Zinc Treatment of Tea Plants Improves the Synthesis of Trihydroxylated Catechins via Regulation of the Zinc-Sensitive Protein CsHIPP3.

The tea plant (Camellia sinensis [L.] O. Kussntze) is a global economic crop. Zinc treatment of tea plants can enhance catechin biosynthesis. However, the underlying molecular mechanism behind catechin formation through zinc regulation remains unclear. This study identified a zinc-responsive protein, C. sinensis heavy metal-associated isoprenylated plant protein 3 (CsHIPP3), from zinc-treated tea seedlings. CsHIPP3 expression was positively correlated with trihydroxylated catechin (TRIC) content. CsF3'5'H1 is a crucial regulator of the TRIC synthesis pathway. The interaction between CsHIPP3 and CsF3'5'H1 was assessed using bimolecular fluorescence complementation, firefly luciferase complementation imaging, and pulldown experiments. CsHIPP3 knockdown using virus-induced gene silencing technology decreased the content of each component of TRICs. Compared with the control, the relative catechin content was reduced by 40.12-55.39%. Co-overexpression of CsHIPP3 and CsF3'5'H1 significantly elevated the TRIC content in tea leaves and calli. Moreover, the TRIC content in transient co-overexpression leaves was 1.44-fold higher than that of the control group, and tea callus was 50.83% higher in transient co-overexpression than in the wild type. Thus, zinc-regulated TRIC synthesis in a zinc-rich environment was mediated by binding CsHIPP3 with CsF3'5'H1 to promote TRIC synthesis and accumulation.

Inhalation of ACE2-expressing lung exosomes provides prophylactic protection against SARS-CoV-2.

Continued emergence of SARS-CoV-2 variants of concern that are capable of escaping vaccine-induced immunity highlights the urgency of developing new COVID-19 therapeutics. An essential mechanism for SARS-CoV-2 infection begins with the viral spike protein binding to the human ACE2. Consequently, inhibiting this interaction becomes a highly promising therapeutic strategy against COVID-19. Herein, we demonstrate that ACE2-expressing human lung spheroid cells (LSC)-derived exosomes (LSC-Exo) could function as a prophylactic agent to bind and neutralize SARS-CoV-2, protecting the host against SARS-CoV-2 infection. Inhalation of LSC-Exo facilitates its deposition and biodistribution throughout the whole lung in a female mouse model. We show that LSC-Exo blocks the interaction of SARS-CoV-2 with host cells in vitro and in vivo by neutralizing the virus. LSC-Exo treatment protects hamsters from SARS-CoV-2-induced disease and reduced viral loads. Furthermore, LSC-Exo intercepts the entry of multiple SARS-CoV-2 variant pseudoviruses in female mice and shows comparable or equal potency against the wild-type strain, demonstrating that LSC-Exo may act as a broad-spectrum protectant against existing and emerging virus variants.

Sodium-Glucose Cotransporter Protein 2 Inhibitors: Novel Application for the Treatment of Obesity-Associated Hypertension.

Obesity is becoming increasingly prevalent in China and worldwide and is closely related to the development of hypertension. The pathophysiology of obesity-associated hypertension is complex, including an overactive sympathetic nervous system (SNS), activation of the renin-angiotensin-aldosterone system (RAAS), insulin resistance, hyperleptinemia, renal dysfunction, inflammatory responses, and endothelial function, which complicates treatment. Sodium-glucose cotransporter protein 2 (SGLT-2) inhibitors, novel hypoglycemic agents, have been shown to reduce body weight and blood pressure and may serve as potential novel agents for the treatment of obesity-associated hypertension. This review discusses the beneficial mechanisms of SGLT-2 inhibitors for the treatment of obesity-associated hypertension. SGLT-2 inhibitors can inhibit SNS activity, reduce RAAS activation, ameliorate insulin resistance, reduce leptin secretion, improve renal function, and inhibit inflammatory responses. SGLT-2 inhibitors can, therefore, simultaneously target multiple mechanisms of obesity-associated hypertension and may serve as an effective treatment for obesity-associated hypertension.

Transient receptor potential vanilloid type 1: cardioprotective effects in diabetic models.

Cardiovascular disease, especially heart failure (HF) is the leading cause of death in patients with diabetes. Individuals with diabetes are prone to a special type of cardiomyopathy called diabetic cardiomyopathy (DCM), which cannot be explained by heart diseases such as hypertension or coronary artery disease, and can contribute to HF. Unfortunately, the current treatment strategy for diabetes-related cardiovascular complications is mainly to control blood glucose levels; nonetheless, the improvement of cardiac structure and function is not ideal. The transient receptor potential cation channel subfamily V member 1 (TRPV1), a nonselective cation channel, has been shown to be universally expressed in the cardiovascular system. Increasing evidence has shown that the activation of TRPV1 channel has a potential protective influence on the cardiovascular system. Numerous studies show that activating TRPV1 channels can improve the occurrence and progression of diabetes-related complications, including cardiomyopathy; however, the specific mechanisms and effects are unclear. In this review, we summarize that TRPV1 channel activation plays a protective role in the heart of diabetic models from oxidation/nitrification stress, mitochondrial function, endothelial function, inflammation, and cardiac energy metabolism to inhibit the occurrence and progression of DCM. Therefore, TRPV1 may become a latent target for the prevention and treatment of diabetes-induced cardiovascular complications.

Relationship between uric acid to albumin ratio and in-stent restenosis in patients with coronary artery disease undergoing drug-eluting stenting.

BACKGROUND: In-stent restenosis (ISR) in patients undergoing percutaneous coronary intervention (PCI) to treat coronary artery disease (CAD) is an urgent issue in clinical practice. Recent studies have highlighted uric acid-albumin ratio (UAR) as a new marker for evaluating inflammation and oxidative stress, capable of predicting cardiovascular ailments. We aimed to examine the correlation between UAR levels and ISR in patients who underwent drug-eluting stent (DES) implantation. METHODS: We included 503 patients with CAD who underwent initial DES implantation and angiography during the follow-up period. Based on coronary angiographic findings, the patients were categorized into ISR (n = 73) and non-ISR groups (n = 430). Before angiography, laboratory parameters were measured for all enrolled patients. To ascertain the influential factors linked to ISR, multivariate logistic regression analysis was performed. The predictive capability of UAR in determining ISR was assessed using receiver operating characteristic (ROC) curve analysis. Statistical significance was set at P  < 0.05. RESULTS: Multivariate logistic regression analysis revealed that diabetes mellitus, stent length, UAR, albumin levels, and C-reactive protein levels independently predicted ISR. ROC curve analysis revealed that UAR had an area under the curve of 0.767 (95% CI: 0.709 - 0.826) for predicting ISR and demonstrated that UAR outperformed the individual predictive abilities of uric acid and albumin for ISR. CONCLUSION: UAR was associated with ISR in patients with CAD undergoing PCI with DES implantation. Moreover, ROC curve analysis demonstrated that UAR exhibited superior predictive accuracy for ISR compared with evaluating uric acid and albumin levels separately.

Identification of a Non-Invasive Urinary Exosomal Biomarker for Diabetic Nephropathy Using Data-Independent Acquisition Proteomics.

Diabetic nephropathy (DN), as the one of most common complications of diabetes, is generally diagnosed based on a longstanding duration, albuminuria, and decreased kidney function. Some patients with the comorbidities of diabetes and other primary renal diseases have similar clinical features to DN, which is defined as non-diabetic renal disease (NDRD). It is necessary to distinguish between DN and NDRD, considering they differ in their pathological characteristics, treatment regimes, and prognosis. Renal biopsy provides a gold standard; however, it is difficult for this to be conducted in all patients. Therefore, it is necessary to discover non-invasive biomarkers that can distinguish between DN and NDRD. In this research, the urinary exosomes were isolated from the midstream morning urine based on ultracentrifugation combined with 0.22 µm membrane filtration. Data-independent acquisition-based quantitative proteomics were used to define the proteome profile of urinary exosomes from DN (n = 12) and NDRD (n = 15) patients diagnosed with renal biopsy and Type 2 diabetes mellitus (T2DM) patients without renal damage (n = 9), as well as healthy people (n = 12). In each sample, 3372 ± 722.1 proteins were identified on average. We isolated 371 urinary exosome proteins that were significantly and differentially expressed between DN and NDRD patients, and bioinformatic analysis revealed them to be mainly enriched in the immune and metabolic pathways. The use of least absolute shrinkage and selection operator (LASSO) logistic regression further identified phytanoyl-CoA dioxygenase domain containing 1 (PHYHD1) as the differential diagnostic biomarker, the efficacy of which was verified with another cohort including eight DN patients, five NDRD patients, seven T2DM patients, and nine healthy people. Additionally, a concentration above 1.203 µg/L was established for DN based on the ELISA method. Furthermore, of the 19 significantly different expressed urinary exosome proteins selected by using the protein-protein interaction network and LASSO logistic regression, 13 of them were significantly related to clinical indicators that could reflect the level of renal function and hyperglycemic management.

Sodium-glucose Cotransporter 2 Inhibitors and Pathological Myocardial Hypertrophy.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new type of oral hypoglycemic drugs that exert a hypoglycemic effect by blocking the reabsorption of glucose in the proximal renal tubules, thus promoting the excretion of glucose from urine. Their hypoglycemic effect is not dependent on insulin. Increasing data shows that SGLT2 inhibitors improve cardiovascular outcomes in patients with type 2 diabetes. Previous studies have demonstrated that SGLT2 inhibitors can reduce pathological myocardial hypertrophy with or without diabetes, but the exact mechanism remains to be elucidated. To clarify the relationship between SGLT2 inhibitors and pathological myocardial hypertrophy, with a view to providing a reference for the future treatment thereof, this study reviewed the possible mechanisms of SGLT2 inhibitors in attenuating pathological myocardial hypertrophy. We focused specifically on the mechanisms in terms of inflammation, oxidative stress, myocardial fibrosis, mitochondrial function, epicardial lipids, endothelial function, insulin resistance, cardiac hydrogen and sodium exchange, and autophagy.

Serum fibrinogen-to-albumin ratio predicts new-onset atrial fibrillation risk during hospitalization in patients with acute myocardial infarction after percutaneous coronary intervention: a retrospective study.

BACKGROUND: New-onset atrial fibrillation (NOAF) is a common adverse outcome of percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) and is closely correlated with hospital stay and prognosis. In recent years, serum fibrinogen-to-albumin ratio (FAR), a novel biomarker for inflammation and thrombosis, has been used to predict the severity and prognosis of coronary artery disease. Our study aimed to investigate the relationship between FAR and NOAF during hospitalization after PCI in patients with AMI. METHODS: We retrospectively analyzed the incidence of NOAF during hospitalization and follow-up in 670 patients with AMI after PCI. Data were collected on patient age, sex, body mass index, medical history, current medication, heart failure, laboratory tests, culprit blood vessels, echocardiographic characteristics, and AMI type. The enrolled patients were divided into NOAF and non-NOAF groups. The baseline characteristics of patients in the two groups were compared, and the predictive correlation between FAR and NOAF was evaluated using logistic regression analysis and the receiver operating characteristic curve. RESULTS: Fifty-three (7.9%) patients developed NOAF during hospitalization. The occurrence of NOAF was found to be independently associated with higher FAR besides older age, higher neutrophil count, greater left atrial size, worse Killip class upon admission, lower body mass index, lower platelet count, lower left ventricle ejection fraction, and target left circumflex artery disease. FAR exhibited a better predictive value for the occurrence of NOAF during hospitalization (area under the curve, 0.732; 95% confidence interval, 0.659-0.808). CONCLUSIONS: FAR is a robust tool for predicting NOAF risk during hospitalization in patients with AMI after PCI and has a better predictive value than serum fibrin and serum albumin levels alone.

Effects of Gut Microbiota and Metabolites on Heart Failure and Its Risk Factors: A Two-Sample Mendelian Randomization Study.

Introduction: Previous observational studies have indicated that gut microbiota and metabolites may contribute to heart failure and its risk factors. However, with the limitation of reverse causality and confounder in observational studies, such relationship remains unclear. This study aims to reveal the causal effect of gut microbiota and metabolites on heart failure and its risk factors. Methods: This study collected summary statistics regarding gut microbiota and metabolites, heart failure, diabetes, hypertension, chronic kidney disease, myocardial infarction, atrial fibrillation, hypertrophic cardiomyopathy, dilated cardiomyopathy, coronary heart disease, valvular heart disease, and myocarditis. Two-sample Mendelian randomization analysis was performed using MR-Egger, inverse variance weighted (IVW), MR-PRESSO, maximum likelihood, and weighted median. Results: Results from gene prediction showed that among all gut microbiota, candida, shigella, and campylobacter were not associated with higher incidence of heart failure. However, genetic prediction suggested that for every 1 unit increase in shigella concentration, the relative risk increased by 38.1% for myocarditis and 13.3% for hypertrophic cardiomyopathy. Besides, for every 1 unit increased in candida concentration, the relative risk of chronic kidney disease increased by 7.1%. As for intestinal metabolites, genetic prediction results suggested that for every 1 unit increase in betaine, the relative risk of heart failure and myocardial infarction increased by 1.4% and 1.7%, separately. Conclusions: This study suggested new evidence of the relationship between gut microbiota and heart failure and its risk factors, which may shed light on designing microbiome- and microbiome-dependent metabolite interventions on heart failure and its risk factors in clinical trials in the future.

The Enhancement of H2 Evolution over Sr1-1.5xTbxWO4 Solid Solution under Ultraviolet Light Irradiation.

In this work, Sr1-1.5xTbxWO4 (0 ≤ x ≤ 0.2) solid solutions were synthesized via a traditional high-temperature solid state method. Le Bail fitting on the powder X-ray diffraction (XRD) pattern showed that these solid solutions are pure phase. Scanning electron microscopy showed that the SrWO4 and Sr0.82Tb0.12WO4 samples are composed of micrometer particles and submicron crystallites, respectively. Ultraviolet-visible diffuse reflectance spectra suggested that the bandgaps of Sr1-1.5xTbxWO4 are narrower than the undoped sample. The Sr0.82Tb0.12WO4 sample, with the assistance of 1.5 wt % Ru-cocatalyst, exhibits the best performance for H2 evolution in 5 vol % aqueous triethanolamine (TEOA), which results in about 6.1 and 2.8 times efficiency improvement compared with the intrinsic SrWO4 in methanol and aqueous TEOA, respectively. All the photocatalysts recycled after the photocatalytic reactions showed no degradation when checked by powder XRD.

Highly improved photocatalytic degradation of rhodamine B over Bi2Ga4-x Fe x O9 solid solutions under visible light irradiation.

In this work, Bi2Ga4-x Fe x O9 (0 ≤ x ≤ 1.2) solid solutions were prepared via the traditional high-temperature solid-state reaction. The Le Bail fitting on the powder X-ray diffraction patterns shows that these solid solutions were successfully synthesized. Scanning electron microscopy showed that the Bi2Ga3.2Fe0.8O9 sample was composed of sub-micron particle crystallites. Energy dispersive spectroscopy analysis and X-ray photoelectron spectroscopy were used to identify that the Fe element is trivalent when doping into the crystal structure. Ultraviolet-visible diffused reflectance spectra suggested that the bandgap of Bi2Ga3.2Fe0.8O9 is narrower than that of the undoped Bi2Ga4O9 sample. Three strategies, including Fe3+ doping, addition of H2O2, and loading of the cocatalyst, were utilized to improve the photocatalytic degradation activity. The optimum photocatalytic performance was obtained over 2.5 wt% Cu/Bi2Ga3.2Fe0.8O9 sample in 20 ppm RhB aqueous solution (containing 1.5 mL H2O2) under visible light irradiation. Its photodegradation rate is 8.0 times that of Bi2Ga4O9 containing 0.5 mL H2O2. The 2.5 wt% Cu/Bi2Ga3.2Fe0.8O9 photocatalyst remained stable and active even after four cycles. Also, its photocatalytic conversion efficiency for RhB was nearly 100%, which was achieved in 3 hours. The photocatalytic mechanism indicated that ·OH and h+ played an important role in the photocatalytic degradation reaction.

Prognostic Factors and Survival in Primary Central Nervous System Lymphoma: A Population-Based Study.

OBJECTIVE: This study sought to explore the prognostic factors in a large retrospective cohort of patients with primary central nervous system lymphoma (PCNSL) from the Surveillance, Epidemiology, and End Results database. METHODS: There were 5903 patients with PCNSL who had complete clinical information and were identified in the Surveillance, Epidemiology, and End Results program between 1973 and 2014. The epidemiology, therapeutic measures, and clinical characteristics were listed as descriptive statistics. They were grouped into 4 categories: immunocompetent individual with diffuse large B cell lymphoma (DLBCL), immunocompetent individual with non-DLBCL, immunocompromised individual with DLBCL, and immunocompromised individual with non-DLBCL based on different subtypes and immunological status. Survival analysis was conducted with Cox regression models. RESULTS: Different demographics and clinical characteristics were identified as independent factors in different groups. In survival analysis, for patients with DLBCL, chemotherapy involving treatments was associated with the most favorable survival. Received-only radiation could be considered as a primary treatment in immunocompetent patients with non-DLBCL. These differences were statistically significant (P < 0.05). CONCLUSION: PCNSL patients treated with appropriate chemotherapy treatments may receive stable tumor control.

FGF2 Attenuates Neural Cell Death via Suppressing Autophagy after Rat Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) can lead to physical and cognitive deficits, which are caused by the secondary injury process. Effective pharmacotherapies for TBI patients are still lacking. Fibroblast growth factor-2 (FGF2) is an important neurotrophic factor that can stimulate neurogenesis and angiogenesis and has been shown to have neuroprotective effects after brain insults. Previous studies indicated that FGF2's neuroprotective effects might be related to its function of regulating autophagy. The present study investigated FGF2's beneficial effects in the early stage of rat mild TBI and the underlying mechanisms. One hundred and forty-four rats were used for creating controlled cortical impact (CCI) models to simulate the pathological damage after TBI. Our results indicated that pretreatment of FGF2 played a neuroprotective role in the early stage of rat mild TBI through alleviating brain edema, reducing neurological deficits, preventing tissue loss, and increasing the number of surviving neurons in injured cortex and the ipsilateral hippocampus. FGF2 could also protect cells from various forms of death such as apoptosis or necrosis through inhibition of autophagy. Finally, autophagy activator rapamycin could abolish the protective effects of FGF2. This study extended our understanding of FGF2's neuroprotective effects and shed lights on the pharmacological therapy after TBI.

Serum ficolin-2 concentrations are significantly changed in patients with hepatitis B virus infection and liver diseases.

Human ficolin-2 is an important lectin complement pathway activator that is secreted from liver cells and has been implicated as an anti-infection innate immune molecule. However, the role of ficolin-2 protein and its dynamic changes over the course of and in the prognosis of chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC) remain unclear. In this study, we analyzed ficolin-2 protein expression in a cohort of individuals with CHB infection, HCC and cirrhosis. A sandwich enzyme-linked immunosorbent assay (ELISA) method was used to measure serum ficolin-2 concentrations. Ficolin-2 expression in liver tissues was detected by immunohistochemical staining. Serum ficolin-2 concentrations in CHB patients were significantly higher than in healthy controls and HBV carriers. After 48 weeks of routine amelioration liver function treatment, serum ficolin-2 concentrations decreased and were positively correlated with favorable alanine aminotransferase (ALT), HBV DNA and HBeAg-seroconversion outcomes. Interestingly, we observed much lower expression of serum and intrahepatic ficolin-2 in HCC and cirrhosis compared with healthy controls. Our findings suggest that serum and intrahepatic ficolin-2 levels may be considered one of the indicators for the response of chronic HBV infection, HCC and cirrhosis.

7, 8-Dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is characterized by immature dendritic spine architectures and cognitive impairment. 7, 8-Dihydroxyflavone (7, 8-DHF) has recently been identified as a high affinity tropomyosin receptor kinase B (TrkB) agonist. The purpose of this paper was to examine the utility of 7, 8-DHF as an effective pharmacotherapeutic agent that targets dendritic pathology and cognitive impairments in FXS mutant. We synthesized pharmacologic, behavioral, and biochemical approaches to examine the effects of 7, 8-DHF on spatial and fear memory functions, and morphological spine abnormalities in fragile X mental retardation 1 (Fmr1) gene knock-out mice. The study found that 4 weeks of treatment with 7, 8-DHF improved spatial and fear memory, and ameliorated morphological spine abnormalities including the number and elongation of spines in the hippocampus and amygdala. Further mechanism analysis revealed that 7, 8-DHF enhanced the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GluA1 receptor, but reduced the normal levels of GluA2 at the synapses in Fmr1. Potentially related to drug-induced changes in AMPA receptor subunits, 7, 8-DHF at the synapses led to phosphorylation of specific serine sites on subunits Ser818 and Ser813 of GluA1, and Ser880 of GluA2, as well as phosphorylation of TrkB, calcium/calmodulin-dependent protein kinase II, and protein kinase C. However, 7, 8-DHF neither affected behavioral performance nor increased TrkB phosphorylation in WT mice, which suggested that it had FXS-specific correcting effect. Altogether, these results demonstrated that 7, 8-DHF improved learning and memory, and reduced abnormalities in spine morphology, thus providing a potential pharmacotherapeutic strategy for FXS.

Benidipine protects kidney through inhibiting ROCK1 activity and reducing the epithelium-mesenchymal transdifferentiation in type 1 diabetic rats.

We investigated the protective effect of benidipine, by testing the changes of the activity of Rho kinase and transdifferentiation of renal tubular epithelium cells in vivo. Wistar rats were randomly divided into two groups: normal (N) and diabetes. STZ were used to make the rats type 1 diabetic and were randomly assigned as diabetes without treatment (D), diabetes treated with benidipine (B), and diabetes treated with fasudil (F) and treated for 3 months. Immunohistochemistry and western blotting were for protein expressions of ROCK1, α-SMA, and E-cadherin and real-time PCR for the mRNA quantification of ROCK1. Compared with N group, D group had significant proliferation of glomerular mesangial matrix, increased cell number, thickened basement membrane, widely infiltrated by inflammatory cells and fibrosis in the renal interstitial, and dilated tubular. Those presentations in F and B groups were milder. Compared with N group, D group showed elevated MYPT1 phosphorylation, increased expression of ROCK1, α-SMA protein, and ROCK1 mRNA and decreased expression of E-cadherin protein. B group showed attenuated MYPT1 phosphorylation, decreased ROCK1, α-SMA protein, and ROCK1 mRNA expression and increased expression of E-cadherin protein. In conclusion, benidipine reduces the epithelium-mesenchymal transdifferentiation and renal interstitial fibrosis in diabetic kidney by inhibiting ROCK1 activity.

CS-SELEX generates high-affinity ssDNA aptamers as molecular probes for hepatitis C virus envelope glycoprotein E2.

Currently, the development of effective diagnostic reagents as well as treatments against Hepatitis C virus (HCV) remains a high priority. In this study, we have described the development of an alive cell surface--Systematic Evolution of Ligands by Exponential Enrichment (CS-SELEX) technique and screened the functional ssDNA aptamers that specifically bound to HCV envelope surface glycoprotein E2. Through 13 rounds of selection, the CS-SELEX generated high-affinity ssDNA aptamers, and the selected ssDNA aptamer ZE2 demonstrated the highest specificity and affinity to E2-positive cells. HCV particles could be specifically captured and diagnosed using the aptamer ZE2. A good correlation was observed in HCV patients between HCV E2 antigen-aptamer assay and assays for HCV RNA quantities or HCV antibody detection. Moreover, the selected aptamers, especially ZE2, could competitively inhibit E2 protein binding to CD81, an important HCV receptor, and significantly block HCV cell culture (HCVcc) infection of human hepatocytes (Huh7.5.1) in vitro. Our data demonstrate that the newly selected ssDNA aptamers, especially aptamer ZE2, hold great promise for developing new molecular probes, as an early diagnostic reagent for HCV surface antigen, or a therapeutic drug specifically for HCV.

Roles of TNF-alpha gene polymorphisms in the occurrence and progress of SARS-Cov infection: a case-control study.

BACKGROUND: Host genetic factors may play a role in the occurrence and progress of SARS-Cov infection. This study was to investigate the relationship between tumor necrosis factor (TNF)-alpha gene polymorphisms with the occurrence of SARS-CoV infection and its role in prognosis of patients with lung interstitial fibrosis and femoral head osteonecrosis. METHODS: The association between genetic polymorphisms of TNF-alpha gene and susceptibility to severe acute respiratory syndromes (SARS) was conducted in a hospital-based case-control study including 75 SARS patients, 41 health care workers and 92 healthy controls. Relationships of TNF-alpha gene polymorphisms with interstitial lung fibrosis and femoral head osteonecrosis were carried out in two case-case studies in discharged SARS patients. PCR sequencing based typing (PCR-SBT) method was used to determine the polymorphisms of TNF-alpha gene in locus of the promoter region and univariate logistic analysis was conducted in analyzing the collected data. RESULTS: Compared to TT genotype, the CT genotype at the -204 locus was found associated with a protective effect on SARS with OR(95%CI) of 0.95(0.90-0.99). Also, TT genotype, CT and CC were found associated with a risk effect on femoral head necrosis with ORs(95%CI) of 5.33(1.39-20.45) and 5.67(2.74-11.71), respectively and the glucocorticoid adjusted OR of CT was 5.25(95%CI 1.18-23.46) and the combined (CT and CC) genotype OR was 6.0 (95%CI 1.60-22.55) at -1031 site of TNF-alpha gene. At the same time, the -863 AC genotype was manifested as another risk effect associated with femoral head necrosis with OR(95%CI) of 6.42(1.53-26.88) and the adjusted OR was 8.40(95%CI 1.76-40.02) in cured SARS patients compared to CC genotype. CONCLUSION: SNPs of TNF-alpha gene of promoter region may not associate with SARS-CoV infection. And these SNPs may not affect interstitial lung fibrosis in cured SARS patients. However, the -1031CT/CC and -863 AC genotypes may be risk factors of femoral head necrosis in discharged SARS patients.