Human Tumor Necrosis Factor-α Research Articles

Correlation of preoperative inflammatory factors and emotional disorders with postoperative delirium in patients with craniocerebral trauma.

Traumatic brain injury (TBI) imposes a substantial societal and familial burden due to its high disability and fatality rates, rendering it a serious public health problem. Some patients with TBI have poor treatment outcomes and are prone to postoperative delirium (POD), which affects their quality of life. Anxiety has been linked to increased POD incidence in some studies, while others have found no correlation. To investigate the correlation of POD risk factors, preoperative inflammatory factors, and mood disorders in patients with TBI. We retrospectively collected data on the treatment of 80 patients with TBI from November 2021 to September 2023. Patients were grouped as POD and non-POD, according to their POD status, and the general data of the two groups were compared. Inflammatory factor levels were detected preoperatively, and the Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) were used to investigate the risk factors associated with POD in these patients. Logistic regression was used to identify the independent risk factors. Twenty-one patients (26.25%) developed POD, including 7, 10, and 4 cases of the excitatory, inhibitory, and mixed types, respectively. There were 59 cases (73.75%) in the non-POD group. Compared with the non-POD group, the POD group had a significantly higher proportion of patients with low Glasgow Coma Scale (GCS) scores before admission, unilateral mydriasis, preoperative hemorrhagic shock, intraventricular hemorrhage (IVH), and postoperative hyperglycemic hyperosmolar disease (P < 0.05). In the POD group, interleukin-6 (IL-6), human tumor necrosis factor-α (TNF-α), myeloperoxidase levels, HAMA, and HAMD scores were higher than those in the non-POD group (all P < 0.05). Logistic multivariate analysis showed that GCS score at admission, IVH, IL-6, TNF-α, HAMA, and HAMD were independent risk factors for POD in patients with TBI (P < 0.05). Low GCS score at admission, IVH, elevated IL-6 and TNF-α, other inflammatory indicators, anxiety, and depression, can increase the risk of POD in patients with TBI after surgery.

Novel peptide inhibitor of human tumor necrosis factor-α has antiarthritic activity

The inhibition of tumor necrosis factor (TNF)-α trimer formation renders it inactive for binding to its receptors, thus mitigating the vicious cycle of inflammation. We designed a peptide (PIYLGGVFQ) that simulates a sequence strand of human TNFα monomer using a series of in silico methods, such as active site finding (Acsite), protein–protein interaction (PPI), docking studies (GOLD and Flex-X) followed by molecular dynamics (MD) simulation studies. The MD studies confirmed the intermolecular interaction of the peptide with the TNFα. Fluorescence-activated cell sorting and fluorescence microscopy revealed that the peptide effectively inhibited the binding of TNF to the cell surface receptors. The cell culture assays showed that the peptide significantly inhibited the TNFα-mediated cell death. In addition, the nuclear translocation of the nuclear factor kappa B (NFκB) was significantly suppressed in the peptide-treated A549 cells, as observed in immunofluorescence and gel mobility-shift assays. Furthermore, the peptide protected against joint damage in the collagen-induced arthritis (CIA) mouse model, as revealed in the micro focal-CT scans. In conclusion, this TNFα antagonist would be helpful for the prevention and repair of inflammatory bone destruction and subsequent loss in the mouse model of CIA as well as human rheumatoid arthritis (RA) patients. This calls upon further clinical investigation to utilize its potential effect as an antiarthritic drug.

The role of PANoptosis in renal vascular endothelial cells: Implications for trichloroethylene-induced kidney injury

Trichloroethylene (TCE), a widely distributed environmental chemical contaminant, is extensively dispersed throughout the environment. Individuals who are exposed to TCE may manifest occupational medicamentose-like dermatitis due to trichloroethylene (OMDT). Renal impairment typically manifests in the initial phase of OMDT and is intricately linked to the disease progression and patient outcomes. Although recombinant human tumor necrosis factor-α receptor II fusion protein (rh TNFR:Fc) has been employed in the clinical management of OMDT, there was no substantial improvement in renal function observed in patients following one week of treatment. This study primarily examined the mechanism of TNFα- and IFNγ-induced endothelial cells (ECs) PANoptosis in TCE-induced kidney injury and hypothesized that the synergistic effect of TNFα and IFNγ could be the key factor affecting the efficacy of rh TNFR:Fc therapy in OMDT patients. A TCE-sensitized mouse model was utilized in this study to investigate the effects of TNFα and IFNγ neutralizing antibodies on renal vascular endothelial cell PANoptosis. The gene of interferon regulatory factor 1 (IRF1) in human umbilical vein endothelial cells (HUVEC) was silenced by using small interfering RNA (siRNA), and the cells were then treated with TNFα and IFNγ recombinant protein to investigate the mechanism of TNFα combined with IFNγ-induced PANoptosis in HUVEC. The findings indicated that mice sensitized to TCE exhibited increased levels of PANoptosis-related markers in renal endothelial cells, and treatment with TNFα and IFNγ neutralizing antibodies resulted in a significant reduction in PANoptosis and improvement in renal function. In vitro experiments demonstrated that silencing IRF1 could reverse TNFα and IFNγ-induced PANoptosis in endothelial cells. These results suggest that the efficacy of rh TNFR:Fc may be influenced by TNFα and IFNγ-mediated PANoptosis in kidney vascular endothelial cells. The joint application of TNFα and IFNγ neutralizing antibody represented a solid alternative to existing therapeutics.

Protective Effect of Prunella vulgaris L. Whole Plant or Spicas Water Extracts on Hyperthyroidism with Liver-yang Hyperactivity Syndrome

Background: Prunella vulgaris L. (Lamiaceae) is a perennial medicinal plant commonly used to treat thyroid dysfunction, infectious hepatitis, and mastitis in north-east Asia and Europe. In China, there has been a historical change in the medicinal use of P. vulgaris from the use of whole plants to the use of the spicas. Purpose: This study aimed to evaluate the protective effects of whole plant P. vulgaris water extracts and spicas on hyperthyroidism with liver-yang hyperactivity syndrome and to preliminarily explain the mechanism of action of these water extracts. Methods: Rats were induced with aconite decoction and levothyroxine and treated with P. vulgaris whole plant and spicas water extract for 28 days at the same time. Body weight, food intake, and rectal temperature were monitored. The serum thyroid function indicators thyroid stimulating hormone (TSH), thyroid hormone-free triiodothyronine (FT3) and free thyroxine (FT4), liver function index alanine aminotransferase (ALT) and aspartate aminotransferase (AST), oxidative damage index malondialdehyde (MDA), and superoxide dismutase (SOD) were detected. Liver and thyroid tissues were taken for sectioning and observation. The liver inflammatory factors human tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were detected by immunohistochemistry, and the expression levels of the apoptotic proteins caspase-3 and B-cell lymphoma-2 (Bcl-2) were detected. Results: Both P. vulgaris whole plant and spica water extract groups exhibited markedly reduced FT3 and FT4 contents, increased the TSH content, and decreased ALT and AST activities. Furthermore, these agents improve thyroid and liver lesion tissue; reduce MDA content; increase SOD activity; reduce IL-6, TNF-α, and caspase-3 expression; and increase Bcl-2 expression. Conclusion: The whole plant and spicas water extracts of P. vulgaris have obvious protective effects on hyperthyroidism and hyperactivity in liver yang, and the protective effect of the water extract of spicas is greater than that of the whole plant water extract.

THE SEVERITY OF VASCULAR INFLAMMATION AND ITS RELATIONSHIP WITH CLINICAL AND FUNCTIONAL FEATURES IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE WITHOUT CONCOMITANT CARDIOVASCULAR PATHOLOGY

The Russian Federation is one of the countries with a high prevalence of chronic obstructive pulmonary disease (COPD). In the last decade, the list of families of chemical regulators of vascular inflammation in COPD has been supplemented with information about growth factors, whose participation in the processes of regulation of vascular function seems significant. The study of the role of angiogenesis factors in patients with isolated COPD disease is insufficient at this stage and needs to be clarified. Objective. To study was to identify diagnostic and prognostic criteria for the severity of vascular inflammation and to assess its relationship with clinical and functional features in patients with COPD without concomitant cardiovascular pathology in comparison with the clinical phenotype of the disease. Material and methods. 96 patients with COPD were examined, the median age was 61 years. In addition to standard clinical, functional and laboratory research methods, the severity of vascular inflammation was assessed in all examined patients with the determination of quantitative indicators of human platelet growth AA factor and tumor necrosis factor-α (TNFα) by quantitative solid-phase enzyme immunoassay Results. In all patients with isolated COPD, regardless of the risk of developing the underlying disease, an increase in the level of platelet growth AA factor and TNFα was noted. The level of platelet growth AA factor and TNFα in patients with COPD, regardless of the risk of exacerbation, was correlated with the functional state of the lungs, clinical phenotype and severity of clinical manifestations of the disease. The value of platelet growth AA factor above 317 ng/ml in patients with COPD may be an early marker of endothelial dysfunction and a predictor of the development of hemostatic disorders and concomitant cardiovascular pathology.

THE SEVERITY OF VASCULAR INFLAMMATION AND ITS RELATIONSHIP WITH CLINICAL AND FUNCTIONAL FEATURES IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE WITHOUT CONCOMITANT CARDIOVASCULAR PATHOLOGY

The Russian Federation is one of the countries with a high prevalence of chronic obstructive pulmonary disease (COPD). In the last decade, the list of families of chemical regulators of vascular inflammation in COPD has been supplemented with information about growth factors, whose participation in the processes of regulation of vascular function seems significant. The study of the role of angiogenesis factors in patients with isolated COPD disease is insufficient at this stage and needs to be clarified. Objective. To study was to identify diagnostic and prognostic criteria for the severity of vascular inflammation and to assess its relationship with clinical and functional features in patients with COPD without concomitant cardiovascular pathology in comparison with the clinical phenotype of the disease. Material and methods. 96 patients with COPD were examined, the median age was 61 years. In addition to standard clinical, functional and laboratory research methods, the severity of vascular inflammation was assessed in all examined patients with the determination of quantitative indicators of human platelet growth AA factor and tumor necrosis factor-α (TNFα) by quantitative solid-phase enzyme immunoassay Results. In all patients with isolated COPD, regardless of the risk of developing the underlying disease, an increase in the level of platelet growth AA factor and TNFα was noted. The level of platelet growth AA factor and TNFα in patients with COPD, regardless of the risk of exacerbation, was correlated with the functional state of the lungs, clinical phenotype and severity of clinical manifestations of the disease. The value of platelet growth AA factor above 317 ng/ml in patients with COPD may be an early marker of endothelial dysfunction and a predictor of the development of hemostatic disorders and concomitant cardiovascular pathology.

Total flavonoids of Hippophae rhamnoides L. improves type 2 diabetes symptoms in rats through down-regulating of the DAG/PRKCA/MAPK10/p65/TNF-α signalling pathway

Ethnopharmacological relevanceDry mature fruits of Hippophae rhamnoides L. (HRL), Elaeagnaceae, have traditional functions of invigorating spleen and improving spleen insufficiency. Traditional Chinese medicine (TCM) clinics have been proved that HRL is in favor of diabetes treatment. Modern pharmacological studies demonstrated that total flavones of Hippophae rhamnoides (TFH) are the main substance for HRL to develop anti-inflammation and anti-diabetes functions. However, chemical features, active ingredients and anti-diabetes pharmacological mechanism of HRL still remain unclear. Aim of the studyKey targets and metabolites in anti-type-II diabetes mellitus (T2DM) of TFH have been explored based on AGE-RAGE signaling pathway in diabetic complications. The anti-T2DM mechanism of TFH has been elaborated from comprehensive perspectives, including target prediction, metabolites, potential metabolic pathways, and so on. Materials and methodsIn this study, a qualitative test of chemical composition of HRL was carried out based on ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The anti-T2DM targets and pathways of HRL were predicted through network pharmacological approach. The T2DM rat model was induced by high-fat and high-glucose diet combined with streptozotocin (STZ). The T2DM model was evaluated through fasting blood glucose level, body weight, serum biochemical indicators, insulin levels and homeostatic model assessment of insulin resistance. The key metabolic pathways were screened through the correlation between metabolites and key targets. Finally, the quantitative analysis of key targets and metabolites was verified through experiments. ResultsAfter TFH intervention, the fasting blood-glucose level of T2DM rats induced by high-fat and high-glucose diet combined with streptozotocin (STZ) was downregulated significantly, while body weight, serum liquid level, insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) were improved. According to ELISA, Western blotting (WB) and reverse transcriptase polymerase chain reaction (RT-PCR), TFH significantly downregulates expression levels of diglyceride (DAG)-activated protein kinase C (PRKCA), mitogen activated protein kinase 10 (MAPK10), human nuclear factor κB subunit p65 (NF-κB p65) and tumor necrosis factor-α (TNF-α) in pancreas of STZ-induced rats. ConclusionsTFH downregulates expressions of PRKCA, MAPK10 and p65 TNF-α as well as level of the key metabolite DA in the DAG/PRKCA/MAPK10/TNF-α/p65 pathways, improves lipid metabolism disorder, inhibits inflammatory response and thereby relieves symptoms of T2DM.

Ultrasound and microbubble-mediated delivery of miR-424-5p has a therapeutic effect in preeclampsia

ObjectiveTo determine the influence of ultrasound/microbubble-mediated miR-424-5p delivery on trophoblast cells and the underlying mechanism.MethodsBlood pressure and 24-h proteinuria of patients with preeclampsia (PE) were measured as well as the levels of miR-424-5p and amine oxidase copper containing 1 (AOC1) in placental tissues. HTR-8/Svneo and TEV-1 cells were subjected to cell transfection or ultrasonic microbubble transfection for determination of the expression of miR-424-5p, AOC1, β-catenin and c-Myc as well as cell proliferation, apoptosis, migration and invasiveness. The concentrations of placental growth factor (PLGF), human chorionic gonadotropin (β-hCG) and tumor necrosis factor-α (TNF-α) were measured in HTR-8/Svneo and TEV-1 cells. RNA immunoprecipitation (RIP) and dual luciferase reporter assay detected the binding of miR-424-5p to AOC1. A PE mouse model was induced by subcutaneous injection of L-NAME, where the influence of ultrasound/microbubble-mediated miR-424-5p delivery was evaluated.ResultsmiR-424-5p was downregulated while AOC1 was upregulated in the placental tissues from PE patients. Overexpression of miR-424-5p activated Wnt/β-catenin signaling pathway and promoted the proliferation of HTR-8/Svneo and TEV-1 cells as well as enhanced the migratory and invasive behaviors. AOC1 overexpression partly eliminated the effects of miR-424-5p on HTR-8/Svneo and TEV-1 cells. Ultrasound and microbubble mediated gene delivery enhanced the transfection efficiency of miR-424-5p and further promoted the effects of miR-424-5p in trophoblast cells. Ultrasound/microbubble-mediated miR-424-5p delivery alleviated experimental PE in mice.ConclusionUltrasound and microbubble-mediated miR-424-5p delivery targets AOC1 and activates Wnt/β-catenin signaling pathway, thus promoting the aggressive phenotype of trophoblast cells, which indicating that miR-424-5p/AOC1 axis might be involved with PE pathogenesis.

Antiproliferative, Anti-Inflammatory and Anti-Microbial Activities of Synthesized Benzo[f]benzo[4,5]imidazo[1,2-d][1,4]oxazepine and Benzo[f]benzo[4,5]oxazolo[3,2-d][1,4]oxazepine Derivatives

Synthesized benzoxazepine derivatives have been characterized and evaluated using 1 H, 13C nuclear magnetic resonance (NMR), DEPT 135 (distortionless enhancement by polarization transfer), and high resolution mass spectrometry (HRMS) to confirm the leading benzoxazepine chemical structures. X-ray crystal structure of compounds 10 and 13 (10,11-dimethyl-6,7-dihydrobenzo[f] benzo[4,5]imidazo[1,2-d][1,4]oxazepine and 8,9-dihydrobenzo[4,5]imidazo[1,2-d]naphtho[1,2-f] [1,4]oxazepine) were obtained after successful diffraction of the compound crystals. The anti-microbial, anti-cancer and anti-inflammatory activities of the synthesized benzoxazepine derivatives were evaluated. The effect of benzoxazepine derivatives on cancer cell proliferation and microbial growth was studied. Our results revealed limited antimicrobial activity to the synthesized benzoxazepine derivatives with significant activities against certain bacterial pathogens for two compounds. The synthesized benzoxazepine derivatives displayed cytotoxicity against selected solid tumor cell lines with varying effects on the release of human interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) pro-inflammatory cytokines depending on the cancer cell type used. The results of the study suggest that the synthesized benzoxazepine derivatives show anti-cancer and anti-inflammatory agents, though with dependence on the type of cancer cell line.

Comparative Pharmacokinetics, Safety, and Immunogenicity Study of the Prefilled Syringe and Lyophilized Formulation of a Recombinant Human Tumor Necrosis Factor-α Receptor II:lgG Fc Fusion Protein in Healthy Chinese Male Subjects.

This study aimed to compare the pharmacokinetics, safety, and immunogenicity of the prefilled syringe (PFS) with lyophilized (LYO) recombinant human tumor necrosis factor-α receptor II:lgG Fc fusion protein (rhTNFR:Fc) in healthy Chinese male subjects. A single-center, randomized, open-label,2-period, crossover study was performed in healthy Chinese male subjects. Subjects were randomly assigned into 2 sequences and received a subcutaneous injection of 25 mg rhTNFR:Fc PFS or rhTNFR:Fc LYO (Anbainuo), with a 35-day washout between the 2 periods. Blood samples were collected at specified time intervals, and then serum concentrations of rhTNFR:Fc were analyzed by enzyme-linked immunosorbent assay. The maximum serum concentration, area under the concentration-time curve (AUC) from time 0 to the last quantifiable concentration, and AUC from time 0 to infinity were all calculated and evaluated. Meanwhile, safety and immunogenicity were also assessed. A total of 82 subjects completed the study, and six subjects withdrew for various reasons. The 90%CIs for geometric mean ratios of maximum serum concentration, AUC from time 0 to the last quantifiable concentration, and AUC from time 0 to infinity were all within the equivalence range of80% to 125%. Safety was comparable between the 2 formulations with low immunogenicity. rhTNFR:Fc PFS exhibited similar pharmacokinetic and safety profiles of rhTNFR:Fc LYO (Anbainuo) in healthy Chinese male subjects.

Distribution of TNF-α -308 G/A polymorphism among pediatric patients with pneumonia in Ulaanbaatar

Genetic studies indicate to the importance of individual genetic diversity on predictor of mortality. Furthermore, Single Nucleotide Polymorphisms can be used to identify disease-causing genes in humans and they can be either neutral or deleterious. Human Tumor necrosis factor-α is a well-known inflammation factor that is closely associated with sepsis and severe sepsis. Our objective was to evaluate the association of TNF-α -308 G/A promoter polymorphism with dependency to severity of pneumonia. Respiratory diseases, especially pneumonia, is the major cause of mortality and morbidity in Ulaanbaatar, Mongolia and the leading causes of pediatric hospitalization. We collected blood samples from 101 pediatric patients of the age group between "new born" and "school aged", who were treated and diagnosed with pneumonia in February 2019 and 2020, the pneumonia season in the country. Genomic DNA was extracted and performed by PCR-RFLP method to detect the presence of SNPs. The studies showed that the TNF-α -308 G/A polymorphism among pediatric patients, genotype G;G was 73.27%, genotype A;G was 22.77%, and genotype A;A was 3.96%. Our study demonstrated disassociation of TNF-α -308 G/A polymorphism with pneumonia severity in population.

Isolation, physicochemical, and structure–function relationship of the hydrophobic variant of Fc-fusion proteins that bind to TNF-α receptor, HS002 and HS002A

HS002 is the recombinant human tumor necrosis factor-α receptor Ⅱ: IgG Fc fusion protein licensed in China to treat rheumatism and psoriasis. The aim of this study was to isolate and characterize the hydrophobic freeze-dried powder injection (HS002) and ampoule injection (HS002A) variants derived from proteins of the same sequence and then to explore the structure–function relationship. Extensive physicochemical and structural testing was performed during a side-by-side comparison of the monomer peak and variant. Then the TNF-α-related binding activity, cell biological activity and affinity with FcRn were analyzed. Finally, a transformation study of the hydrophobic variant was performed under serum-like redox conditions. This research revealed that HS002A has similar physicochemical and structure–function relationship profiles to those of HS002. The hydrophobic variant exhibited the presence of new incorrect disulfide bridging. At the same time, this novel disulfide scrambled species structure–function relationship was found to be the molecular basis for reduced TNF-α binding and cell biological activities. In addition, incorrect disulfide bridging was found to be reversible under serum-like redox conditions, restoring TNF-α binding and cell biological activities to almost normal levels, all of which indicate that the variant is probably irrelevant to clinical efficacy once the drug enters the bloodstream.

Anti-Inflammatory and Antioxidant Activity of Hydroxytyrosol and 3,4-Dihydroxyphenyglycol Purified from Table Olive Effluents.

New liquid effluents based on the use of acetic acid in the table olive industry make it easier to extract bioactive compounds to be used for food, cosmetic, and pharmaceutical purposes. The use of water acidified with acetic acid or in brine with or without acetic acid for storing the table olive enhances the extraction of two more active phenolic compounds: hydroxytyrosol (HT) and 3,4-dihydroxyphenylglycol (DHPG). This work has two aims: (1) measure the solubilization of phenolics controlled for two years using more than thirty olive varieties with different ripeness index as a potential source of HT and DHPG, and (2) evaluate the anti-inflammatory activity of the purified phenolics. The effluents with a higher concentration of phenolics were used for the extraction of HT and DHPG in order to evaluate its antioxidant and anti-inflammatory activity in vitro by the determination of pro-inflammatory cytokines such as Human Tumor Necrosis Factor-α (TNF), Interleukin-6 (IL-6), and Interleukin-1β (Il-1β). The anti-inflammatory activity of these phenolic extracts was demonstrated by studying the expression of cytokines by qPCR and the levels of these proteins by enzyme-linked immunosorbent assay (ELISA).

Safety and tolerability of a humanized rabbit monoclonal antibody (SSS07) in healthy adults: Randomized double-blind placebo-controlled single ascending dose trial

Background/objectiveSSS07, a humanized rabbit monoclonal antibody, can selectively block human tumor necrosis factor-α (TNF-α). The objective of this study was to assess the safety, tolerability, and relative immunogenicity of SSS07 after multiple single subcutaneous (SC) doses in healthy volunteers. MethodsA total of 71 healthy volunteers were randomized to six sequential ascending-dose groups (5, 15, 30, 50, 75, and 100 mg), and except for the 100 mg group that only had one subject who received a placebo, all of the other groups included two placebo-control subjects. Safety, tolerability, and immunogenicity were assessed by physical examinations, vital signs, electrocardiography (ECG), clinical laboratory tests, and plasma anti-drug antibody (ADA) over 28 days for each group. Their concentrations of TNF-α were also analyzed. Only after safety and tolerance were determined in the lower-dose groups was the next dose group initiated. The dose increments did not exceed 100 mg. ResultsNo serious adverse events or dose-limited toxicity (DLT) were observed, so 100 mg was defined as the maximum tolerated dose (MTD). Overall, 71 AEs and 59 treatment-related adverse events (TRAEs) were reported in 36 (60.0%) and 30 (50.0%) volunteers, respectively, who received SSS07. All AEs and TRAEs were mild or moderate and expected based on previous results with similar types of drugs, without new safety concerns. Except for infections and administration site reactions, the frequency and intensity of the other TRAEs were similar for SSS07 and placebo. No severe acute immune reactions occurred. The lower dose’s immunogenicity was stronger than the higher doses. The highest ADA titer was observed 3 to 6 months after administration. ConclusionSSS07 was generally safe and well tolerated in healthy Chinese volunteers. Higher immunogenicity was observed at low SSS07 concentration levels. The infections and administration site conditions might have been related to the immunogenicity and the degree of inhibition of TNF-α. However, the existence of ADA did not appear to affect the safety of the subjects throughout the follow-up period. These findings could support further investigations of treatments with humanized monoclonal antibodies.

RhTSG-6 inhibits IL-1β-induced extracellular matrix degradation and apoptosis by suppressing the p38, and JNK pathways in nucleus pulposus cells.

Intervertebral disc degeneration (IDD) is one of the major causes of low back pain (LBP) which seriously affects health and normal physical activity. Recombinant human tumor necrosis factor-a (TNF-a) induced protein 6 (rhTSG-6) has been reported to have therapeutic effects on a variety of inflammatory diseases, but the effect and mechanism of rhTSG-6 action in IDD are not fully understood. The present study was aimed to explore the functional role of rhTSG-6 in interleukin (IL)-1b-induced nucleus pulposus (NP) cell model. Experimental human NP cells were isolated from the patients with idiopathic scoliosis and treated with culture medium containing IL-1b (10 ng/mL) for 24 hours to induce extracellular matrix degradation and apoptosis, simulating an IDD model in vitro. The viability of NP cells was analyzed by the CCK-8 assay. The relevant mRNA and protein levels were measured by RT-qPCR and western blot. The apoptosis of NP cells was determined by flow cytometry analysis and western blot. Compared with the NP cells without IL-1b treatment, IL-1b caused approximately 70% reduction in the viability of NP cells, while RhTSG-6 partly increased the decrease of IL-1b on cell viabilities. Moreover, treatment with rhTSG-6 considerably attenuated the upregulation of extracellular matrix (ECM)-catabolic factors (MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5), and increased the downregulation of ECM-anabolic factor (collagen II) in NP cells induced by IL-1b, indicating that ECM degradation was suppressed. Furthermore, rhTSG-6 also protected NP cells from IL-1b-induced apoptosis. Mechanically, rhTSG-6 inhibited the activation of members of mitogen-activated protein kinase (MAPK) pathway by blocking the phosphorylation of p38, c-Jun N-terminal kinase (JNK) and ERK in IL-1b-induced NP cells. RhTSG-6 can attenuate ECM degradation and apoptosis in IL-1b-induced NP cells by inhibiting the p38, JNK and ERK pathways, which may contribute to its potential application in the therapy of IDD.

Treatment of intestinal graft-versus-host disease with unrelated donor fecal microbiota transplantation capsules

Introduction:Fecal microbiota transplantation (FMT), administering fecal suspensions via a nasoduodenal tube, has achieved a promising effect in the treatment of intestinal graft-versus-host disease (GvHD) in some pilot studies. In this study, oral FMT capsules from unrelated donor were used for the first time in the treatment of intestinal GvHD. Patient concerns: A 31-year-old male who was diagnosed as “myelodysplastic syndromes with excess blasts II” (intermediate risk 2 of international prognostic scoring system) received human leukocyte antigen -matched sibling donor allogeneic hematopoietic stem cell transplantation. The patient developed diarrhea, vomiting, and bloody stool on 28 days after transplantation.Diagnosis:Intestinal acute GvHD was diagnosed clinically with histological confirmation by colonoscopy and pathological biopsy.Interventions:This patient was treated with first cycle of oral FMT capsules after failure to initial treatment of methylprednisolone (2 mg/kg/d) combined with recombinant human tumor necrosis factor–α receptorII: IgG Fc fusion protein (25 mg, biw). The symptoms of intestinal GvHD were relieved but recurred 11 days later. Second cycle of oral FMT capsules was carried out.Outcomes:After 2 cycles of fecal bacteria transplantation, intestinal GvHD was gradually controlled and did not recur again during the 2-month follow-up. The diversity and structure of the intestinal flora after FMT was closer to that of healthy donors than that before.Conclusion:Our case showed oral FMT capsules could be used as a treatment option for corticosteroid refractory intestinal GvHD. Further studies are warranted to assess the clinical efficacy and safety of oral FMT capsules in the treatment of intestinal GvHD.Rationale:Fecal microbiota transplantation (FMT), administering fecal suspensions via a nasoduodenal tube, has achieved a promising effect in the treatment of intestinal graft-versus-host disease (GvHD) in some pilot studies. In this study, oral FMT capsules from unrelated donor were used for the first time in the treatment of intestinal GvHD.Patient concerns:A 31-year-old male who was diagnosed as “myelodysplastic syndromes with excess blasts II” (intermediate risk 2 of international prognostic scoring system) received human leukocyte antigen -matched sibling donor allogeneic hematopoietic stem cell transplantation. The patient developed diarrhea, vomiting, and bloody stool on 28 days after transplantation.Diagnoses:Intestinal acute GvHD was diagnosed clinically with histological confirmation by colonoscopy and pathological biopsy.Interventions:This patient was treated with first cycle of oral FMT capsules after failure to initial treatment of methylprednisolone (2 mg/kg/d) combined with recombinant human tumor necrosis factor–a receptorII: IgG Fc fusion protein (25 mg, biw). The symptoms of intestinal GvHD were relieved but recurred 11 days later. Second cycle of oral FMT capsules was carried out.Outcomes:After 2 cycles of fecal bacteria transplantation, intestinal GvHD was gradually controlled and did not recur again during the 2-month follow-up. The diversity and structure of the intestinal flora after FMT was closer to that of healthy donors than that before.Conclusion: Our case showed oral FMT capsules could be used as a treatment option for corticosteroid refractory intestinal GvHD. Further studies are warranted to assess the clinical efficacy and safety of oral FMT capsules in the treatment of intestinal GvHD.Lessons:There is still a possibility of recurrence after the treatment of GvHD with capsule fecal microbiota transplantation. How to optimize the dosage and treatment course of fecal microbiota capsule administration needs further exploration.

Clinical study of anti-human T cell porcine immunoglobulin with recombinant human tumor necrosis factor-α receptor II: IgG Fc in the treatment of 35 cases of grade III/IV acute graft-versus-host disease after allo-HSCT

目的评估抗人T细胞猪免疫球蛋白（P-ATG）联合重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白（益赛普）治疗Ⅲ/Ⅳ度急性移植物抗宿主病（aGVHD）的疗效及安全性。方法对接受P-ATG（5 mg·kg−1·d−1×3～5 d，序贯5 mg/kg隔日1次～每周2次）联合益赛普（25 mg每周2次，儿童剂量减半）方案治疗的35例异基因造血干细胞移植（allo-HSCT）后合并Ⅲ/Ⅳ度aGVHD患者进行回顾性分析。结果①35例Ⅲ/Ⅳ度aGVHD患者中，男21例，女14例，中位年龄10（3～54）岁。急性髓系白血病（AML）19例，急性淋巴细胞白血病（ALL）13例，重型再生障碍性贫血（SAA）、骨髓增生异常综合征（MDS）、混合表型急性白血病（MPAL）各1例。②治疗28 d疗效评估：完全缓解（CR）12例（34.3％），部分缓解（PR）18例（51.4％），总有效率为85.7％（30/35），Ⅲ度aGVHD组总有效率高于Ⅳ度aGVHD组［100％（19/19）对68.8％（11/16），P＝0.004］。③治疗56 d疗效评估：CR 22例（62.9％），PR 5例（14.3％），总有效率为77.2％（27/35），Ⅲ度aGVHD组总有效率高于Ⅳ度aGVHD组［89.5％（17/19）对62.5％（10/16），P＝0.009］。④不良反应：35例患者输注P-ATG过程中均为发生发热、寒战、皮疹等不良反应，亦无明显肝肾功能损害发生。巨细胞病毒、EB病毒再激活率分别为77.1％（27/35）、22.9％（8/35），细菌感染发生率为48.6％（17/35）。⑤中位随访时间为13（1～55）个月，移植后1、2年的总生存率分别为（68.1±8.0）％、（64.3±8.4）％，Ⅲ度aGVHD组移植后1年总生存率高于Ⅳ度aGVHD组［（84.2±8.4）％对（47.6±13.1）％，χ2＝3.38，P＝0.05］。结论P-ATG联合重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白治疗allo-HSCT后Ⅲ/Ⅳ度aGVHD有较好的疗效和安全性。

Designing a new bispecific tandem single-chain variable fragment antibody against tumor necrosis factor-α and interleukin-23 using in silico studies for the treatment of rheumatoid arthritis.

Rheumatoid arthritis disease is a chronic auto-immune inflammatory disease that mainly causes synovial joint inflammation and cartilage destruction. The tumor necrosis factor-α (TNF-α) is a pivotal cytokine that plays an important role in rheumatoid arthritis. The treatments focusing on a single cytokine inhibition are clinically able to produce meaningful responses in only about half of the treated patients due to multiple cytokines involved in this disease. In the present study, a bispecific tandem single-chain variable fragment was designed in order to suppress both human tumor necrosis factor-α and interleukin-23 (IL23) as a potential therapeutic drug candidate for this disease. To do so, at first, eight bispecific tandem single-chain variable fragment models were built against tumor necrosis factor-α and interleukin-23 cytokines with different domain orders by the homology modeling, and then 50ns molecular dynamics simulation was performed for each one and then structural properties were exploited. The MD simulation results indicate the fact that the domains' order strongly affects tandem single-chain variable fragment properties, and in overall, the fragment VLAIL23+Linker+VHAIL23+linker+VLATNF+Linker +VHATNF +His6 (VL and VH are light and heavy chain variable fragments and AIL23 and ATNF are anti-interleukin 23 and anti-tumor necrosis factor-α, respectively, and His6 is the six histidine) not only separated antibody domains accurately but also had better stability and solvation free energy. Therefore, this structure can be considered as an effective potential drug for rheumatoid arthritis. It is expected that the findings of this research could shed a light on the treatment approaches of the rheumatoid arthritis disease.

重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白联合糖皮质激素治疗一例中毒性表皮坏死松解症

重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白联合糖皮质激素治疗一例中毒性表皮坏死松解症

重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白治疗中毒性表皮坏死松解症的临床疗效观察

重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白治疗中毒性表皮坏死松解症的临床疗效观察