-satellite formations requires inter-satellite radio frequency (RF) measurement to be both precise and scalable. The navigation estimation of multi-satellite formations using a unified time reference demands the simultaneous RF measurement of the inter-satellite range and time difference. However, high-precision inter-satellite RF ranging and time difference measurements are investigated separately in existing studies. Different from the conventional two-way ranging (TWR) method, which is limited by its reliance on a high-performance atomic clock and navigation ephemeris, asymmetric double-sided two-way ranging (ADS-TWR)-based inter-satellite measurement schemes can eliminate such reliance while ensuring measurement precision and scalability. However, ADS-TWR was originally proposed for ranging-only applications. In this study, by fully exploiting the time-division non-coherent measurement characteristic of ADS-TWR, a joint RF measurement method is proposed to obtain the inter-satellite range and time difference simultaneously. Moreover, a multi-satellite clock synchronization scheme is proposed based on the joint measurement method. The experimental results show that when inter-satellite ranges are hundreds of kilometers, the joint measurement system has a centimeter-level accuracy for ranging and a hundred-picosecond-level accuracy for time difference measurement, and the maximum clock synchronization error was only about 1 ns.

Combination of an autophagy inhibitor with immunoadjuvants and an anti-PD-L1 antibody in multifunctional nanoparticles for enhanced breast cancer immunotherapy.

BACKGROUND: The application of combination therapy for cancer treatment is limited due to poor tumor-specific drug delivery and the abscopal effect. METHODS: Here, PD-L1- and CD44-responsive multifunctional nanoparticles were developed using a polymer complex of polyethyleneimine and oleic acid (PEI-OA) and loaded with two chemotherapeutic drugs (paclitaxel and chloroquine), an antigen (ovalbumin), an immunopotentiator (CpG), and an immune checkpoint inhibitor (anti-PD-L1 antibody). RESULTS: PEI-OA greatly improved the drug loading capacity and encapsulation efficiency of the nanoplatform, while the anti-PD-L1 antibody significantly increased its cellular uptake compared to other treatment formulations. Pharmacodynamic experiments confirmed that the anti-PD-L1 antibody can strongly inhibit primary breast cancer and increase levels of CD4+ and CD8+ T cell at the tumor site. In addition, chloroquine reversed the "immune-cold" environment and improved the anti-tumor effect of both chemotherapeutics and immune checkpoint inhibitors, while it induced strong immune memory and prevented lung metastasis. CONCLUSIONS: Our strategy serves as a promising approach to the rational design of nanodelivery systems for simultaneous active targeting, autophagy inhibition, and chemotherapy that can be combined with immune-checkpoint inhibitors for enhanced breast cancer treatment.

An efficient domino strategy for synthesis of 3-substituted 4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine derivatives in water.

A strategy for catalyst-free domino reaction of 4-aminopyridin-2(1H)-ones, arylglyoxal hydrates and different 1,3-dicarbonyl compounds in water has been established. The mild and efficient procedure afforded pyrrolo[3,2-c]pyridine derivatives with 76-94% yields after simple crystallization. The present procedure shows promising characteristics, such as readily available starting materials, the use of water as reaction media, simple and efficient one-pot operation, and avoiding the need for any hazardous or expensive catalysts.

A long-wavelength activable AIEgen fluorescent probe for HClO and cell apoptosis imaging.

Hypochlorous acid (HClO) is an important bactericide, and adjusting the content of HClO helps to improve the host's innate immunity and resist microbial invasion. Aggregation-induced luminescence (AIE) is the opposite of aggregation-induced quenching (ACQ). Compounds with AIE properties emit weakly in a dispersed state in solution and they can emit strong fluorescence in an aggregated state. In this article, we proposed a new AIE fluorescent probe QM-ClO based on the quinoline-malononitrile (QM) fluorophore and dimethylthiocarbamate (DMTC) to detect HClO. The probe QM-ClO showed a fast response time, a low detection limit of 30.8 nM and a large Stokes shift (190 nm). Carbonyl cyanide metachlorophenyl-hydrazone (CCCP) was used to induce cell apoptosis, and then an increase in the HClO content was observed in the cell. It is proved that cell apoptosis can lead to the increase of the HClO content in the cell. This probe provides an effective tool for studying apoptosis-related diseases.

Simple and efficient one-pot multi-step strategy for the synthesis of 2-substituted (1,2,5-triarylpyrrolo[3,2-c]pyridin-3-yl)-N-arylacetamide derivatives in water.

A novel one-pot multi-step domino strategy for the synthesis of functionalized 2-substituted acetic acids, 2-substituted (1,2,5-triarylpyrrolo[3,2-c]pyridin-3-yl)acetates and 2-substituted-(1,2,5-triarylpyrrolo[3,2-c]pyridin-3-yl)-N-arylacetamides has been established from inexpensive and readily available starting materials. The reaction can be easily performed by employing different substrates via a one-pot multi-step domino reaction. The target products can be easily obtained with satisfactory yields by only simple recrystallization from a mixture of hot 95% ethanol and N,N-dimethylformamide. The reaction features of readily available starting materials, broad substrate scope, bond-forming efficiency, simple one-pot multi-step synthesis as well as green reaction media, make the procedure highly useful for the construction of potential pharmacological heterocyclic molecules.

Box-copper catalyzed cascade asymmetric amidation for chiral exo-methylene aminoindoline derivatives.

Enantioselective copper-catalyzed cascade inter- and intramolecular amidation was achieved between ethynyl benzoxazinanones and α-halohydroxamates in the presence of an indapybox ligand. The one-pot cascade transformation was triggered by the attack of hydroxamates to dipolar copper-allenylidene intermediates, followed by a nucleophilic annulation reaction. Thus, a series of exo-methylene 3-aminoindoline derivatives were obtained in good yields with high enantioselectivities under mild reaction conditions.

Guideline conformity to the Stupp regimen in patients with newly diagnosed glioblastoma multiforme in China.

Aims: To determine how consistently Chinese glioblastoma multiforme (GBM) patients were treated according to the Stupp regimen. Patients and methods: The proportion of treatments conforming to the Stupp regimen and reasons for nonconformity were evaluated in 202 newly diagnosed GBM patients. Results: Only 15.8% of GBM patients received treatments compliant with the Stupp regimen. The main deviations were temozolomide dosages >75 mg/m2 (58/120; 48.3%) and treatment durations <42 days (84/120; 70.0%) in the concomitant phase and temozolomide dosages <150 mg/m2 (89/101; 88.1%) in the maintenance phase. Median overall survival (27.09 vs 18.21 months) and progression-free survival (14.27 vs 12.10 months) were longer in patients who received Stupp regimen-compliant treatments. Conclusion: Increased conformity to the Stupp regimen is needed for GBM patients in China.

Lay abstract In 2005 the European Organization for Research and Treatment of Cancer 26981 study led to US FDA approval for the use of temozolomide in combination with radiotherapy to treat glioblastoma multiforme (GBM). The Stupp regimen consists of fractionated focal irradiation in daily fractions of 2 Gy given 5 days/week for 6 weeks (a total of 60 Gy), plus concomitant daily temozolomide (75 mg/m²/day, 7 days/week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150­200 mg/m²/day for 5 days during each 28-day cycle). In 2012 the Chinese guidelines for the diagnosis and treatment of glioma of the CNS recommended the Stupp regimen as first-line therapy for newly diagnosed GBM. In the present study, compliance of GBM treatments with the Stupp regimen in 28 Chinese centers from 2012­2016 was evaluated. Only 15.8% of GBM patients received treatments compliant with the Stupp regimen. The main deviations related to temozolomide dosages and treatment durations in the concomitant and maintenance phases. Median overall survival (27.09 vs 18.21 months) and progression-free survival (14.27 vs 12.10 months) were longer in patients who received Stupp regimen-compliant treatments.

Measurement of Nasalance Scores Without Touching the Philtrum for Better Comfort During Speech Assessment and Therapy: A Preliminary Study.

OBJECTIVE: The Kay Pentax nasometer uses a separator plate that touches the philtrum of a patient to separate the nasal and oral sound energies for nasalance measurement. However, the separator plate can restrict the natural movement of the patient's upper lip and generate unpleasant pressure on the patient's philtrum. The present study was intended to measure nasalance scores without touching the philtrum for better comfort during speech assessment and therapy. METHODS: Nasalance scores of 10 males and 10 females having no speech disorders were measured under 4 levels (0, 5, 10, and 15 mm) of the gap between the plate and the philtrum (denoted as plate-to-philtrum gap) using Nasometer II 6450 for nasal (Nasal Sentences) and oral (Zoo Passage) stimuli. Regression formulas were established to examine the relationships between nasalance score and plate-to-philtrum gap for the stimuli. To provide nasalance scores equivalent to those measured for the contact condition, compensation factors for the 5 mm plate-to-philtrum gap measurement condition were identified for the stimuli. RESULTS: The nasalance scores were significantly different between the 4 different plate-to-philtrum gaps for the stimuli. Compensation factors for the Nasal Sentences and the Zoo Passage were identified as 1.17 and 0.71, respectively. CONCLUSIONS: The 5 mm plate-to-philtrum gap condition after multiplying the compensation factors can provide equivalent nasalance scores to the conventional contact measurement condition which may provide better comfort in speech assessment and therapy.

Imaging Hg2+-Induced Oxidative Stress by NIR Molecular Probe with "Dual-Key-and-Lock" Strategy.

Mercury (Hg) is considered an extremely toxic heavy metal which is extremely harmful to both the human body and environment. In addition, Hg2+-induced oxidative stress also exerts a crucial role to play in pathophysiological mechanisms of mercury toxicity. Thus, efficient and specific fluorescent probes for imaging Hg2+-induced oxidative stress are necessary. In the present study, we rationally design a novel Hg2+-activated and ICT-based NIR emission fluorescent probe NIR-HO for sequentially monitoring the ONOO- level with a "dual-key-and-lock" strategy. The probe NIR-HO showed rapid response and excellent specificity and sensitivity for the detection of Hg2+ and ONOO- in vitro. Cell imaging demonstrated that Hg2+-induced oxidative stress was involved in ONOO- upregulation. Also, GSH, NAC, and EDTA were employed as excellent detoxifying drugs against Hg2+-induced toxicity. Moreover, the probe NIR-HO was successfully used for imaging Hg2+ and ONOO- in vivo. In brief, NIR-HO provides a simple and powerful approach which can be used to image Hg2+-induced oxidative stress in the pathological environment.

A FRET-based ratiometric fluorescent probe to detect cysteine metabolism in mitochondria.

As an important biothiol in living cells, cysteine is closely related to oxidative damage in living organisms. Sulfite from cysteine metabolism in living cells plays a crucial role in maintaining homeostasis in an organism, and the unbalance of sulfite in vivo would lead to multiple diseases. Thus the development of a new fluorescent probe for cysteine metabolism is needed urgently in mitochondria which are the main place of cysteine metabolism. Herein we construct a novel targeting mitochondria fluorescent probe CP-K based on the FRET mechanism to visualize sulfite in living MCF-7 cells. Probe CP-K displays a large Stokes shift of 150 nm, a low detection limit (26.3 nM) and "naked eye" detection after the addition of HSO3-. Importantly, it is appropriate for imaging the endogenous sulfite from cysteine metabolism in living cells.

Coumarin-Based Reversible Fluorescent Probe for Selective Detection of Cu2+ in Living Cells.

Copper ion plays an important role in many biological processes in human body. H2S is considered as the third gasses transmitter after carbon monoxide and nitric oxide. Here a novel ICT-based fluorescent ON-OFF-ON probe for Cu2+ and H2S detection was developed. Selectivity and sensitivity of probe was confirmed in aqueous Tris-HCl buffer (10 mM, pH 7.4, containing 90% acetonitrile). Probe DF-CU shows high selectivity over other analytes. The degree of fluorescence quenching is linearly associated with the concentration of Cu2+ (R2 = 0.9919). The limit of detection (LOD, calculated according to the 3σ/slope) for Cu2+ was 6.4 µM. Probe can work in almost all pH. The probe shows a very fast response to Cu2+ (within 10 s). Its response to copper ion could be reversed by H2S. The complex of probe with Cu2+ could be used for H2S detection. Furthermore, this ON-OFF-ON fluorescent probe successfully applied in the living cells for the detection of Cu2+ and H2S.

Interaction between SNCA gene polymorphisms and T2DM with Parkinson's disease.

AIMS: To investigate the association of several single nucleotide polymorphisms (SNPs) within alpha-synuclein (SNCA) gene and additional gene-environment interaction with Parkinson's disease (PD) risk. METHODS: Hardy-Weinberg equilibrium (HWE) is tested for controls using SNPstats (http://bioinfo.iconcologia.net/SNPstats). Logistic regression is used to calculate the ORs (95% CI) for relations between the four SNPs and PD risk. The generalized multifactor dimensionality reduction (GMDR) model is used to evaluate the synergy between gene and environment. RESULTS: A total of 1161 people were included in this study, including 386 cases of PD and 775 normal controls. In this study, the genotype frequency of the control group was consistent with HWE distribution. Rs356219-G allele frequency was 30.0% in patients and 19.8% in control group. The rs356221-T allele frequency was 29.7% in the patients and 20.8% in the control group. Rs356219-G and rs356221-T alleles were associated with increased PD risk, with adjusted ORs (95% CI) of 1.92 (1.28-2.52) and 1.52 (1.05-2.02), respectively. We also found no significant correlation between rs2301134 and rs2301135 and susceptibility to PD. The best gene-environment interaction models were determined by GMDR analysis, which shown a significant gene-T2DM interaction combinations, but the gene-alcohol drinking interaction combinations were all not significant. We also conducted stratified analysis for interaction effect using logistic regression. We found that T2DM patients with rs356221-AT/ TT genotype have the highest PD risk, compared to subjects with rs356219-AA genotype, OR (95%CI) = 2.67 (1.83-3.46). CONCLUSIONS: The rs356219-G and rs356221-T, gene-environment interaction between rs356221 and T2DM were all associated with increased PD risk.