[Neuroprotective effect and mechanism of Zuogui Jiangtang Jieyu Formula on diabetes mellitus complicated with depression model rats based on CX3CL1-CX3CR1 axis].

Based on the CX3C chemokine ligand 1(CX3CL1)-CX3C chemokine receptor 1(CX3CR1) axis, this study explored the potential mechanism by which Zuogui Jiangtang Jieyu Formula(ZGJTJY) improved neuroinflammation and enhanced neuroprotective effect in a rat model of diabetes mellitus complicated with depression(DD). The DD rat model was established by feeding a high-fat diet combined with streptozotocin(STZ) intraperitoneal injection for four weeks and chronic unpredictable mild stress(CUMS) combined with isolated cage rearing for five weeks. The rats were divided into a control group, a model group, a positive control group, an inhibitor group, and a ZGJTJY group. The open field test and forced swimming test were used to assess the depression-like behaviors of the rats. Enzyme-linked immunosorbent assay(ELISA) was performed to measure the expression levels of the pro-inflammatory cytokines interleukin-1ß(IL-1ß) and tumor necrosis factor-α(TNF-α) in plasma. Immunofluorescence staining was used to detect the expression of ionized calcium-binding adapter molecule 1(Iba1), postsynaptic density protein-95(PSD95), and synapsin-1(SYN1) in the hippocampus. Hematoxylin-eosin(HE) staining, Nissl staining, and TdT-mediated dUTP nick end labeling(TUNEL) fluorescence staining were performed to assess hippocampal neuronal damage. Western blot was used to measure the expression levels of CX3CL1, CX3CR1, A2A adenosine receptor(A2AR), glutamate receptor 2A(NR2A), glutamate receptor 2B(NR2B), and brain-derived neurotrophic factor(BDNF) in the hippocampus. Compared with the model group, the ZGJTJY group showed improved depression-like behaviors in DD rats, enhanced neuroprotective effect, increased expression of PSD95, SYN1, and BDNF(P<0.01), and decreased expression of Iba1, IL-1ß, and TNF-α(P<0.01), as well as the expression of CX3CL1, CX3CR1, A2AR, NR2A, and NR2B(P<0.01). These results suggest that ZGJTJY may exert its neuroprotective effect by inhibiting the CX3CL1-CX3CR1 axis and activation of hippocampal microglia, thereby improving neuroinflammation and abnormal activation of N-methyl-D-aspartate receptor(NMDAR) subunits, and ultimately enhancing the expression of synaptic-related proteins PSD95, SYN1, and BDNF in the hippocampus.

[Therapeutic effect and mechanism of Xiaoyao Kangai Jieyu Recipe on mice with breast cancer related depression through regulating COX pathway].

This study aimed to investigate the intervention effect and mechanism of Xiaoyao Kangai Jieyu Recipe(XKJR) on hip-pocampal microglia and neuronal damage in mice with breast cancer related depression. The mouse model of breast cancer related depression was established by inoculation of 4T1 breast cancer cells in axilla and subcutaneous injection of corticosterone(30 mg·kg~(-1)). The successfully modeled mice were randomly divided into a model group, a positive drug group(capecitabine 60 mg·kg~(-1)+fluoxetine 19.5 mg·kg~(-1)), and XKJR group(19.5 mg·kg~(-1) crude drug), with 6 in each group. Another 6 normal mice were taken as a normal group. The administration groups were given corresponding drugs by gavage, while the normal and model groups were given an equal volume of distilled water, once a day for 21 consecutive days. The depressive behavior of mice was assessed by glucose consumption test, open field test and novelty-suppressed feeding test. Hematoxylin and eosin(HE) staining and tumor suppression rate were used to evaluate the changes of axillary tumors. The mRNA expressions and the relative protein expressions of interleukin-1ß(IL-1ß), interleukin-18(IL-18), cyclooxyganese-2(COX-2) and glutamyl-prolyl-tRNA synthetase(EPRs) in the hippocampus of mice were determined by quantitative real-time polymerase chain reaction(qRT-PCR) and immunohistochemistry, respectively. Immunofluorescence was performed to detect the mean fluorescence intensity of CD11b, a marker of hippocampal microglia activation. Nissler staining and transmission electron microscopy were employed to observe the morphological changes and the ultramorphological changes of hippocampal neurons, respectively. The experimental results indicated that compared with the normal group, the model group had reduced glucose consumption and lowered number of total activities in open field test(P<0.05, P<0.01), prolonged first feeding latency in no-velty-suppressed feeding test(P<0.01), and significant depression-like behavior; the contents of IL-1ß, IL-18, COX-2, and EPRs in hippocampus were increased(P<0.05, P<0.01), with hippocampal microglia activation and obvious neuronal damage. Compared with the model group, the positive drug group and the XKJR group presented an improvement in depressive behaviors, a decrease in the contents of IL-1ß, IL-18, COX-2 and EPRs in hippocampus, and an alleviation in the activation of hippocampal microglia and neuronal damage; the tumor suppression rates of positive drug and XKJR were 40.32% and 48.83%, respectively, suggesting a lower tumor growth rate than that of the model group. In summary, XKJR may improve hippocampal microglia activation and neuronal damage in mice with breast cancer related depression through activating COX signaling pathway.

Use of different ligand modification liposomes to evaluate the anti-liver tumor activity of cantharidin.

In this study, cantharidin(CTD), a bioactive terpenoid in traditional Chinese medicine cantharidin, was selected as a model component to construct novel nano liposome delivery systems for hepatocellular carcinoma therapy. Previous studies have shown that although cantharidin has definite curative effects on primary liver cancer, it is associated with numerous toxic and side effects. Therefore, based on the glycyrrhetinic acid (GA) binding site and the asialoglycoprotein receptor (ASGPR) on the hepatocyte membrane, the surface of CTD liposomes was modified with stearyl alcohol galactoside (SA-Gal) or/and the newly synthesized 3-succinic-30-stearyl deoxyglycyrrhetinic acid (11-DGA-Suc) ligands, and the physicochemical properties, pharmacokinetics, in vivo and in vitro anti-liver tumor activity and its mechanism of modified liposomes were investigated. Compared to CTD-lip, SA-Gal-CTD-lip, and 11-DGA-Suc + SA-Gal-CTD-lip, 11-DGA-Suc-CTD-lip showed stronger cytotoxicity and increased inhibition of HepG2 cell migration had the highest apoptosis rate. The cell cycle results indicated that HepG2 cells was arrested mainly at G0/G1phase and G2/M phase. The results of in vivo pharmacokinetic experiments revealed that the distribution of modified liposomes in the liver was significantly increased compared with that of unmodified liposome. In vivo tumor inhibition experiment showed that 11-DGA-Suc-CTD-lip had excellent tumor inhibition, and the tumor inhibition rates was 80.96%. The 11-DGA-Suc-CTD-lip group also displayed the strongest proliferation inhibition with the lowest proliferation index of 7% in PCNA assay and the highest apoptotic index of 49% in TUNEL assay. Taken together, our findings provide a promising solution for improving the targeting of nano liposomes and further demonstrates the encouraging potential of poor solubility and high toxicity drugs applicable to tumor therapy.

Compound Chaijin Jieyu Tablets ameliorating insomnia complicated with depression by improving synaptic plasticity via regulating orexin A, melatonin, and acetylcholine contents / 数字中医药（英文）

@#Objective To investigate the efficacy and mechanism of action of Compound Chaijin Jieyu Tablets (复方柴金解郁片, CCJJYT) in rats with insomnia complicated with depression. Methods Seventy-two Sprague-Dawley rats were randomly assigned into eight groups: the control, chronic unpredictable mild stress (CUMS), sleep deprivation (SD), CUMS + SD, positive drug (venlafaxine hydrochloride + diazepam), CCJJYT high-dose (CCJJYT˗2×), medium-dose (CCJJYT˗1×), and low-dose (CCJJYT˗0.5×) groups, with nine rats in each group. Depression-like behavior was evaluated by body weight, food intake, and behavioral tests such as the sucrose preference test (SPT), open field test (OFT), forced swimming test (FST), and pentobarbital-induced sleep test (PST). Hematoxylin-eosin (HE) staining and Golgi-Cox staining were used to observe changes in pathological tissue and synaptic morphology, respectively. Enzyme-linked immunosorbent assay (ELISA) was used to detect the contents of orexin-A and acetylcholine. The expression levels of orexin receptor 1 (OXR1), melatonin receptor 1 (MT1A), melatonin receptor 2 (MT1B), acetylcholinesterase (AChE), and choline acetyltransferase (ChAT) were detected by immunohistochemistry and Western blot. Results In the present study, rats in the model group showed significant behavioral changes as well as a reduction in hippocampal dendritic branch length and synaptic number, along with increasing the content of orexin A and acetylcholine (P< 0.05), and altered expression levels of OX1R, MT1A, MT1B, ChAT, and AChE in the hippocampus and prefrontal cortex after modeling (P < 0.05). CCJJYT can improve depressive insomnia behavior and synaptic plasticity of rats (P < 0.05), which is similar to that of the positive drug group. It can also decrease the content of orexin A and acetylcholine, and reduce the expression levels of OXR1 and ChAT in hippocampus and prefrontal cortex (P < 0.05), and increase the expression levels of MT1A, MT1B, and AChE proteins (P < 0.05). Conclusion CCJJYT has good antidepressant and insomnia effects, probably through the regu-lation of orexin-A, melatonin, and acetylcholine content in hippocampus and prefrontal cortex of rats, improving synaptic plasticity and thus exerting antidepressant and insomnia effects.