Targeting kinase ITK treats autoimmune arthritis via orchestrating T cell differentiation and function.

IL-2 inducible T cell kinase (ITK) is critical in T helper subset differentiation and its inhibition has been suggested for the treatment of T cell-mediated inflammatory diseases. T follicular helper (Tfh), Th17 and regulatory T cells (Treg) also play important roles in the development of rheumatoid arthritis (RA), while the role of ITK in the development of RA and the intricate balance between effector T and regulatory T cells remains unclear. Here, we found that CD4+ T cells from RA patients presented with an elevated ITK activation. ITK inhibitor alleviated existing collagen-induced arthritis (CIA) and reduced antigen specific antibody production. Blocking ITK kinase activity interferes Tfh cell generation. Moreover, ITK inhibitor effectively rebalances Th17 and Treg cells by regulating Foxo1 translocation. Furthermore, we identified dihydroartemisinin (DHA) as a potential ITK inhibitor, which could inhibit PLC-γ1 phosphorylation and the progression of CIA by rebalancing Th17 and Treg cells. Out data imply that ITK activation is upregulated in RA patients, and therefore blocking ITK signal may provide an effective strategy to treat RA patients and highlight the role of ITK on the Tfh induction and RA progression.

Comprehensive Understanding and Evolutional Therapeutic Schemes for Pseudomyxoma Peritonei: A Literature Review.

Pseudomyxoma peritonei is an infrequent solid tumor in clinical practice. The low morbidity and deficient understanding of this mucus-secreting malignant disease increase the risks of delayed identification or uncontrollable deterioration. In quite a lot cases, patients go through complete cytoreduction surgery and hyperthermic intraperitoneal chemotherapy could receive a long time survival over 5 years. But the recurrence rate is also hard to overlook. Unlike other types of cancer, the standard treatment for this considerable groups has not been confirmed yet. With the advanced medical progression, studies have been carrying out based on pathogenesis, biological characters, and mutated gene location. All but a few get statistical survival benefits, let alone the breaking progress on research or therapeutic practice in the field. We try to give a comprehensive exposition of pseudomyxoma peritonei around the epidemiology, radiologic features, clinical manifestation, present treatment and promising schemes, hoping to arise much attention and reflection on the feasible solutions, especially for the recrudescent part.

NF-κB and AMPK-Nrf2 pathways support the protective effect of polysaccharides from Polygonatum cyrtonema Hua in lipopolysaccharide-induced acute lung injury.

ETHNOPHARMACOLOGICAL RELEVANCE: The raw and honey-processed P. cyrtonema recorded in ancient classics of Chinese medicine as having the effect of moisturizing the lungs and relieving coughs, and it has also been proved to have therapeutic effects on lung diseases in modern research. Polysaccharides are the main components with biological activities in raw and honey-processed P. cyrtonema, but there is no research for their lung-protective effect. AIM OF STUDY: This study aimed to investigate the protective effect and the possible mechanism of polysaccharides from raw and honey-processed P. cyrtonema in LPS-induced acute lung injury in mice. MATERIALS AND METHODS: Polysaccharides, PCP and HPCP, were respectively separated and extracted from raw and honey-processed P. cyrtonema, and the molecular weight, monosaccharide composition and other basic chemical characteristics were analyzed by HPGCP, HPLC, FI-IR, and NMR. The model of ALI mice was established by intratracheal instillation of LPS. Moreover, the protective effects of PCP and HPCP for ALI mice were evaluated by detecting the wet-to-dry ratio and histopathology in the lungs, the content of inflammatory factors TNF-α, IL-6, IL-1ß in BLAF, and the content of MPO and SOD in lung tissue. In addition, the lung-protective mechanism of PCP and HPCP was explored by detecting the levels of some proteins and mRNA related to inflammation and oxidative stress pathways. RESULTS: PCP and HPCP with molecular weights of 8.842 × 103 and 5.521 × 103Da were mainly composed of three monosaccharides. Moreover, it is found that fructose and galactose were mainly ß-D, and glucose was α-D. Both PCP and HPCP could significantly improve lung injury, reduce the level of inflammatory factors in BALF and the level of MPO in lung tissue, and increase the level of SOD. In addition, PCR and WB indicated that PCP and HPCP at least inhibited pulmonary inflammation through the NF-κB pathway, and reduced the occurrence of pulmonary oxidative stress through the AMPK-Nrf2 pathway. CONCLUSIONS: Polysaccharides from raw and honey-processed P. cyrtonema had a protective effect in LPS-induced lung injury in mice. This effect may be related to the antioxidant and anti-inflammatory activities of PCP and HPCP in the lungs through the NF-κB pathway and AMPK-Nrf2 pathway. And HPCP seems to perform more than PCP.

Oridonin Alters Hepatic Urea Cycle via Gut Microbiota and Protects against Acetaminophen-Induced Liver Injury.

Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Oridonin (OD), which is the major active ingredient of the traditional Chinese medicine Rabdosia rubescens, reportedly exerts anti-inflammatory and antioxidative effects. Here, we first find that OD protects against APAP-induced hepatotoxicity. The results of hepatic tissue-associated RNA-seq and metabolomics showed that the protective effects of OD were dependent upon urea cycle regulation. And such regulation of OD is gut microbiota partly dependent, as demonstrated by fecal microbiota transplantation (FMT). Furthermore, using 16S rRNA sequencing, we determined that OD significantly enriched intestinal Bacteroides vulgatus, which activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to regulate redox homeostasis against APAP by urea cycle. In conclusion, our study suggests that the Bacteroides vulgatus-urea cycle-Nrf2 axis may be a potential target for reducing APAP-induced liver injury, which is altered by OD.

Microstructure and mechanical behaviors of tibia for collagen-induced arthritic mice treated with gingiva-derived mesenchymal stem cells.

Rheumatoid arthritis (RA) is a systemic polyarticular arthritis that primarily affects the small joints but also causes bone erosion in large joints. None of the currently existing treatment approaches is curable. In this study, the effects of human gingiva-derived mesenchymal stem cells (GMSCs) on collagen-induced arthritis (CIA) mice are examined by experimentally assessing the microstructure and mechanical behaviors of tibia. Bone morphology and mineral density of mouse tibiae were assessed using micro-X-ray computed tomography (micro-CT). Compression testing was performed on mouse tibia to access its stiffness. The deformation and strain localized inside proximal tibia were mapped using mechanical testing coupled with micro-CT and digital volume correlation of micro-CT images. The results show that CIA disease caused bone erosion in epiphyseal cortical bone, which manifested into the adjacent epiphyseal trabecular bone, and also affected the metaphyseal cortical bone. CIA disease also weakened the load-bearing function of proximal tibia. GMSC treatment interfered with the progress of CIA, attenuated the bone erosion in epiphyseal and metaphyseal trabecular bone and resulted in improved load-bearing function of proximal tibia. GMSCs provide a promising potential treatment of autoimmune arthritis.

[Heat-sensitive moxibustion combined with western medication for low back pain of osteoporosis with kidney-yang deficiency: a randomized controlled trial].

OBJECTIVE: To compare the clinical therapeutic effect between heat-sensitive moxibustion combined with western medication and simple western medication for low back pain of osteoporosis with kidney-yang deficiency. METHODS: A total of 60 patients with osteoporosis were randomized into an observation group (32 cases, 2 cases dropped off) and a control group (32 cases, 3 cases dropped off). In the control group, alendronate sodium tablet and calcium carbonate and vitamin D3 tablet were taken orally. On the basis of the control group, heat-sensitive moxibustion was applied at Mingmen (GV 4), Yaoyangguan (GV 3), Guanyuan (CV 4), Shenshu (BL 23), Zusanli (ST 36) in the observation group, once a day, 5 times a week for 8 weeks. Before and after treatment，the visual analogue scale (VAS) score, Oswestry disability index (ODI) score, bone mineral density (BMD) and TCM clinical symptom score were compared in the two groups. RESULTS: The VAS scores, ODI scores and TCM clinical symptom scores after treatment were reduced in the two groups (P<0.05, P<0.01), and those in the observation group were lower than the control group (P<0.05, P<0.01). The BMD after treatment was increased in the two groups (P<0.01), and that in the observation group was higher than the control group (P<0.05). CONCLUSION: Heat-sensitive moxibustion combined with western medication could relieve low back pain, improve BMD in patients of osteoporosis with kidney-yang deficiency, and its clinical effect is superior to simple western medication.

Hyperthermic intraperitoneal chemotherapy combined with systemic chemotherapy for gastric cancer peritoneal carcinomatosis: A protocol for systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The prognosis of gastric cancer peritoneal carcinomatosis (GCPC) remains poor despite recent advances in systemic chemotherapy (SC) with an average survival less than 6 months. Current evidence supporting the utility of hyperthermic intraperitoneal chemotherapy (HIPEC) combined with SC for GCPC is limited. We plan to provide a systematic review and meta-analysis of randomized controlled trials to evaluate the comparative effects and safety of HIPEC combined with SC in the management of GCPC. METHODS: Randomized controlled trials evaluating HIPEC combined with SC versus SC as first-line treatment for GCPC will be searched in MEDLINE, EMBASE, Web of Science, the Cochrane Library, ClinicalTrials.gov, and Google Scholar, from database inception to April 30, 2020. Data on study design, participant characteristics, intervention details, and outcomes will be extracted. Primary outcomes to be assessed are: median progression-free survival; secondary outcomes are: median survival time, 1- year survival rate, 2-year survival rate, objective response rate, and adverse events. Meta-analysis will be performed using RevMan V.5.3 statistical software. Data will be combined with a random effect model. Study quality will be assessed using the Cochrane Risk of Bias Tool. Heterogeneity will be assessed, and if necessary, a subgroup analysis will be performed to explore the source of heterogeneity. RESULTS: The results will provide useful information about the effectiveness and safety of HIPEC combined with systemic chemotherapy regimens in patients with gastric cancer peritoneal carcinomatosis. CONCLUSION: The findings of the study will be disseminated through peer-reviewed journal. THE REGISTRATION NUMBER: INPLASY202050006. DOI NUMBER: 10.37766/inplasy2020.5.0006.

Secoeudesma sesquiterpenes lactone A alleviates inflammation and offers adjuvant protection in severe infection of carbapenem-resistant Klebsiella pneumoniae.

ETHNOPHARMACOLOGICAL RELEVANCE: Secoeudesma sesquiterpenes lactone A (SESLA) is a sesquiterpene compound isolated from Inula japonica Thunb. (I. japonica). It is an herb widely distributed in Asian countries often used for the treatment of various conditions including tumors, bronchitis and bacterial and viral infections. It has been reported that SESLA could significantly inhibit the production of nitric oxide (NO) by lipopolysaccharide (LPS) in Raw264.7 cells. However, the mechanism responsible for this anti-inflammatory role and its role in the treatment of antibiotic-resistant bacterial infection, e.g., carbapenem-resistant Klebsiella pneumoniae (CRKP), remain to be investigated. AIM OF THE STUDY: This study was carried out to investigate the protective anti-inflammatory role and the underlying molecular mechanisms of SESLA in LPS or CRKP evoked inflammation. MATERIALS AND METHODS: ELISA and PCR were utilized to detect the expression of inflammatory mediators in LPS or heat-killed CRKP (HK CRKP)-stimulated immune cells containing different concentrations of SESLA. The protective role of SESLA was observed in mice challenged with a lethal dose of CRKP. Mice were intraperitoneally injected with CRKP to create a septic mouse model to evaluate the protective role of SESLA in vivo. Phosphorylated proteins, which represented the activation of signaling pathways, were examined by Western blot. RESULTS: SESLA was showed to inhibit the expression of inflammatory mediators in various macrophages and dendritic cells upon stimulation of LPS or HK CRKP. It also facilitated phagocytosis of bacteria by Raw264.7 cells. The combined use of SELSA and the ineffective antibiotic, meropenem, increased the survival rate of CRKP infected mice from 25% to 50%. ERK, NF-κB and PI3K/Akt pathways accounted for the anti-inflammatory role of SESLA with the stimulation of LPS. CONCLUSION: According to the notable anti-inflammatory effect in vitro and its joint protective effects on a septic mouse model, SESLA might act as an adjuvant drug candidate for sepsis, even those caused by antibiotic-resistant bacteria, e.g., CRKP.

Proteomic and bioinformatic analysis of condyloma acuminata: mild hyperthermia treatment reveals compromised HPV infectivity of keratinocytes via regulation of metabolism, differentiation and anti-viral responses.

BACKGROUND: Hyperthermia has proved successful in treating cutaneous human papillomavirus infectious diseases such as plantar wart and condyloma acuminata (CA). Moreover, this treatment provides improved therapeutic efficacy in these conditions as compared with conventional therapies. OBJECTIVES: To investigate the global proteome changes in CA in response to hyperthermia and achieve a better understanding of the mechanisms of hyperthermia therapy against HPV-infectious diseases. METHODS: CA tissue was obtained from patients undergoing pathological examinations. Diagnosis was verified as based on results of both HE staining and HPV-DNA PCR assay. Hyperthermia was achieved with a 44 °C water bath. Differentially expressed proteins (DEPs) were identified by iTRAQ labeling, SCX chromatography and LC-MS/MS assay. Validation of proteomic results was performed using real-time qPCR and western blot, while bioinformatic analysis of DEPs was accomplished by R 3.4.1, STRING and Cytoscape softwares. RESULTS: In response to hyperthermia, a total of 102 DEPs were identified with 37 being upregulated and 65 downregulated. Among these DEPs, hyperthermia induced proteins involved with anti-viral processes such as OAS1, MX1, BANF1, CANX and AP1S1, whereas it inhibited proteins that participated in cellular metabolism, such as GALT, H6PD, EXOSC4 and EXOSC6; protein translation, such as RPS4Y1; as well as keratinocyte differentiation, such as KRT5, KRT27, KRT75, KRT76 and H2AFY2. CONCLUSIONS: Hyperthermia inhibited enzymes and molecules responsible for metabolism modulation and keratinocyte differentiation in CA tissue, whereas it promoted factors involved in anti-viral responses. Such effects may, in part, contribute to the efficacy of local hyperthermia therapy against HPV infection.

1,25-Dihydroxyvitamin D3 Ameliorates Collagen-Induced Arthritis via Suppression of Th17 Cells Through miR-124 Mediated Inhibition of IL-6 Signaling.

Objectives: To explore the molecular mechanisms in which vitamin D (VD) regulates T cells, especially Th17 cells in collagen-induced arthritis (CIA). Methods: DBA1/J mice induced for CIA were intraperitoneally treated with VD. CIA clinical symptoms and inflammatory responses including Th1/Th17/Tregs percentages were determined and compared. Mouse naïve CD4+ T cells transduced with miR-124 inhibitor or not were polarized to Th17 cells with or without VD. Subsequently, cellular differentiation and IL-6 signaling moleculars were analyzed. Results: VD treatment significantly delayed CIA onset, decreased incidence and clinical scores of arthritis, downregulated serum IgG levels and ameliorated bone erosion. VD downregulated IL-17A production in CD4+ T cells while increased CD4+Foxp3+Nrp-1+ cells both in draining lymph nodes and synovial fluid in arthritic mice. VD inhibited Th17 cells differentiation in vivo and in vitro and potentially functioning directly on T cells to restrain Th17 cells through limiting IL-6R expression and its downstream signaling including STAT3 phosphorylation, while these effects were blocked when naïve CD4+ T cells were transduced with miR-124 inhibitor. Conclusions: VD treatment ameliorates CIA via suppression of Th17 cells and enhancement of Tregs. miR-124-mediated inhibition of IL-6 signaling, provides a novel explanation for VD's role on T cells in CIA mice or RA patients and suggests that VD may have treatment implications in rheumatoid arthritis.

Effect of Naoxintong Capsule on Inflammation in Peripheral Ischemic Tissue and Its Mechanism / 中国实验血液学杂志

OBJECTIVE@#To study the mechanism of naoxintong capsule (NXT) -inhibiting peripheral ischemic inflammation.@*METHODS@#Mice were randomly double-blindly divided into 3 groups: sham-operation group, model group and NXT group. Both model and NXT groups underwent the hind limb ischemia (HLI) surgery followed by oral gavage with saline or NXT, respectively, one hour after operation. Three days after operation, the percentages of neutrophils and macrophages in the gastrocnemius muscle were examined by flow cytomety and immunohistochemical method. The changes in gene and protein expressions induced by NXT were examined by real-time PCR and protein chip, respectively. The changes of signaling pathways were analyzed.@*RESULTS@#Compared with sham oparation and model groups, NXT could decrease the ratios of neutrophils and macrophages in gastrocnemius inflammation site (P＜0.01), and downregulate the mRNA expression of gene EMR1 (P＜0.01). NXT reduced the expression of TNF-α and IL-1β at both mRNA (P＜0.001) and protein levels (P＜0.05). The proteomic analysis showed that the use of NXT resulted in the expression changes of 13 proteins. The expression of 6 cytokines was increased, and the secretion of 7 proteins was upregulated. Besides, most of identified 13 proteins were involved in the function regulation of other immune cells.@*CONCLUSION@#NXT can significantly alleviate ischemia-induced peripheral inflammation by reducing the ratio of immune cells and altering the expression patterns of mRNA and protein. The expression changes provide theoretical guidance and the potential targets for the clinical use of NXT in the treatment of ischemia-induced peripheral inflammatory diseases.

Update of humanized animal disease models in studying Graft-versus-host disease.

Graft-versus-host disease (GVHD) is a severe adverse effect that results from bone marrow or peripheral blood cells transplantation and has a high rate of mortality. About 50% of the patients are accompanied with acute Graft-versus-Host Disease (aGVHD) after bone marrow cell transplantation and need systematic treatment. It has an important clinical significance to evaluate the prevention and treatment effects of GVHD. The stable and reliable approaches of humanized animal models are crucial for advancing on the study the biology of GVHD. Relative models transplanting the human immune cells into the mouse body can trigger immunoreaction similar to the humans. As it is a disease triggered by human immune cells, any intervention research prior to clinical treatment has more clinical interrelations compared with the general animal models. In this review, we update the current understanding on humanized animal disease models on studying Graft-versus-host disease and expect to provide more theoretical basis to further study on Graft-versus-host disease.

Sea Buckthorn (Hippophaë rhamnoides L.) Oil Improves Atopic Dermatitis-Like Skin Lesions via Inhibition of NF-κB and STAT1 Activation.

BACKGROUND AND OBJECTIVES: The objective of this study was to evaluate the topical effects of sea buckthorn (SBT) oil on atopic dermatitis (AD)-like lesions in a mouse model generated by repeated topical administration of DNCB in BALB/c mice. METHODS: DNCB was applied repeatedly on the dorsal skin of mice to induce AD-like lesions. Following AD induction, SBT oil was applied daily on the dorsal skin for 4 weeks. The severity of skin lesions was examined macroscopically and histologically. We further measured the production of MDC/CCL22 and TARC/CCL17 in IFN-γ/TNF-α activated HaCaT cells. RESULTS: Topically applied SBT oil in DNCB-treated mice ameliorated the severity score of dermatitis, decreased epidermal thickness, reduced spleen and lymph node weights, and prevented mast cell infiltration. In addition, SBT oil suppressed the Th2 chemokines TARC and MDC via dose-dependent inhibition of NF-κB, JAK2/STAT1, and p38-MAPK signaling pathways in IFN-γ/TNF-α-activated HaCaT cells. CONCLUSION: These results suggest that SBT oil had a beneficial effect on AD-like skin lesions, partially via inhibition of the Th2 chemokines TARC and MDC in inflamed skin.

Observations on the Efficacy of Sheng's Six-meridian Diagnosis and Treatment-based Acupuncture in Treating Cervical Spondylotic Arteriopathy / 上海针灸杂志

Objective To investigate the clinical efficacy of Sheng's six-meridian diagnosis and treatment-based acupuncture in treating cervical spondylotic arteriopathy.Method Seventy patients with cervical spondylotic arteriopathy were randomly allocated to treatment and control groups, 35 cases each. The treatment group received Sheng's six-meridian diagnosis and treatment-based acupuncture and the control group, conventional acupuncture. Doppler-detected vertebral artery blood flow velocity was measured, and the clinical symptom and sign score and the cervical vertigo symptom and functional assessment scale score were recorded in the two groups before and after treatment. The clinical therapeutic effects were compared between the two groups.Result The total efficacy rate was 85.7% in the treatment group and 62.9% in the control group; there was a statistically significant difference between the two groups (P<0.05). There were statistically significant pre-/post-treatment differences in Doppler-detected vertebral artery blood flow velocity, the clinical symptom and sign score and the cervical vertigo symptom and functional assessment scale score in the two groups (P<0.01,P<0.05).Conclusion Sheng's six-meridian diagnosis and treatment-based acupuncture is an effective way to treat cervical spondylotic arteriopathy.

Observations on the Efficacy of Sheng's Six-meridian Diagnosis and Treatment-based Acupuncture in Treating Cervical Spondylotic Arteriopathy / 上海针灸杂志

Objective To investigate the clinical efficacy of Sheng's six-meridian diagnosis and treatment-based acupuncture in treating cervical spondylotic arteriopathy.Method Seventy patients with cervical spondylotic arteriopathy were randomly allocated to treatment and control groups, 35 cases each. The treatment group received Sheng's six-meridian diagnosis and treatment-based acupuncture and the control group, conventional acupuncture. Doppler-detected vertebral artery blood flow velocity was measured, and the clinical symptom and sign score and the cervical vertigo symptom and functional assessment scale score were recorded in the two groups before and after treatment. The clinical therapeutic effects were compared between the two groups.Result The total efficacy rate was 85.7% in the treatment group and 62.9% in the control group; there was a statistically significant difference between the two groups (P<0.05). There were statistically significant pre-/post-treatment differences in Doppler-detected vertebral artery blood flow velocity, the clinical symptom and sign score and the cervical vertigo symptom and functional assessment scale score in the two groups (P<0.01,P<0.05).Conclusion Sheng's six-meridian diagnosis and treatment-based acupuncture is an effective way to treat cervical spondylotic arteriopathy.

The ecological filter system for treatment of decentralized wastewater.

A vertical flow constructed wetland was combined with a biological aerated filter to develop an ecological filter, and to obtain the optimal operating parameters: The hydraulic loading was 1.55 m3/(m2·d), carbon-nitrogen ratio was 10, and gas-water ratio was 6. The experimental results demonstrated considerable removal efficiency of chemical oxygen demand (COD), ammonia nitrogen (NH4+-N), total nitrogen (TN), and total phosphorus (TP) in wastewater by the ecological filter, with average removal rates of 83.79%, 93.10%, 52.90%, and 79.07%, respectively. Concentration of NH4+-N after treatment met the level-A discharge standard of GB18918-2002. Compared with non-plant filter, the ecological filter improved average removal efficiency of COD, NH4+-N, TN, and TP by 13.03%, 25.30%, 14.80%, and 2.32%, respectively: thus, plants significantly contribute to the removal of organic pollutants and nitrogen. Through microporous aeration and O2 secretion of plants, the ecological filter formed an aerobic-anaerobic-aerobic alternating environment; thus aerobic and anaerobic microbes were active and effectively removed organic pollutants. Meanwhile, nitrogen and phosphorus were directly assimilated by plants and as nutrients of microorganisms. Meanwhile, pollutants were removed through nitrification, denitrification, filtration, adsorption, and interception by the filler. High removal rates of pollutants on the ecological filter proved that it is an effective wastewater-treatment technology for decentralized wastewater of mountainous towns.

HSPB1 deficiency sensitizes melanoma cells to hyperthermia induced cell death.

Hyperthermia has shown clinical potency as a single agent or as adjuvant to other therapies in cancer treatment. However, thermotolerance induced by thermosensitive genes such as the heat shock proteins can limit the efficacy of hyperthermic treatment. In the present study, we identified HSPB1 (HSP27) is hyperthermically inducible or endogenously highly expressed in both murine and human melanoma cell lines. We used a siRNA strategy to reduce HSPB1 levels and showed increased intolerance to hyperthermia via reduced cell viability and/or proliferation of cells. In the investigation of underlying mechanisms, we found knock down of HSPB1 further increased the proportion of apoptotic cells in hyperthermic treated melanoma cells when compared with either single agent alone, and both agents leaded to cell cycle arrest at G0/G1 or G2/M phases. We concluded that hyperthermia combined with silencing of HSPB1 enhanced cell death and resulted in failure to thrive in melanoma cell lines, implying the potential clinical utility of hyperthermia in combination with HSPB1 inhibition in cancer treatment.