Effect of berbamine hydrochloride on the absorption of berberine hydrochloride in an in situ single-pass intestinal perfusion system in rats

Purpose: To investigate the intestinal absorption characteristics of berberine hydrochloride (BBH) under different perfusion conditions in rats.Methods: Based on the in situ single-pass intestinal perfusion model of rats, HPLC was used to determine the content of berberine hydrochloride in solution after perfusion under different conditions. The absorption rate constant (Ka), effective permeability coefficient (Papp) and cumulative absorption per unit area (Q) under different perfusion conditions were analyzed by one-way ANOVA.Results: The Papp and Ka of BBH in perfusion solution at pH 7.4 were greater than those in perfusion solution at pH 6 and 8. There was no significant difference (p > 0.05) in Papp and Ka of duodenum, jejunum and ileum at high, medium and low concentrations of berberine hydrochloride perfusion solution. The Q increased linearly with increase of mass concentration of perfusion solution. The Ka and Papp of BBH in duodenum, jejunum, and ileum of BBH and berbamine hydrochloride (BAH) combined at different ratios were higher than those of BBH control group at the same BBH concentration, but absorption of BBH in the ratio B40:A50 and B30:A20 groups was highest. In the ratio of B40:A50 ratio, B30:A20 ratio group or the same concentration's BBH group, Ka and Papp of BBH decreased in the order of jejunum > duodenum > ileum.Conclusion: Berberine hydrochloride is absorbed in neutral environment of pH 7.4. The intestinal absorption mechanism of BBH is passive diffusion, and jejunum is the best intestinal segment for absorption. BAH promotes the absorption of BBH

Automated turnkey microcomb for low-noise microwave synthesis

Microresonator-based optical frequency comb (microcomb) has the potential to revolutionize the accuracy of frequency synthesizer in radar and communication applications. However, fundamental limit exists for low noise microcomb generation, especially in low size, weight, power and cost (SWaP-C) package. Here we resolve this limit, by the demonstration of an automated turnkey microcomb, operating close to its low quantum-limited phase noise, within a compact setup size of 85 mm * 90 mm * 25 mm. High quality factor fiber Fabry-Perot resonator (FFPR), with Q up to 4.0 * 10^9, is the key for both low quantum noise and pump noise limit, in the diode-pump case in a self-injection locking scheme. Low phase noise of -80 and -105 dBc/Hz at 100 Hz, -106 and -125 dBc/Hz at 1 kHz, -133 and -148 dBc/Hz at 10 kHz is achieved at 10.1 GHz and 1.7 GHz repetition frequencies, respectively. With the simultaneous automated turnkey, low-noise and direct-diode-pump capability, our microcomb is ready to be used as a low-noise frequency synthesizer with low SWaP-C and thus field deployability

Causal effects of gut microbiota on diabetic neuropathy: a two-sample Mendelian randomization study

ObjectivePrevious observational studies have suggested an association between gut microbiota and diabetic neuropathy (DN). However, confounding factors and reverse causality make the causal relationship between gut microbiota and DN uncertain. We aimed to investigate the interactive causal relationships between the abundance of gut microbiota and DN.MethodsWe conducted a Mendelian randomization (MR) analysis to examine the causal relationship between gut microbiota and DN. Genomic data on gut microbiota at the genus level were obtained from the MiBioGen Consortium, including 18,340 individuals of European descent. Data on diabetic polyneuropathy (DPN) were obtained from the FinnGen Consortium, which included 1,048 cases and 374,434 controls, while data on diabetic autonomic neuropathy (DAN) were also obtained from the FinnGen Consortium, including 111 cases and 374,434 controls. Causal effects were primarily estimated using inverse variance weighted (IVW) analysis, supplemented with four validation methods, and additional sensitivity analyses to assess the pleiotropy, heterogeneity, and robustness of instrumental variables.ResultsThe IVW analysis indicated that Prevotella 9 had a protective effect on DPN (OR = 0.715, 95% CI: 0.521-0.982, P = 0.038), and Bacteroides also showed a protective effect (OR = 0.602, 95% CI: 0.364-0.996, P = 0.048). On the other hand, Ruminococcus 2 had a promoting effect on DPN (OR = 1.449, 95% CI: 1.008-2.083, P = 0.045). Blautia (OR = 0.161, 95% CI: 0.035-0.733, P = 0.018), Clostridium innocuum group (OR = 3.033, 95% CI: 1.379-6.672, P = 0.006), and Howardella (OR = 2.595, 95% CI: 1.074-6.269, P = 0.034) were causally associated with DAN in the IVW analysis, with no evidence of heterogeneity or pleiotropy. Sensitivity analyses showed no significant pleiotropy or heterogeneity.ConclusionOur study identified a causal relationship between gut microbiota and the increased or decreased risk of diabetic neuropathy. These findings underscore the importance of adopting a comprehensive approach that combines gut microbiota modulation with other therapeutic interventions in the management of diabetic neuropathy

Copy Number Variation of Immune-Related Genes and Their Association with Iodine in Adults with Autoimmune Thyroid Diseases

Background. Autoimmune thyroid diseases (AITD) are complex conditions that are caused by an interaction between genetic susceptibility and environmental triggers. Iodine is already known to be an environmental trigger for AITD, but genes associated with susceptibility need to be further assessed. Therefore, the aims of this study were to assess the association between copy number variations (CNVs) and AITD, to identify genes related with susceptibility to AITD, and to investigate the interaction between iodine status and CNVs in the occurrence of AITD. Methods. Blood samples from 15 patients with AITD and 15 controls were assessed by chromosome microarray to identify candidate genes. The copy number of candidate genes and urinary iodine level was determined in adults from areas of different iodine statuses including 158 patients and 181 controls. Results. The immune-related genes, SIRPB1 and TMEM91, were selected as candidate genes. The distribution of SIRPB1 CNV in AITD patients and controls was significantly different and was considered a risk factor for AITD. There was no significant association between urinary iodine level and candidate gene CNVs. Conclusion. SIRPB1 CNV and an excess of iodine were risk factors for AITD, but an association with the occurrence of AITD was not found

Obesity and clinical outcomes in COVID-19 patients without comorbidities, a post-hoc analysis from ORCHID trial

ObjectiveLarge body of studies described individuals with obesity experiencing a worse prognosis in COVID-19. However, the effects of obesity on the prognosis of COVID-19 in patients without comorbidities have not been studied. Therefore, the current study aimed to provide evidence of the relationship between obesity and clinical outcomes in COVID-19 patients without comorbidities.MethodsA total of 116 hospitalized COVID-19 patients without comorbidities from the ORCHID study (Patients with COVID-19 from the Outcomes Related to COVID-19 Treated with Hydroxychloroquine among Inpatients with Symptomatic Disease) were included. Obesity is defined as a BMI of ≥30 kg/m2. A Cox regression analysis was used to estimate the hazard ratio (HR) for discharge and death after 28 days.ResultsThe percentage of obesity in COVID-19 patients without comorbidities was 54.3% (63/116). Discharge at 28 days occurred in 56/63 (84.2%) obese and 51/53 (92.2%) non-obese COVID-19 patients without comorbidities. Four (3.4%) COVID-19 patients without any comorbidities died within 28 days, among whom 2/63 (3.2%) were obese and 2/53 (3.8%) were non-obese. Multivariate Cox regression analyses showed that obesity was independently associated with a decreased rate of 28-day discharge (adjusted HR: 0.55, 95% CI: 0.35–0.83) but was not significantly associated with 28-day death (adjusted HR: 0.94, 95% CI: 0.18–7.06) in COVID-19 patients without any comorbidities.ConclusionsObesity was independently linked to prolonged hospital length of stay in COVID-19 without any comorbidity. Larger prospective trials are required to assess the role of obesity in COVID-19 related deaths

Robust adaptive immune response against Babesia microti infection marked by low parasitemia in a murine model of sickle cell disease.

The intraerythrocytic parasite Babesia microti is the number 1 cause of transfusion-transmitted infection and can induce serious, often life-threatening complications in immunocompromised individuals including transfusion-dependent patients with sickle cell disease (SCD). Despite the existence of strong long-lasting immunological protection against a second infection in mouse models, little is known about the cell types or the kinetics of protective adaptive immunity mounted following Babesia infection, especially in infection-prone SCD that are thought to have an impaired immune system. Here, we show, using a mouse B microti infection model, that infected wild-type (WT) mice mount a very strong adaptive immune response, characterized by (1) coordinated induction of a robust germinal center (GC) reaction; (2) development of follicular helper T (TFH) cells that comprise ∼30% of splenic CD4+ T cells at peak expansion by 10 days postinfection; and (3) high levels of effector T-cell cytokines, including interleukin 21 and interferon γ, with an increase in the secretion of antigen (Ag)-specific antibodies (Abs). Strikingly, the Townes SCD mouse model had significantly lower levels of parasitemia. Despite a highly disorganized splenic architecture before infection, these mice elicited a surprisingly robust adaptive immune response (including comparable levels of GC B cells, TFH cells, and effector cytokines as control and sickle trait mice), but higher immunoglobulin G responses against 2 Babesia-specific proteins, which may contain potential immunogenic epitopes. Together, these studies establish the robust emergence of adaptive immunity to Babesia even in immunologically compromised SCD mice. Identification of potentially immunogenic epitopes has implications to identify long-term carriers, and aid Ag-specific vaccine development. © 2018 by The American Society of Hematology

Role of recombinant human granulocyte colony-stimulating factor in development of cancer-associated venous thromboembolism in lung cancer patients who undergo chemotherapy

BackgroundThe role of recombinant human granulocyte colony-stimulating factor (rhG-CSF), especially the long-acting factor in the development of cancer-associated venous thromboembolism (VTE) in lung cancer patients who undergo chemotherapy has been understudied, although the use of rhG-CSF has been reported to be associated with an increased risk of VTE.MethodsWe retrospectively reviewed 1,673 lung cancer patients who underwent hospitalized chemotherapy. We performed propensity score matching to offset confounding factors related to cancer-associated VTE development and classified the patients into short-acting (N = 273), long-acting (N = 273), and no rhG-CSF (N = 273) groups. The primary outcome was cumulative cancer-associated VTE development three months after all cycles of chemotherapy.ResultsThe overall VTE incidence in the short-acting, long-acting, and no rhG-CSF groups was 5.5%, 10.3%, and 2.2%, respectively (P <0.001). The VTE incidence in the long-acting rhG-CSF group was higher than that in the short-acting (P = 0.039) and no rhG-CSF groups (P <0.001). The VTE incidence in the short-acting rhG-CSF group was higher than that in the no rhG-CSF group (P = 0.045). The use of rhG-CSF (hazard ratio [HR] 2.337; 95% confidence interval [CI] [1.236–5.251], P = 0.006) was positively correlated with VTE development among all patients, whereas the use of long-acting rhG-CSF (HR 1.917, 95% CI [1.138–4.359]; P = 0.016), was positively correlated with VTE development in patients receiving rhG-CSF.ConclusionThe use of rhG-CSF, especially long-acting rhG-CSF, increases the risk of cancer-associated VTE development compared to no rhG-CSF use in lung cancer patients who undergo hospitalized chemotherapy

A novel Bifidobacterium infantis-mediated TK/GCV suicide gene therapy system exhibits antitumor activity in a rat model of bladder cancer

Bladder cancer is the ninth most common malignancy in the world. Successful clinical management remains a challenge. In order To search for novel targeted and efficacious treatment, we sought to investigate anti-tumor activity of BI-TK suicide gene therapy system in a rat model of bladder tumors. We first constructed and tested an anaerobic Bifidobacterium infantis-mediated thymidine kinase (BI-TK) suicide gene therapy system. To test the in vivo efficacy of this system, we established a rat model of bladder tumors, which was induced by N-methyl-nitrosourea perfusion. Bifidobacterium infantis containing the HSV-TK (i.e., BI-TK) were constructed by transformation of recombinant plasmid pGEX - TK. The engineered BI-TK was injected into tumor-bearing rats via tail vein, followed by intraperitoneal injection of ganciclovir (GCV). Using the rat model of bladder tumors, we found that bladder tumor burdens were significantly lower in the rats treated with BI-TK/GCV group than that treated with normal saline control group (p <0.05). While various degrees of apoptosis of the tumor cells were detected in all groups using in situ TUNEL assay, apoptosis was mostly notable in the BI-TK/GCV treatment group. Immunohistochemical staining further demonstrated that the BI-TK/GCV treatment group had the highest level of caspase3 protein expression than that of the empty plasmid group and normal saline group (p < 0.05). Thus, our results demonstrate that the Bifidobacterium infantis-mediated TK/GCV suicide gene therapy system can effectively inhibit rat bladder tumor growth, possibly through increasing caspase 3 expression and inducing apoptosis