A co-crystal berberine-ibuprofen improves obesity by inhibiting the protein kinases TBK1 and IKKɛ.

Berberine (BBR) exerts specific therapeutic effects on various diseases such as diabetes, obesity, and other inflammation-associated diseases. However, the low oral bioavailability (below 1%) of berberine due to its poor solubility and membrane permeability limits its clinical use. In this paper, we have prepared a 1:1 co-crystal berberine-ibuprofen (BJ) using drug salt metathesis and co-crystal technology. Pharmacokinetic studies demonstrate a 3-fold increase in vivo bioavailability of BJ compared to that of BBR, and BJ is more effective in treating obesity and its related metabolism in vitro and in vivo. We also find that BJ promotes mitochondrial biogenesis by inhibiting TBK1 and inducing AMP-activated protein kinase (AMPK) phosphorylation, and BJ increases adipocyte sensitivity to catecholamine by inhibiting IKKε. Together, our findings support that co-crystal BJ is likely to be an effective agent for treating obesity and its related metabolic diseases targeting TBK1 and IKKε.

Silibinin Schiff Base Derivatives Counteract CCl4-Induced Acute Liver Injury by Enhancing Anti-Inflammatory and Antiapoptotic Bioactivities.

Background: Silibinin (Sil), a flavonoid lignan-like natural compound derived from milk thistle seeds, has been used to treat hepatic diseases, including early-phase hepatocirrhosis and fatty liver, for many years. However, its poor water solubility limits its gastrointestinal absorption and bioavailability. It clinical use has been limited due to its slow onset of action. Faced with this problem, research on the derivatives of silibinin has been receiving much attention. Purpose: A series of silibinin derivatives with good biosafety and higher hepatoprotective activity were obtained by a safe, efficient and green chemical synthesis method. Patients and Methods: First, the carbonyl group in the structure of silibinin was used to obtain silibinin Schiff base derivatives by dehydration condensation with the carboxyl group in the sulfur-containing amino acid. Next, relevant experiments were performed to characterize the structure, physical form and solubility of the derivatives. Then, toxicity tests of the derivatives were performed in LO-2 cells and SD rats to evaluate their biosafety. Finally, the anti-inflammatory and antiapoptotic activities were observed using a carbon tetrachloride (CCl4)-induced acute liver injury model in C57BL/6J mice using silibinin as a control. Results: The studies showed that SS and ST behaved as amorphous substances and showed a significant increase in solubility compared to silibinin. These two derivatives showed low toxicity in biosafety tests and higher bioactivity (anti-inflammatory and anti-apoptotic) than silibinin against acute liver injury induced by CCl4. Conclusion: Two silibinin derivatives (SS and ST) obtained by the Schiff base reaction improved the solubility of the silibinin parent nucleus in biological media with the help of the hydrophilic and amorphous morphology of the ligand. The low toxicity in vivo and in vitro ensures the biosafety of the derivatives. The hepatoprotective activity (anti-inflammatory and anti-apoptotic) was significantly improved compared to silibinin.

Duloxetine alleviates oxaliplatin-induced peripheral neuropathy by regulating p53-mediated apoptosis.

Oxaliplatin (OXA) is a key platinum-based chemotherapeutic agent for treatment of metastatic colorectal cancer, but the side effects of acute and chronic neuropathies limit its clinical application. Duloxetine has been found to have the potential to prevent OXA-induced peripheral neuropathy in several studies, but the underlying mechanisms remain unclear. The purpose of this study was to evaluate the effects of duloxetine on OXA-induced peripheral neuropathy and to find the potential mechanisms. The neuropathic pain mice model was used to explore the role of duloxetine on OXA-induced peripheral neuropathy by measuring the change of thermal withdrawal latency (TWL), paw withdrawal threshold (PWT), and intraepidermal nerve fiber density (IENFD). Moreover, to explore molecular mechanisms, effects of duloxetine on OXA-induced changes in mRNA and protein expression of components of the p53-related pathways in cultured rat dorsal root ganglion (DRG) neurons were measured. In vivo, we found duloxetine treatment could significantly prevent the changes in the TWL, PWT to mechanical stimulation, and the IENFD of mice caused by OXA. In vitro, we found duloxetine notably inhibits the relative mRNA and protein expression levels of p53, Bax/Bcl2, caspase-3, and caspase-9 in DRG neurons, which may indicate duloxetine protected the DRG neuron by inhibiting p53-related pathways. These results suggest that duloxetine could alleviate the OXA-induced peripheral neuropathy. Duloxetine deserves further consideration as a potential protective agent against peripheral neuropathy.

A highly selective turn-on fluorescence probe with large Stokes shift for detection of palladium and its applications in environment water and living cells.

Nowadays, palladium has been widely used in many fields, which facilitates all aspects of our life. However, it may cause water and soil pollution and bring irreversible damage to the environment and organisms. Developing a fluorescence probe for rapid, highly sensitive and selective detection of palladium is still a poser. In this work, we designed and synthesized a novel fluorescence probe (RHS) for specific detection of palladium. Based on Pd0-mediated Tsuji-Trost reaction, the fluorescence probe was constructed by a rhodol derivative as thefluorophore and an allyl carbonate moiety as the specific palladium reactive site. The probe displayed excellent properties for detecting palladium, such as high selectivity and sensitivity, rapid response (20 min) and large Stokes shift (155 nm). The detection limit was determined to be as low as 0.140 µM with a linear range from 20 to 80 µM. After addition of palladium in RHS solution, the color of the solution turned from yellow to blue, indicating palladium could be monitored by the naked eyes. Moreover, probe RHS was successfully applied to palladium detection in environmental water samples. Importantly, with low cytotoxicity and good biocompatibility, the probe could monitor palladium in living cells.

Berberine Alleviate Cisplatin-Induced Peripheral Neuropathy by Modulating Inflammation Signal via TRPV1.

Chemotherapy induced peripheral neuropathy (CIPN) is a severe neurodegenerative disorder caused by chemotherapy drugs. Berberine is a natural monomer compound of Coptis chinensis, which has anti-tumor effect and can improve neuropathy through anti-inflammatory mechanisms. Transient receptor potential vanilloid (TRPV1) can sense noxious thermal and chemical stimuli, which is an important target for the study of pathological pain. In both vivo and in vitro CIPN models, we found that berberine alleviated peripheral neuropathy associated with dorsal root ganglia inflammation induced by cisplatin. We confirmed that berberine mediated the neuroinflammatory reaction induced by cisplatin by inhibiting the overexpression of TRPV1 and NF-κB and activating the JNK/p38 MAPK pathways in early injury, which inhibited the expression of p-JNK and mediated the expression of p38 MAPK/ERK in late injury in vivo. Moreover, genetic deletion of TRPV1 significantly reduced the protective effects of berberine on mechanical and heat hyperalgesia in mice. In TRPV1 knockout mice, the expression of NF-κB increased in late stage, and berberine inhibited the overexpression of NF-κB and p-ERK in late injury. Our results support berberine can reverse neuropathic inflammatory pain response induced by cisplatin, TRPV1 may be involved in this process.

Siwei Jianbu decoction improves painful paclitaxel-induced peripheral neuropathy in mouse model by modulating the NF-κB and MAPK signaling pathways.

BACKGROUND: Paclitaxel, a commonly used chemotherapeutic agent, is usually associated with peripheral neuropathy. Paclitaxel induced peripheral neuropathy (PIPN) can be dose limiting and may have detrimental influence on patients' quality of life. However, the mechanism of PIPN remains unclear. Medicinal herbs and their formulas might offer neuronal protection with their multitarget and integrated benefits in chemotherapy-induced peripheral neuropathy (CIPN). Siwei Jianbu decoction (J12) is a classic formula of traditional Chinese medicine which can promote blood circulation and treat diabetic nephropathy in clinical with the symptoms of weakness and pain. METHODS: The effects of J12 were treated in C57BL/6 mice before injected with Paclitaxel.Behaviour studies: Measurement of mechanical hyperalgesia, thermal nociception and cold allodynia. On the last day at the end of week 6, DRGs were obtained from mice for western blot and immunohistochemical analysis containing NF-κB, p-ERK1/2 and p-SAPK/JNK protein expression. Quantitative real-time polymerase chain reaction: mRNA expression of NF-κB, IL-1ß and TNF-α was analyzed. Additionally, the blood samples collected from the eye socket of the mouse were prepared to examine the levels of NF-κB, TNF-α, IL-6 and IL-1ß using ELISA assay kits. RESULTS: Hypersensitivity tests and pathology analysis have demonstrated that J12 could improve paclitaxel-induced peripheral pain. J12 acts by inhibiting the activation of (C-Jun N-terminal kinases) JNK, (extracellular signal-regulated kinase) ERK1/2 phosphorylation in (Mitogen-activated protein kinases) MAPK signaling pathway and the nuclear factor-κB (NF-κB) in C57BL/6 mice model, J12 also inhibits the production of inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and IL-6. CONCLUSION: The present study showed that J12 ameliorates paclitaxel-induced peripheral neuropathic pain.

Influence of childhood abuse on implicit and explicit self-esteem among children in Sichuan / 中国学校卫生

Objective@#To investigate association between childhood abuse and self-esteem among children in Sichuan.@*Methods@#A total of 700 students aged 10-16 years from four cities of Sichuan were selected through stratified random sampling method. All the participants were investigated with Screen Questionnaire of Child Abuse(SQCA), the Self-esteem Scale (SES) and the E-Prime based Implicit-Association Test(IAT).@*Results@#The prevalence of childhood abuse in Sichuan is 11.3%(65/574). Among them, 55.4% reported one type of abuse experience, 29.2% reported two types and 15.4% reported 3 or more types of abusive experiences. The average level of explicit self-esteem for the total sample children (x〖TX-*3〗=28.92, higher than 26) was in the medium level. For children with abuse experiences, explicit (t=-2.56, P<0.05) and implicit self-esteem (t=-2.40, P<0.05) was significantly lower than average level of the total sample. Educational background of primary caregivers was positively associated with explicit self-esteem(P<0.05). Gender and childhood abuse entered in the final regression model for implicit self-esteem(F=6.11, P<0.01), and childhood abuse negatively correlated with implicit self-esteem(t=-2.83, P<0.01).@*Conclusion@#Children with abuse experiences are more likely to have low implicit self-esteem.