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Qiaoping Li,1,* Ziwei Huang,2,* Defu Liu,3 Jingna Zheng,1 Jianhui Xie,4– 6 Jiannan Chen,1 Huifang Zeng,2 Ziren Su,1 Yucui Li1 1School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China; 2The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People’s Republic of China; 3School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China; 4The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 5State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 6Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou, 510120, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yucui Li; Ziren SuGuangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of ChinaTel +86 20 39358517Fax +86 20 39358390Email liyucui@gzucm.edu.cn; suziren@gzucm.edu.cnPurpose: Berberine (BBR) is an active component of Phellodendri Cortex (PC), which is a traditional Chinese medicine that has been prescribed clinically for hyperuricemia (HUA) for hundreds of years. Many studies reported the anti-inflammatory and nephroprotective properties of BBR and PC; however, the therapeutic effects of BBR on HUA have not been explored. This study aims to investigate the efficacy and mechanism of BBR for treating HUA.Methods: The mechanism of BBR in the treatment of HUA were predicted by network pharmacology. A mouse model of HUA established by potassium oxonate and hypoxanthine was used to verify the prediction. The levels of serum uric acid (UA), urea nitrogen (BUN) and creatinine (CRE) were determined by biochemical test kits. Hematoxylin and eosin staining of kidney tissues was used to observe the kidney damage. ELISA kits were applied to detect the levels of interleukin (IL)-1β and IL-18 in serum and kidney tissues. Quantitative real-time PCR and Western blotting were adopted to analyze the expression of NLRP3, ASC, Caspase1, IL-1β and URAT1. The expressions of URAT1 in the kidney tubules were visualized by immunohistochemical staining. Molecular docking was used to assess the interaction between URAT1 and BBR.Results: The network pharmacology screened out 82 genes and several inflammation-related signaling pathways related to the anti-hyperuricemia effect of BBR. In the in vivo experiment, BBR substantially decreased the level of UA, BUN and CRE, and alleviated the kidney damage in mice with HUA. BBR reduced IL-1β and IL-18, and downregulated expressions of NLRP3, ASC, Caspase1 and IL-1β. BBR also inhibited expression of URAT1 and exhibited strong affinity with this target in silico docking.Conclusion: BBR exerts anti-HUA and nephroprotective effects via inhibiting activation of NLRP3 inflammasome and correcting the aberrant expression of URAT1 in kidney. BBR might be a novel therapeutic agent for treating HUA.Keywords: berberine, hyperuricemia, URAT1, NLRP3 signaling pathway

Qiao-Ping Li,1,* Jing Li,1,* Hong-Ying Pan2 1Department of Spine Surgery, Lishui Central Hospital, Lishui, People’s Republic of China; 2Department of Nursing, Lishui Central Hospital, Lishui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong-Ying PanDepartment of Nursing, Lishui Central Hospital, No. 289 of Kuocang Road, Liandu District, Lishui, People’s Republic of ChinaTel +86 13587179166Email panhongying_56@163.comObjective: This study aims to explore the effects of an online home nursing care model application on patients with traumatic spinal cord injury (TSCI).Methods: Eighty patients with TSCI discharged from the hospital between January 2015 and January 2018 were included in the study. The patients were randomly divided into two groups: the control group and the observation group (n = 40, each). The patients in the control group were given routine discharge guidance, while the patients in the observation group were given online home nursing care. The Oswestry Disability Index (ODI), Medical Outcomes Study 36-item short-form health survey (MOS SF-36), and complication-incidence rate were used to evaluate the efficiency of the online home nursing care model.Results: There were no differences in the ODI and MOS SF-36 scores between the two groups at discharge. However, the ODI and MOS SF-36 scores in the observation group showed significant improvement compared with the control group (p < 0.05) during the most recent follow-up. The incidence of complications, such as constipation, joint stiffness, muscle atrophy, foot drop, and pressure sores, were significantly lower in the observation group than in the control group (p < 0.05).Conclusion: The online home nursing care model can reduce complication incidence, alleviate dysfunction, and improve the quality of life of patients with TSCI.Keywords: online, home nursing care, spinal cord injury, Oswestry Disability Index, SF-36

Berberine (BBR) is a promising anti-diabetic isoquinoline alkaloid from Rhizoma coptidis, while its bioavailability was extremely low. Here, the existing form and pharmacokinetics of BBR were comparatively characterized in conventional and antibiotic-induced pseudo germ-free (PGF) rats. Furthermore, we comparatively investigated the antidiabetic effect and potential mechanism of BBR and its intestinal oxidative metabolite oxyberberine (OBB) in STZ-induced diabetic rats. Results showed that BBR and OBB existed mainly as protein-bound form in blood, while protein-bound OBB was significantly depleted in PGF rats. Treatment with OBB and BBR effectively decreased clinical symptoms of diabetic rats, reduced blood glucose level, ameliorated the pancreatic damage, and mitigated oxidative stress and inflammatory markers. However, the anti-diabetes effect of BBR was obviously compromised by antibiotics. In addition, OBB exerted superior anti-diabetes effect to BBR of the same dose, significantly up-regulated the mRNA expression of Nrf2 signaling pathway and substantially promoted the pancreatic levels of PI3K/Akt signaling pathway. In conclusion, BBR and its absorbed oxidative metabolite OBB were mainly presented and transported in the protein-bound form in vivo. The gut microbiota may play an important role in the anti-diabetes effect of BBR through transforming itself into the superior hypoglycemic metabolite OBB. OBB possessed favorable hypoglycemic and pancreatic β-cells protective effects, which may stand a huge potential to be further developed into a promising anti-diabetes candidate.

Background Berberine (BBR) has been widely used to treat non-alcoholic fatty liver disease (NAFLD). The metabolites of BBR were believed to contribute significantly to its pharmacological effects. Oxyberberine (OBB), a gut microbiota-mediated oxidative metabolite of BBR, has been firstly identified in our recent work. Purpose Here, we aimed to comparatively investigate the anti-NAFLD properties of OBB and BBR. Methods The anti-NAFLD effect was evaluated in high-fat diet-induced obese NAFLD rats with biochemical/ELISA tests and histological staining. The related gene and protein expressions were detected by qRT-PCR and Western blotting respectively. Molecular docking and dynamic simulation were also performed to provide further insight. Results Results indicated OBB remarkably and dose-dependently attenuated the clinical manifestations of NAFLD, which (100 mg/kg) achieved similar therapeutic effect to metformin (300 mg/kg) and was superior to BBR of the same dose. OBB significantly inhibited aberrant phosphorylation of IRS-1 and up-regulated the downstream protein expression and phosphorylation (PI3K, p-Akt/Akt and p-GSK-3β/GSK-3β) to improve hepatic insulin signal transduction. Meanwhile, OBB treatment remarkably alleviated inflammation via down-regulating the mRNA expression of MCP-1, Cd68, Nos2, Cd11c, while enhancing Arg1 mRNA expression in white adipose tissue. Moreover, OBB exhibited closer affinity with AMPK in silicon and superior hyperphosphorylation of AMPK in vivo, leading to increased ACC mRNA expression in liver and UCP-1 protein expression in adipose tissue. Conclusion Taken together, compared with BBR, OBB was more capable of maintaining lipid homeostasis between liver and WAT via attenuating hepatic insulin pathway and adipocyte inflammation, which was associated with its property of superior AMPK activator.

Graphical abstract, Highlights • In the same content, Nano-HO could effectively enhance the bioactivity of HO remarkably and prolonged its circulation time in rats. • Nano-HO improved cognitive deficits in TgCRND8 mice. • Nano-HO suppressed neuroinflammatory response (TNF-α, IL-Iβ, IL-6) inhibited the activation of microglia, astrocyte and A-β plaque burdens in TgCRND8 mice. • Nano-HO ameliorated AD through regulating APP processing, preventing tau hyperphosphorylation and modulating JNK/CDK5/GSK-3β pathway. • Nano-HO regulated the composition and structure of gut microbiota to protect the gut microflora and its stability., Introduction Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer’s disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy. Objectives A novel honokiol nanoscale drug delivery system (Nano-HO) with smaller size and excellent stability was developed in this study to improve the solubility and bioavailability of HO. The anti-AD effects of Nano-HO was determined. Methods Male TgCRND8 mice were daily orally administered Nano-HO or HO at the same dosage (20 mg/kg) for 17 consecutive weeks, followed by assessment of the spatial learning and memory functions using the Morris Water Maze test (MWMT). Results Our pharmacokinetic study indicated that the oral bioavailability was greatly improved by Nano-HO. In addition, Nano-HO significantly improved cognitive deficits and inhibited neuroinflammation via suppressing the levels of TNF-α, IL-6 and IL-1β in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing β-amyloid (Aβ) deposition in the cortex and hippocampus of TgCRND8 mice. Moreover, Nano-HO was more effective than HO in modulating amyloid precursor protein (APP) processing via suppressing β-secretase, as well as enhancing Aβ-degrading enzymes like neprilysin (NEP). Furthermore, Nano-HO more markedly inhibited tau hyperphosphorylation via decreasing the ratio of p-Tau (Thr 205)/tau and regulating tau-related apoptosis proteins (caspase-3 and Bcl-2). In addition, Nano-HO more markedly attenuated the ratios of p-JNK/JNK and p-35/CDK5, while enhancing the ratio of p-GSK-3β (Ser9)/GSK-3β. Finally, Nano-HO prevented the gut microflora dysbiosis in TgCRND8 mice in a more potent manner than free HO. Conclusion Nano-HO was more potent than free HO in improving cognitive impairments in TgCRND8 mice via inhibiting Aβ deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3β signaling pathway. Nano-HO also more potently modulated the gut microbiota community to protect its stability than free HO. These results suggest that Nano-HO has good potential for further development into therapeutic agent for AD treatment.

Background Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer’s disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy. A novel honokiol nanoscale drug delivery system (Nano-HO) with smaller size and excellent stability was developed in this study to improve the solubility and bioavailability of HO. Methods Male TgCRND8 mice were administered with Nano-HO or HO at the same dosage (20 mg/kg) by oral gavage daily for 17 consecutive weeks, followed by assessment of the spatial learning and memory functions with the Morris Water Maze test (MWMT). Results Nano-HO and HO could significantly improve cognitive deficits and inhibit neuroinflammation via suppressing the levels of tumor necrosis factor (TNF-α), interleukin 6 (IL-6) and IL-1β in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing β-amyloid (Aβ) deposition in the cortex and hippocampus of TgCRND8 mice. In addition, Nano-HO and HO could modulate amyloid precursor protein (APP) processing and phosphorylation via suppressing β-secretase including β-site APP cleaving enzyme-1 (BACE-1) and phosphorylated APP (Thr 668), inhibiting γ-secretase including presenilin-1 (PS-1) and anterior pharynx-defective-1 (APH-1), as well as enhancing Aβ-degrading enzymes such as insulin degrading enzyme (IDE) and neprilysin (NEP). Moreover, Nano-HO remarkably inhibited tau hyperphosphorylation via decreasing the levels of p-tau (Thr 205) and p-tau (Ser 404), as well as regulating tau-related apoptosis proteins including caspase-3 and Bcl-2. Furthermore, Nano-HO and HO markedly attenuated the ratios of p-JNK/JNK and p-35/CDK5, while enhancing the ratio of p-GSK-3β (Ser9)/GSK-3β. On the other hand, Nano-HO and HO prevented the alterations on the composition of gut microbiota in TgCRND8 mice. Conclusions Nano-HO was more effective than regular HO in improving cognitive impairments in TgCRND8 mice via inhibiting Aβ deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3β signaling pathway. Nano-HO was also more potently modulate the gut microbiota community to protect its stability as compared with that of regular HO. Our results amply indicated that HO with nano-sized drug delivery system has good potential for further development into therapeutic agent for AD treatment.

Brucea javanica is an important Chinese folk medicine traditionally used for the treatment of dysentery (also known as inflammatory bowel diseases). Brucea javanica oil emulsion (BJOE), the most common preparation of Brucea javanica, has a variety of pharmacological activities. In this follow-up investigation, we endeavored to illuminate the potential benefit of BJOE on 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced Crohn’s disease (CD) in rats and decipher the mechanism of action. The result illustrated that BJOE treatment significantly reduced the body weight loss, disease activity index and macroscopic scores, ameliorated shortening of colon length, arrested colonic histopathological deteriorations, lowered the histological scores in parallel to the model group. Furthermore, BJOE also decreased the levels of MPO and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17, IL-23 and IFN-γ), and increased the levels of anti-inflammatory cytokines (IL-4, IL-10 and TGF-β) as compared with the model group. In addition, the elevated mRNA expression of MMP-1, MMP-3 and RAGE induced by TNBS was remarkably inhibited by BJOE, SASP or AZA treatments, while the mRNA expression of PPAR-γ was significantly enhanced. Furthermore, the activation of TLR4/NF-κB signaling pathway was significantly inhibited by AZA and BJOE treatment when compared with that of TNBS-treated rats. Our study suggested that BJOE exerted superior therapeutic effect to SASP and AZA in treating TNBS-induced colitis in rats. The protective effect of BJOE may involve the inhibition of the TLR4/NF-κB-mediated inflammatory responses. These results indicated that BJOE held promising potential to be further developed into a novel candidate for the treatment of CD.

This article is devoted to investigate some properties of solutions for several systems of complex differential-q-difference equations. Some results about the existence and the estimate for the growth of solutions for a series of systems of q-difference–differential equations are obtained. Moreover, it is a very satisfactory fact that some examples are given to illustrate the existence of solutions for such systems in each case of some results.

Brucea javanica oil (BJO), one of the main products of Brucea javanica, has been widely used in treating different kinds of malignant tumors. Quassinoids are the major category of anticancer phytochemicals of B. javanica. However, current researches on the anti-cancer effect of BJO mainly focused on oleic acid and linoleic acid, the common major components of dietary edible oils, essential and characteristic components of B. javanica like quassinoids potentially involved remained unexplored. In the current investigation, we developed an efficient HPLC method to detect brusatol, a characteristic quassinoid, and comparatively scrutinized the anti-hepatocellular carcinoma (anti-HCC) effect of BJO, brusatol-free BJO (BF-BJO), and brusatol-enriched BJO (BE-BJO) against hepatoma 22 (H22) in mice. High-performance liquid chromatography (HPLC) was utilized to identify the components in BJO. BE-BJO was extracted with 95 % ethanol. The anti-tumor effect of BJO, BF-BJO and BE-BJO was comparatively investigated, and the potential underlying mechanism was explored in H22 ascites tumor-bearing mice. The results indicated that BJO and BE-BJO significantly prolonged the survival time of H22 ascites tumor-bearing mice, while BF-BJO exhibited no obvious effect. BJO and BE-BJO exhibited pronounced anti-HCC activity by suppressing the growth of implanted hepatoma H22 in mice, including ascending weight, abdominal circumference, ascites volume and cancer cell viability, with a relatively wide margin of safety. BJO and BE-BJO significantly induced H22 cell apoptosis by upregulating the miRNA-29b gene level and p53 expression. Furthermore, BJO and BE-BJO treatment substantially downregulated Bcl-2 and mitochondrial Cytochrome C protein expression, and upregulated expression levels of Bax, Bad, cytosol Cytochrome C, caspase-3 (cleaved), caspase‑9 (cleaved), PARP and PARP (cleaved) to induce H22 cells apoptosis. Brusatol was detected in BJO and found to be one of its major active anti-HCC components, rather than fatty acids including oleic acid and linoleic acid. The anti-HCC effect of BJO and BE-BJO was intimately associated with the activation of miRNA-29b, p53-associated apoptosis and mitochondrial-related pathways. Our study gained novel insight into the material basis of BJO in the treatment of HCC, and laid a foundation for a novel specific standard for the quality evaluation of BJO and its commercial products in terms of its anti-cancer application.

The Anti-synchronization of chaotic systems with uncertainty by sliding mode control is studied. Using the principle of poles assignment method, the switching function is designed to guarantee Anti-synchronization of slide mode with nonlinearity terms. Using exponent hitting condition of sliding mode, a robust anti-synchronization controller is proposed. In contrast to the previous works, sliding mode of this controller is free from the influence of disturbance, and the system has both better robustness and quick tracking. Therefore the computation is simple and the conservation is smaller. Finally, Simulation results verify the effectiveness of the proposed scheme.

This paper deals with the output feedback sliding mode control for uncertain Ito neutral stochastic time-delay systems. The system states are unmeasured, and the uncertainties are unmatched. A sliding mode control scheme is proposed based on the state estimates. By utilizing a novel switching function, the derivative of the switching function is ensured to have a finite variation. It is shown that the sliding mode in the estimation space can be attained in finite time. A sufficient condition for the asymptotic stability (in probability) of the overall closed-loop stochastic system is derived. Finally, a simulation example is given to illustrate the proposed method.

Hybrid synchronization of the unified chaotic system with disturbance is investigated. Using the principle of poles assignment method, the switching function is designed to guarantee Anti-synchronization of slide mode with nonlinearity terms. Using modified exponent hitting condition of sliding mode, a robust synchronization controller is proposed. In contrast to the previous works, sliding mode of this controller is free from the influence of disturbance, and the system has both better robustness and quick tracking. Therefore the computation is simple and the conservation is smaller. Finally, the simulation is put forward to demonstrate the correctness and effectiveness of the proposed methods.