Berberine Enhances Intestinal Mucosal Barrier Function by Promoting Vitamin D Receptor Activity.

OBJECTIVE: To evaluate if berberine can act on vitamin D receptors (VDR) and thereby regulate the expression of tight junction proteins (TJPs) in irritable bowel syndrame-diarrhea-predominant (IBS-D) rats. METHODS: The newborn rats were induced into IBS-D rat model via neonatal maternal separation combined with acetic acid chemical stimulation. After modeling, the model was evaluated and rats were divided into the control group and berberine treatment groups (0.85, 1.7 and 3.4 mg/kg, once a day for 2 weeks). The distal colon was obtained and colonic epithelial cells (CECs) were isolated and cultured after IBS-D model evaluation. The vitamin D receptor response element (VDRE) reporter gene was determined in the CECs of IBS-D rats to analyze the effect of berberine on the VDRE promoter. VDR overexpression or silencing technology was used to analyze whether VDR plays a role in promoting intestinal barrier repair, and to determine which region of VDR plays a role in berberine-regulated intestinal TJPs. RESULTS: The IBS-D rat model was successfully constructed and the symptoms were improved by berberine in a dose-dependent manner (P<0.05). The activity of VDRE promoter was also effectively promoted by berberine (P<0.05). Berberine increased the expression of TJPs in IBS-D CECs (P<0.05). VDR expression was significantly increased after transfection of different domains of VDR when compared to normal control and basic plasmid groups (all P<0.05). RT-qPCR and Western blot results showed that compared with the blank group, expressions of occludin and zonula occludens-1 were significantly higher in VDR containing groups (all P<0.05). Berberine plus pCMV-Myc-VDR-N group exerted the highest expression levels of occludin and zonula occludens-1 (P<0.05). CONCLUSION: Berberine enhances intestinal mucosal barrier function of IBS-D rats by promoting VDR activity, and the main site of action is the N-terminal region of VDR.

Gut microbiota mediates the pharmacokinetics of Zhi-zi-chi decoction for the personalized treatment of depression.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhi-zi-chi decoction (ZZCD), from "Treatise on Febrile Diseases", is a typical traditional Chinese medicine herb pair, which consists of Gardeniae Fructus (GF) and Semen Sojae Praeparatu (SSP). In clinical research, ZZCD was widely used to fight depression, remove annoyance. Many studies have reported that gut microbiota is critical target for the influence of depress through gut-brain axis, and our previously studies have found that ZZCD exhibiting antidepressant effect was through the gut-brain axis. However, the specific mechanism by which gut microbiota mediates the pharmacokinetics parameters of active compounds from ZZCD during the process of depression treatment has not yet been studied. AIM OF THE STUDY: To explore the differences in pharmacokinetics characters of bioactive iridoids from ZZCD and study the changes of gut microbiota at different stages of depression with the personalized medicine of ZZCD. MATERIALS AND METHODS: A new strategy exploring the relationship among disease phenotypes (D), intestinal microbiota (I), enzymes (E) and traits of metabolism (T) named as "DIET" was established. Firstly, a fast, selective and sensitive ultra-performance liquid chromatography coupled with tandem mass spectrometer (UPLC-MS/MS) was established and validated to quality the main bioactive compounds from ZZCD and compare the pharmacokinetics and bioavailability of different iridoids prototypes and metabolites from ZZCD between normal and chronic unpredictable mild stress rats. Subsequently, the activity of corresponding metabolic enzymes of anti-depressive compounds, ß-glucosidases and sulfotransferases, were analyzed by ρ-nitrophenyl-ß -D-glucopyranoside and sulfotransferases ELISA kits, respectively. Finally, 16S rRNA gene sequencing was adopt to analyze intestinal bacteria composition for the treatment of depression by ZZCD. RESULTS: The antidepressant effect of ZZCD was promoted due to the increased exposures and reduced eliminations of anti-depressive compounds, especially geniposide and genipin 1-gentiobioside, under the depression state. With the ZZCD treatment, the depression was improved, but the exposures of anti-depressive compounds from ZZCD gradually decreased. Meanwhile, there were the corresponding decreased trends on the activity of ß-glucosidases and sulfotransferases. With the consumption of ZZDC and the improvement of depression, the exposures of anti-depressive iridoid glycosides decreased and the activity of metabolism enzymes restored. Meanwhile, the dysbiosis of pathogenic bacteria (Bacteroidota) induced by depression was ameliorated and the probiotics (Firmicutes) at the phylum and genus level raised, the two phyla are closely related to the production of ß-glucosidase and sulfotransferases. CONCLUSIONS: It is the first proposed that ZZCD could personalized to treat depression at different stages targeting gut microbiota and gut microbiome could emerged as a potential diagnostic and therapeutic biomarker in depression.

PD-1 engineered cytomembrane cloaked molybdenum nitride for synergistic photothermal and enhanced immunotherapy of breast cancer.

Incomplete tumor ablation and subsequent tumor metastasis usually occur during photothermal anti-tumor processes. The combination of photothermal and immunotherapy has proven to be a promising method to conquer technical challenges. Inhibiting the programmed death ligand-1 (PD-L1)/programmed cell death protein 1 (PD-1) immune pathway represents one of the most successful immunotherapy strategies. Whereas, the PD-L1 expression level significantly differs, leading to a relatively low response rate to the immune checkpoint blockade (ICB) approaches. Therefore, improving the expression level of PD-L1 becomes one potential method to enhance the response rate. Herein, NIH 3T3 cells were educated to steadily express PD-1 protein. Furthermore, the synthesized molybdenum nitride was then coated with PD-1 protein-modified cytomembrane, which endows it with immune checkpoint blocking capability. Moreover, under the irradiation of near-infrared light, the local mild heat released from the molybdenum nitride causes the apoptosis of tumor cells. More importantly, the elevated temperature simultaneously helps elevate the expression level of PD-L1, further enhancing the response rate of ICB. Finally, the PD-1 cytomembrane coatings interact with the upregulated PD-L1, leading to the activation of the immune system. In summary, we confirmed that the PD-1 protein-coated molybdenum nitride could synergistically ablate tumors and avoid metastasis.

A pH reversibly activatable NIR photothermal/photodynamic-in-one agent integrated with renewable nanoimplants for image-guided precision phototherapy.

Phototherapy has great potential to revolutionize conventional therapeutic modalities. However, most phototherapeutic strategies based on multicomponent therapeutic agents generally lack tumor-specificity, resulting in asynchronous therapy and superimposed side-effects. Severe heat damage is also inevitable because of the necessity of continuous external irradiation. Here we show the design of an acid-activated and continuous external irradiation-free photothermal and photodynamic (PTT/PDT) synchronous theranostic nanoplatform for precision tumor-targeting near-infrared (NIR) image-guided therapy. pH-reversibly responsive brominated asymmetric cyanine is designed as the tumor-specific NIR PTT/PDT-in-one agent to enhance anticancer efficiency and reduce side-effects. Ultra-small NIR persistent luminescence nanoparticles are prepared as both the imaging unit and renewable nanoimplant. Biotin functionalized polyethylene glycol is introduced to endow active tumor-targeting ability and prolong blood-circulation. The developed smart platform offers merits of reversible activation, PTT/PDT synergetic enhancement, tumor targetability and continuous external irradiation-free properties, allowing autofluorescence-free image-guided phototherapy only in tumor sites. This work paves the way to developing smart theranostic nanoplatforms for precision medicine.

[Effect of acupuncture on blood pressure variability in elderly patients with cerebral infarction complicated with essential hypertension].

OBJECTIVE: To observe the therapeutic effect of acupuncture on blood pressure variability (BPV) in elderly patients with cerebral infarction complicated with essential hypertension. METHODS: Seventy-six elderly patients with cerebral infraction complicated with essential hypertension were randomized into an observation group and a control group, 38 cases in each group. Xingnao Kaiqiao acupuncture and nifedipin were given in the control group. On the basis treatment in the control group, the Huoxue Sanfeng and Tiaohe Ganpi acupuncture was applied at Renying (ST 9), Hegu (LI 4), Quchi (LI 11), Zusanli (ST 36) and Taichong (LR 3) in the observation group for 30 min. The treatment was given once a day, 5 times a week for 8 weeks. The 24-hour ambulatory blood pressure was monitored in the two groups. The changes of blood pressure and blood pressure variability were observed before and after 8 weeks of treatment, and the occurrence of adverse reactions during the treatment were recorded. RESULTS: The mean systolic blood pressure (SBP), diastolic blood pressure (DBP), daytime SBP, DBP, nighttime SBP and DBP were reduced in the two groups after 8 weeks of treatment (P<0.05), and the results in the observation group were lower than those in the control group (P<0.05). After 8 weeks of treatment, the daytime, nighttime, 24 h systolic blood pressure variability (SBPV) and diastolic blood pressure variability (DBPV) in the observation group were lower than those before treatment (P<0.05), there was no significant difference between before and after treatment in the control group (P>0.05). CONCLUSION: Huoxue Sanfeng and Tiaohe Ganpi acupuncture method can effectively control the blood pressure and blood pressure variability in the elderly patients with cerebral infraction complicated with essential hypertension.

[Effect of modified sijunzi decoction on the bone metabolism of adriamycin induced nephropathy rats].

OBJECTIVE: To explore the effect of Modified Sijunzi Decoction (MSD) on the bone metabolism of prednisone intervened adriamycin-induced nephropathy rats. METHODS: The adriamycin-induced nephropathy rat model was prepared. Totally 50 SD rats were randomly divide into five groups, i.e., the model group, the hormone group, the Chinese medicine (CM) group, the CM + hormone group, and the normal control group. The 24-h urine samples were collected on the 7th, 21st, and 35th day after modeling. The 24-h urine protein was measured by biuret colorimetry. Serum levels of osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB ligand (RANKL), osteocalcin (BGP), and tartrate-resistant acid phosphatase (TRACP) were determined by ELISA. Expressions of OPG and RANKL in the tibia tissue were detected using real-time quantitative PCR and Western blot. RESULTS: (1) Compared with the normal control group, the 24-h urine protein increased in each group on the 7th, 21st, and 35th day (P < 0.05, P < 0.01). Compared with the model group, the 24-h urinary protein decreased in the hormone group and the CM + hormone group (P < 0.05, P < 0.01). The decrement was more obvious along with the treatment time went by (P < 0.05, P < 0.01). There was statistical difference in the reduction of urine protein on the 35th day between the CM group and the model group (P < 0.05). (2) Compared with the 21st-day of the same group, the serum levels of TRACP and RANKL increased (P < 0.05, P < 0.01). Compared with the model group, the serum levels of the TRACP and RANKL increased (P < 0.05, P < 0.01), OPG and BGP decreased (P < 0.05, P < 0.01) in the hormone group. Compared with the CM group at the same period, serum OPG level decreased and the RANKL level increased in the hormone group and the CM + hormone group (P < 0.05, P < 0.01). Besides, the serum level of TRACP increased and BGP decreased (P < 0.05, P < 0.01). Compared with the hormone group at the same period, OPG and BGP increased (P < 0.05, P < 0.01), RANKL decreased (P < 0.01) in the CM + hormone group. On the 35th day TRACP decreased (P < 0.01). (3) Compared with the normal group, mRNA expressions of OPG and RANKL on the 21st day increased (P < 0.05, P < 0.01), mRNA expressions of OPG and RANKL on the 35th day decreased in the model group (P < 0.01). Compared with the CM group at the same period, OPG mRNA expression decreased (P < 0.01) and RANKL mRNA expression increased in the hormone group (P < 0.05). OPG mRNA expression decreased in the CM +hormone group (P < 0.05). (4) Compared with the hormone group on the 21st day, the OPG level decreased and the RANKL protein increased (both P < 0.05). RANKL decreased in the CM + hormone group (P < 0.05). Compared with the model group at the same period, OPG decreased and RANKL increased in the hormone group (P < 0.01). Compared with the CM group at the same period, OPG decreased (P < 0.01), RANKL increased (P < 0.01) in the hormone group and the CM + hormone group. Compared with the hormone group at the same period, OPG increased and RANKL decreased in the CM + hormone group (both P < 0.01). CONCLUSIONS: Prednisone could induce osteoporosis through the OPG/RANKL/RANK pathway. MSZ could slow down the formation of prednisone-induced osteoporosis through promoting osteoblast differentiation, and inhibiting osteoclastogenesis.

Sesquiterpenes from the marine red alga Laurencia composita.

Four new chamigrane derivatives, laurecomin A (1), laurecomin B (2), laurecomin C (3), and laurecomin D (4), one new naturally occurring sesquiterpene, 2,10-dibromo-3-chloro-7-chamigren-9-ol acetate (5), and three known halogenated structures, deoxyprepacifenol (6), 1-bromoselin-4(14),11-diene (7), and 9-bromoselin-4(14),11-diene (8), were isolated from the marine red alga Laurencia composita collected from Pingtan Island, China. The structures of these compounds were unambiguously established by 1D, 2D NMR and mass spectroscopic techniques. The bioassay results showed that 2 was active against both brine shrimp and fungus Colletotrichum lagenarium.

[Indications of acupuncture outpatient based on clinical investigation].

OBJECTIVE: The present situation of clinical indications of acupuncture in China is investigated in this article which provides clinical evidence for the establishment of acupuncture indications. METHODS: Out-patients of acupuncture departments of 31 Chinese provinces in the year 2008 were investigated through the method of cluster random sampling. And the analysis was made on diseases sorting and distribution based on Pareto principle and with EpiMap software. RESULTS: Information of 31 858 out-patients of the first treatment from 36 hospitals were collected which referred to 368 diseases of 16 disease systems. Among them, there were 57 most commonly-encountered diseases, 60 commonly-encountered diseases and 251 rare diseases. CONCLUSION: There are totally 368 acupuncture clinical indications at present according to the investigation with disproportional distribution in administrative districts. It is held that indications of acupuncture have high centralization degree. Thus, the populariza tion and promotion on application of acupuncture indications should be strengthened.

[Survey clinical evidence of acupuncture therapy for depressive neurosis].

OBJECTIVE: To evaluate the clinical studies of acupuncture for treatment of depressive neurosis, collect the high quality evidence relative to clinical acupuncture practice for clinical decision-making reference. METHODS: Around crucial common questions of acupuncture clinical practice, the documents of clinical study were comprehensively retrieved. According to 5-grade criterion of evidence-based medicine, the evidence from high to low level were selected to answer corresponding clincal questions and RevMan 5.0.20 was used to analyze the final indicator. RESULTS: Nineteen documents of clinical study accord with the inclusive criterion were retrieved. Level-A evidence showed effectiveness of acupuncture. Acupuncture might be superior or equal to fluoxetine, with little adverse effect and high safety. Level-C evidence showed acupuncture might be superior or equal to Amitriptyline, with little adverse effect and high safety. And no relative clinicial evidence compared effect of acupuncture with that of psychotherapy or behavior therapy. Only one level-C evidence showed there was no effect difference between acupuncture combined with bloodletting therapy and bloodletting alone. Two level-C evidence showed the effect of acupuncture combined with western medicine was superior to that of medicine alone, eg. catgut embedding therapy combined with Fluoxetine, electroacupuncture combined with Seroxat. CONCLUSION: Acupuncture for depressive nerosis has a positive effect. Acupuncture has an equal effect compared with western medicine, while strictly designed equivalent and non-inferior studies are demanded. The effect of acupuncture combined with medicine has some advantage, but need high quality studies to verify.

Study of the effect of leeching on plasma endothelin and soluble interleukin-2 receptor in patients with systemic lupus erythematosus.

OBJECTIVE: to explore the mechanism of leeching in treating systemic lupus erythematosus (SLE). METHODS: Forty-four patients with SLE were randomly divided into conventional corticosteroid treated group (control group, n = 20) and conventional treatment group with leeching intervention added (leeching group, n = 24). Before and after treatment the concentration of plasma endothelin (ET) and soluble interleukin-2 receptor (sIL-2R) were determined. RESULTS: Before treatment the level of plasma ET and sIL-2R in the SLE patients were all higher than those in the normal healthy group, (P < 0.01). But after treatment the level of these in both groups were significantly improved than those of before treatment (P < 0.05), and comparison between these two treated groups showed that the difference between them was significant (P < 0.05). CONCLUSION: Leeching added to conventional treatment of SLE could be more effective in improving the level of plasma ET and sIL-2R, and ameliorating the impairment of renal tissues.