Abstract Background： Allergen specific immunotherapy (AIT) is the only potential disease-modifying treatment of house dust mite (HDM) allergic asthma and rhinitis. The conventional treatment procedure lasted for 3 years, but biomarkers indicating early efficacy from this long-term treatment has not been well illustrated. In this single arm, observation study, we evaluated non-invasive airway inflammation parameters such as Exhaled nitric oxide (FeNO), nasal NO levels (FnNO), and small airway function parameter-impulse oscillometry system (IOS) as well as serum parameters Dermatophagoides pteronyssinus (Derp) specific IgG4 and sIgG4/IgE ratio as potential biomarkers for AIT. Methods： Patients with mild allergic asthma concomitant with allergic rhinitis were treated with subcutaneous immunotherapy of Der p extract. Clinical evaluations including symptom score and medication score, small airway function of spirometer and non-invasive airway inflammation parameters from the nose (FnNO) and lung (FeNO) were collected before and after half year and one year of AIT. Serum Derp specific IgE and IgG4 measurement data were also collected. Results： Symptoms and medication score of patients were alleviated both after half and one-year HDM immunotherapy according to VAS (visual analogue score) and medication score. Improved small airway function (evaluated through IOS) and reduced non-invasive airway allergic inflammation parameters both from the nose (FnNO) and lung (FeNO) were achieved after half and one year AIT. As to serum biomarkers, Der p specific IgG4 increased and Der P specific IgE/IgG4 decreased significantly after one year treatment. Conclusions: One year HDM subcutaneous allergen immunotherapy improved allergic symptoms and reduced medication score in patients with allergic asthma concomitant with rhinitis. Non-invasive airway inflammation parameters such as FeNO and FnNO and small airway function parameter IOS are potential biomarkers for evaluating early efficacy of AIT. Derp specific IgG4 as well as IgE/IgG4 ratio maybe good therapeutic predictors to reflect the efficacy of AIT in the first year of treatment.
The advent of immunotherapy, especially immune checkpoint inhibitors (ICIs), has revolutionized antitumor therapy. Programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are among the most promising targets for encouraging the immune system to eliminate cancer cells. PD-1/PD-L1 have made clinical remission for numerous solid tumors, including metastatic triple-negative breast cancer (TNBC). In recent years, integrating PD-1/PD-L1 inhibitors into existing treatments in early-stage TNBC has attracted wide attention. Herein, we summarize the clinical benefit of PD-1/PD-L1 inhibitors plus neoadjuvant chemotherapy, adjuvant chemotherapy, and targeted therapy in early-stage TNBC. Possible immunotherapy biomarkers, immune-related adverse events (irAEs), and the key challenges faced in TNBC anti-PD-1/PD-L1 therapy are also concluded. Numerous studies on immunotherapy are ongoing, and PD-1/PD-L1 inhibitors have demonstrated great clinical prospects in early-stage TNBC. To maximize the efficacy of anti-PD-1/PD-L1 therapy, further research into the challenges which still exist is necessary.
Axonal regeneration following peripheral nerve injury (PNI) depends on the complex interaction between Schwann cells (SCs) and macrophages, but the mechanisms underlying macrophage recruitment and activation in axonal regeneration remain unclear.RNA sequencing (RNA-seq) was conducted to identify differentially expressed long noncoding RNAs (DElncRNAs) between crushed sciatic nerves and intact contralateral nerves. The putative role of lncRNAs in nerve regeneration was analyzed in vitro and in vivo.An lncRNA, called axon regeneration-associated transcript (lncARAT), was upregulated in SCs and SC-derived exosomes (SCs-Exo) after sciatic nerve injury. LncARAT contributed to axonal regeneration and improved motor function recovery. Mechanistically, lncARAT epigenetically activated C-C motif ligand 2 (CCL2) expression by recruiting KMT2A to CCL2 promoter, resulting in increased histone 3 lysine 4 trimethylation (H3K4me3) and CCL2 transcription in SCs. CCL2 facilitated the infiltration of macrophages into the injured nerves. Meanwhile, lncARAT-enriched exosomes were released from SCs and incorporated into macrophages. LncARAT functioned as an endogenous sponge to adsorb miRNA-329-5p in macrophages, resulting in increased suppressor of cytokine signaling (SOCS) 2 expression, which induced a proregenerative function of macrophages through a signal transducer and activator of transcription (STAT) 1/6-dependent pathway.LncARAT may represent a promising therapeutic avenue for peripheral nerve repair.
Objective To study the effects of different fluids on on cardiac function of rabbits with thermal burn-induced shock Methods 40 rabbits were randomly divided into four groups,group Ⅰ:control group (without thermal injury),group Ⅱ:0.9％ NaC1 solution,group Ⅲ:lactated Ringer's solution,group Ⅳ:acetated Ringer's injection.The infusion rate was 0.33 ml/kg/％(area percentage of heat injury)/h in 4 h when the thermal injury of rabbit body surface area was 25％ to 30％.Cardiac function were measured in each group by working heart preparation in vitro model.Results Cardiac output(CO)[ (85±9),(90±9),(102±11),(103±10),(99±10),(101±11) ml/min],dp/dt[(1 200±110),(1 350±125),(1 210±100),(1 200±115),(1 150±120),(1 000±95) mmHg/s (1 mm Hg=0.133 kPa)],-dp/dt[(1 000±95),(1 150±100),(1 110±105),(1 100±110),(1 050±105),(1 000±100) mm Hg/s]in group Ⅱ were significantly lower than those in group Ⅰ (P＜0.05,P＜0.01 ),and these parameters were improved in group Ⅲ,but could not return to the levels in group.The parameters in group Ⅳ were similar to those in group Ⅰ (P＞0.05).Stroke work [ (21.2±2.3 ),(23.3±2.1),(27.2±2.3),(26.3±2.4),(26.1±3.2),(25.1±2.3) Q·mm Hg·bpm-1] and aortic peak systolic pressure[(55±4),(54±4),(56±4),(55±4),(53±4),(53±5) mm Hg] in group Ⅱ were significantly lower than those of group Ⅰ (P＜0.05,P＜0.01) while these parameters in group Ⅲ and Ⅳ were not different,compared to those of group. Conclusions Compound electrolyte solution infusion can improve cardiac function of rabbits with thermal burn-induced shock.
Key words:
Acetated ringer's injection; Lactated ringer's injection; Cardiac function; Rabbit
Context: Berberine (BBR) can regulate enteric glial cells (EGCs) and the gut vascular barrier (GVB).Objective: To explore whether BBR regulates GVB permeability via the S100B pathway.Materials and methods: GVB hyperpermeability in C57BL/6J mice was induced by burns or S100B enema. BBR (25 or 50 mg/kg/d, 3 d) was gavaged preburn. S100B monoclonal antibody (S100BmAb) was i.v. injected postburn. Mouse intestinal microvascular endothelial cells (MIMECs) were treated with S100B, S100B plus BBR, or Z-IETD-FMK. GVB permeability was assayed by FITC-dextran, S100B by ELISA, caspase-8, β-catenin, occludin and PV-1 by immunoblot.Results: Burns elevated S100B in serum and in colonic mucosa to a peak (147.00 ± 4.95 ng/mL and 160.30 ± 8.50 ng/mg, respectively) at 36 h postburn, but BBR decreased burns-induced S100B in serum (126.20 ± 6.30 or 90.60 ± 3.78 ng/mL) and in mucosa (125.80 ± 12.40 or 91.20 ± 8.54 ng/mg). Burns raised GVB permeability (serum FITC-dextran 111.40 ± 8.56 pg/mL) at 48 h postburn, but BBR reduced GVB permeability (serum FITC-dextran 89.20 ± 6.98 or 68.60 ± 5.50 ng/mL). S100B enema (1 μM) aggravated burns-raised GVB permeability (142.80 ± 8.07 pg/mL) and PV-1, but the effect of S100B was antagonized by BBR. Z-IETD-FMK (5 μM) increased S100B-induced permeability to FITC-dextran (205.80 ± 9.70 to 263.80 ± 11.04 AUs) while reducing β-catenin in MIMECs. BBR (5 μM) reduced S100B-induced permeability (104.20 ± 9.65 AUs) and increased caspase-8, β-catenin and occludin.Discussion and conclusion: BBR decreases burns-induced GVB hyperpermeability via modulating S100B/caspase-8/β-catenin pathway and may involve EGCs.
To investigate whether serum uric acid (SUA) is associated with 2-hour postload glucose (2-h PG) in predibetic patients.There were 3 588 subjects enrolled in this study from May 2014 to March 2015 in the department of physical examination center and outpatient clinic of West China Hospital of Sichuan University. All the subjects received a 75-g oral glucose tolerance test (OGTT) and measurements of serum uric acid (SUA), Creatinine, Cystatin (Cys-C), serum lipid and glycosylated hemoglobin (HbAlc). According to the results of glucose and HbAlc, the subjects were divided into three groups, including normal glucose regulation (NGT), impaired glucose regulation (IGR) and Type 2 Diabetes Mellitus (T2DM) group. The correlation between 2-h PG and serum uric acid in each group was analyzed.Based on the exam results, there were 556 cases of NGT, 1 019 cases of IGR, 2 013 cases of T2DM. There were statistically significant differences of glucose, serum insulin, triglycerides, high density lipoprotein, HbAlc, SUA, Creatinine, Cys-C levels among the three groups (P<0. 05). Multiple linear regression analysis showed that SUA level was positively correlated to 2-h PG level (P<0. 05) in NGT and IGR groups, but there was no correlation in T2DM group (P=0. 156). In the entire study population, levels of HbAlc and FPG were positive to 2-h PG correlated (P<0. 05). Positive correlation existed between FPG and 2-h PG in NGT group (P=0. 031). In IGR and T2DM group, HbAlc and 2-h PG were positively correlated (P<0. 05). HbAlc, FPG and SUA levels were independent risk factors for 2-h PG.In prediabetes, 2-h PG is associated with SUA and independent of FPG, HbAlc and other known risk factors. SUA may play a key role in the prediabetic condition as a risk indicator of T2DM.
Hypothalamic AMP-activated protein kinase (AMPK) and orexins/hypocretins are both involved in the control of feeding behavior, but little is known about the interaction between these two signaling systems. Here, we demonstrated that orexin-A elicited significant activation of AMPK in the arcuate nucleus (ARC) of the hypothalamus by elevating cytosolic free Ca²⁺ involving extracellular calcium influx. Electrophysiological results revealed that orexin-A increased the L-type calcium current via the orexin receptor-phospholipase C-protein kinase C signaling pathway in ARC neurons that produce neuropeptide Y, an important downstream effector of orexin-A's orexigenic effect. Furthermore, the L-type calcium channel inhibitor nifedipine attenuated orexin-A-induced AMPK activation in vitro and in vivo. We found that inhibition of AMPK by either compound C (6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-3-(4-pyridinyl)-pyrazolo[1,5-a]pyrimidine) or the ATP-mimetic 9-β-D-arabinofuranoside prevented the appetite-stimulating effect of orexin-A. This action can be mimicked by nifedipine, the blocker of the L-type calcium channel. Our results indicated that orexin-A activates hypothalamic AMPK signaling through a Ca²⁺-dependent mechanism involving the voltage-gated L-type calcium channel, which may serve as a potential target for regulating feeding behavior.
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