Development and validation of an ultra-performance liquid chromatography-tandem mass spectrometry method for the determination of baloxavir in rat plasma and its application to pharmacokinetic studies.

In this study, an ultra-performance liquid chromatography-tandem mass spectrometry method was established for the development and validation of baloxavir acid (BXA) concentrations and the active ingredients of the antiviral drug baloxavir marboxil (BXM). Further, the method was applied to study the pharmacokinetics of BXA. BXA was determined by the electrospray ionization multiple reaction monitoring positive ion mode, and the mass-to-charge ratios (m/z) of BXA and internal standard baloxavir-d4 were 484.2 → 247.2 and 488.1 → 247.2. An Oasis max online column (2.1 × 20 mm, 30 µm) was used with 1% formic acid in water (A) and 2% formic acid in acetonitrile (B) as mobile phases at a flow rate of 0.5 mL·min-1 for chromatographic separation. The linearity was good in the range of 3-200 ng·mL-1 (r = 0.9994), with 3.00 ng·mL-1 lower limit of quantification. The relative standard deviation of the inter-assay precision was less than or equal to 6.51%, and the accuracy was in the range of 91.28%-104.29%. This method is suitable for the determination of BXA and for performing pharmacokinetic studies in clinical research.

Synthesis and evaluation of new 5-aminolevulinic acid derivatives as prodrugs of protoporphyrin for photodynamic therapy.

Protoporphyrin IX (PpIX) is used as a photosensitizer in the photodynamic diagnosis (PDD) and photodynamic therapy (PDT) of cancer and is synthesized intracellularly from 5-aminolevulinic acid (5-ALA) precursors. Thirteen novel 5-ALA derivatives were designed and synthesized appropriately with tailored hydrophilicity and lipophilicity. The generation of PpIX was detected and their antitumor activity in vitro and in vivo was also investigated. It was shown that compounds 9b-c, 11b-c and 13a displayed a characteristic long wavelength absorption peak at 593 nm after 5 h incubation in mice fibrosarcoma S180 cells. After being exposed to 600 nm laser light irradiation, these compounds can inhibit cell proliferation in S180 cells in vitro. The growth of S180 cell tumors in Kunming mice was significantly inhibited by these compounds in vivo. Among these compounds, 13a has low dark toxicity and high phototoxicity, which makes it an effective and promising prodrug for PDT.

Profiling Proteins in the Hypothalamus and Hippocampus of a Rat Model of Premenstrual Syndrome Irritability.

Premenstrual syndrome (PMS) refers to several physical and mental symptoms (such as irritability) commonly encountered in clinical gynaecology. The incidence of PMS has been increasing, attracting greater attention from medical fields. However, PMS pathogenesis remains unclear. This study employed two-dimensional gel electrophoresis (2DE) for proteomic map analysis of the hypothalamus and hippocampus of rat models of premenstrual syndrome (PMS) irritability. Matrix-assisted laser desorption/ionisation time of flight mass spectroscopy (MALDI-TOF-MS) was used to identify proteins possibly related with PMS irritability. Baixiangdan, a traditional Chinese medicine effective against PMS irritability, was used in the rat model to study putative target proteins of this medicine. The hypothalamus and hippocampus of each group modelling PMS displayed the following features: decreased expression of Ulip2, tubulin beta chain 15, α actin, and interleukin 1 receptor accessory protein; increased expression of kappa-B motif-binding phosphoprotein; decreased expression of hydrolase at the end of ubiquitin carboxy, albumin, and aldolase protein; and increased expression of M2 pyruvate kinase, panthenol-cytochrome C reductase core protein I, and calcium-binding protein. Contrasting with previous studies, the current study identified new proteins related to PMS irritability. Our findings contribute to understanding the pathogenesis of PMS irritability and could provide a reference point for further studies.

Synthesis, photophysical properties and biological evaluation of ß-alkylaminoporphyrin for photodynamic therapy.

A series of ß-alkylaminoporphyrins conjugated with different amines at ß position (D1-D3) or with electron-donating and electron-withdrawing substituents at phenyl position (D4-D6) were synthesized. Their photophysical and photochemical properties, intracellular localization, photocytotoxicities in vitro and vivo were also investigated. All target compounds exhibited no cytotoxicities in the dark and excellent photocytotoxicities against HeLa cells. Among them, D6 showed the highest phototoxicity and the lowest dark toxicity, which was more phototoxic than Hematoporphyrin monomethyl ether (HMME). In addition, D6 exhibited best photodynamic antitumor efficacy on BALB/c nude mice bearing HeLa tumor. Therefore, D6 is a powerful and promising antitumor photosensitizer for photodynamic therapy.

Shuyu Capsules Relieve Premenstrual Syndrome Depression by Reducing 5-HT3AR and 5-HT3BR Expression in the Rat Brain.

The effects of the Shuyu capsule on 5-HT3AR and 5-HT3BR expression in a rat model of premenstrual syndrome (PMS) depression and on 5-HT3AR and 5-HT3BR expression and hippocampal neuron 5-HT3 channel current were investigated, to elucidate its mechanism of action against PMS depression. PMS depression model rats were divided into depression and Shuyu- and fluoxetine-treated groups, which were compared to control rats for frontal lobe and hippocampal 5-HT3AR and 5-HT3BR expression and behavior. The depressed model rats displayed symptoms of depression, which were reduced in treated and normal control rats. Frontal lobe and hippocampal 5-HT3AR and 5-HT3BR levels were significantly higher in the model versus the control group and were significantly lower in the Shuyu group. As compared to control rats, the 5-HT3R channel current in the model group was significantly higher; the 5-HT3R channel current in hippocampal neurons treated with serum from Shuyu group rats was significantly lower than that in those treated with model group serum. Thus, PMS depression may be related to 5-HT3AR and 5-HT3BR expression and increased 5-HT3 channel current. Shuyu capsules rectified abnormal 5-HT3AR and 5-HT3BR expression and 5-HT3 channel current changes in a rat model; this finding may provide insight into treating PMS depression.

LDHA contributes to nicotine induced cardiac fibrosis through autophagy flux impairment.

Cardiac fibrosis is a typical feature of cardiac pathological remodeling, which is associated with adverse clinical outcomes and has no effective therapy. Nicotine is an important risk factor for cardiac fibrosis, yet its underlying molecular mechanism remains poorly understood. This study aimed to identify its potential molecular mechanism in nicotine-induced cardiac fibrosis. Our results showed nicotine exposure led to the proliferation and transformation of cardiac fibroblasts (CFs) into myofibroblasts (MFs) by impairing autophagy flux. Through the use of drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) technology, it was discovered that nicotine directly increased the stability and protein levels of lactate dehydrogenase A (LDHA) by binding to it. Nicotine treatment impaired autophagy flux by regulating the AMPK/mTOR signaling pathway, impeding the nuclear translocation of transcription factor EB (TFEB), and reducing the activity of cathepsin B (CTSB). In vivo, nicotine treatment exacerbated cardiac fibrosis induced in spontaneously hypertensive rats (SHR) and worsened cardiac function. Interestingly, the absence of LDHA reversed these effects both in vitro and in vivo. Our study identified LDHA as a novel nicotine-binding protein that plays a crucial role in mediating cardiac fibrosis by blocking autophagy flux. The findings suggest that LDHA could potentially serve as a promising target for the treatment of cardiac fibrosis.

Recent advances in targeted gene silencing and cancer therapy by nanoparticle-based delivery systems.

Nanomedicine has emerged as a promising platform for disease treatment and much progress has been achieved in the clinical translation for cancer treatment. Several types of nanomedicines have been approved for therapeutic application. However, many nanoparticles still suffer from challenges in the translation from bench to bedside. Currently, nanoparticle-based delivery systems have been developed to explore their functions in targeted gene silencing and cancer therapy. This review describes the research progress of different nano-carriers in targeted gene editing, and the recent progress in co-delivery of anticancer drugs and small ribonucleic acid. We also summarize the strategies for improving the specificity of carrier systems. Finally, we discuss the functions of targeted nano-carriers in overcoming chemotherapeutic drug resistance in cancer therapy. As research continues to advance, a better understanding of the safety including long-term toxicity, immunogenicity, and body metabolism may impel nanoparticle translation.

Xiangshao Granules reduce the aggressive behavior and hippocampal injury of premenstrual irritability in rats by regulating JIK/JNK/p38 signal pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: As a typical prescription for soothing the liver, Xiangshao granule has a good effect on the symptoms of irritability and anxiety. Clinical evidence suggests that it has significant efficacy in the treatment of Premenstrual dysphoria disorder (PMDD). However, the underlying mechanism remains unclear. AIM OF THE STUDY: PMDD is a common disease in women of childbearing age, seriously affecting their family, society, and daily work life. The registered herbal medicine, Xiangshao granules, is used for relieving PMDD dysphoria and irritability symptoms with excellent efficacy in China. This study was focused on the deep intervention mechanism of Xiangshao granules in treating PMDD. MATERIALS AND METHODS: The vaginal smear and open field test were used to screen rats in nonreception phase of estrus cycle with similar macroscopic behaviors and regular estrus cycle. The rat model of PMDD irritability was established through social isolation and residential invasion, with which, the irritability symptoms of PMDD patients with menstrual cycle dependence was also well simulated. Elevated plus Maze Test and Social interaction activities were used to measure the anxiety-like behavior of rats. TUNEL Staining and Hematoxylin-Eosin staining were used to measure apoptosis of hippocampal neurons. RT-PCR, Western blot and immunofluorescence were used to measure the expression of GR, JIK, p-JIK, p38, P-P38, JNK, caspase 3, and caspase 12. RESULTS: In this study, Xiangshao granules showed consistent therapeutic effects similar with those in clinic, significantly reducing aggressive and anxiety-like behaviors with improved social skills in PMDD rats. In mechanism, Xiangshao granules lowered the apoptosis of hippocampal neurons and weakened the morphological damage of the hippocampal brain evidenced by the decreased mRNA and protein expression of glucocorticoid receptor, caspase-3, and caspase-12. In addition, administration of Xiangshao granules led to the decreased expression of JIK in the PMDD irritability rat model which agreed well with the previous studies. The JNK/p38 mitogen-activated protein kinases (MAPKs) signaling pathway is abnormally activated in the hippocampal brain region of PMDD rats, while treated with Xiangshao granules could increase JIK expression and inhibit the abnormal activation of the JNK/p38 MAPK signaling pathway, effectively reducing the stress damage in the hippocampus. CONCLUSIONS: Xiangshao Granules Reduce the Aggressive Behavior and Hippocampal Injury of Premenstrual Irritability in Rats by Regulating JIK/JNK/p38 Signal Pathway.

Tamoxifen induced cardiac damage via the IL-6/p-STAT3/PGC-1α pathway.

Tamoxifen (TAM) is an effective anticancer drug for breast and ovarian cancer. However, increased risk of cardiotoxicity is a long-term clinical problem associated with TAM, while the underlying mechanisms remain unclear. Here, we performed experiments in cardiomyocytes and tumor-bearing or nontumor-bearing mice, and demonstrated that TAM induced cardiac injury via the IL-6/p-STAT3/PGC-1α/IL-6 feedback loop, which is responsible for reactive oxygen species (ROS) accumulation. Compared with non-tumor bearing mice, tumor-bearing mice showed stronger cardiac toxicity after TAM injection, although there was no significant difference. In vitro experiments demonstrated STAT3 phosphorylation inhibitor can increase PGC-1α expression and protect cardiomyocyte via decreasing ROS. Since tumor has higher STAT3 phosphorylation and IL-6 expression level, our research results indicated combining TAM and STAT3 inhibitor might be an effective treatment strategy which can provide both tumor killing and cardioprotective function. Further in vivo research is needed to fully elucidate the effect and mechanisms of the combination therapy of TAM and STAT3 inhibitor.

Paeonol ameliorates hippocampal neuronal damage by inhibiting GRM5/GABBR2/ß-arrestin2 and activating the cAMP-PKA signaling pathway in premenstrual irritability rats.

Premenstrual dysphoric disorder (PMDD) is a periodic psychiatric disorder with high prevalence in women of childbearing age, seriously affecting patients' work and life. Currently, the international first-line drugs for PMDD have low efficiency and increased side effects. Paeonol, a major component of the traditional Chinese medicine Cortex Moutan, has been applied in treating PMDD in China with satisfactory results, but the therapeutic mechanism is not fully understood. This study aims to evaluate the therapeutic effects and pharmacological mechanisms of paeonol on the main psychiatric symptoms and hippocampal damage in PMDD. We established a premenstrual irritability rat model by the resident-intruder paradigm and performed elevated plus maze and social interactions. And we employed the HE and Nissl staining techniques to observe the therapeutic effect of paeonol on hippocampal damage in PMDD rats. Subsequently, Elisa, qRT-PCR Array, Western Blotting, and cell models were utilized to elucidate the underlying molecular mechanisms through which paeonol intervenes in treating PMDD. In this study, we demonstrated the therapeutic effects of paeonol on irritability, anxiety, and social withdrawal behaviors in rats. In addition, we found that paeonol significantly reduced the serum corticosterone (CORT) level, improved hippocampal morphological structure and neuron number, and reduced hippocampal neuron apoptosis in PMDD rats. Paeonol reduced GRM5, GABBR2, ß-arrestin2, and GRK3 expression levels in hippocampal brain regions of PMDD rats and activated the cAMP/PKA signaling pathway. Inhibitor cell experiments showed that paeonol specifically ameliorated hippocampal injury by modulating the ß-arrestin2/PDE4-cAMP/PKA signaling pathway. The present study demonstrates, for the first time, that paeonol exerts a therapeutic effect on periodic psychotic symptoms and hippocampal injury in PMDD through inhibiting GRM5/GABBR2/ß-arrestin2 and activating cAMP-PKA signaling pathway. These findings enhance our understanding of the pharmacological mechanism underlying paeonol and provide a solid scientific foundation for its future clinical application.

Discovery of novel N-benzylarylamide-dithiocarbamate based derivatives as dual inhibitors of tubulin polymerization and LSD1 that inhibit gastric cancers.

In this work, N-benzylarylamide-dithiocarbamate based derivatives were designed, synthesized, and their biological activities as anticancer agents were explored. Some of the 33 target compounds displayed significant antiproliferative activities with IC50 values at the double-digit nanomolar level. The representative compound I-25 (also named MY-943) not only showed the most effective inhibitory effects on three selected cancer cells MGC-803 (IC50 = 0.017 µM), HCT-116 (IC50 = 0.044 µM) and KYSE450 (IC50 = 0.030 µM), but also exhibited low nanomolar IC50 values from 0.019 to 0.253 µM against the other 11 cancer cells. Compound I-25 (MY-943) effectively inhibited tubulin polymerization and suppressed LSD1 at the enzymatic levels. Compound I-25 (MY-943) could act on the colchicine binding site of ß-tubulin, thus disrupting the construction of cell microtubule network and affecting the mitosis. In addition, compound I-25 (MY-943) could dose-dependently induce the accumulation of H3K4me1/2 (MGC-803 and SGC-7091 cells) and H3K9me2 (SGC-7091 cells). Compound I-25 (MY-943) could induce G2/M phase arrest and cell apoptosis, and suppress migration in MGC-803 and SGC-7901 cells. In addition, compound I-25 (MY-943) significantly modulated the expression of apoptosis- and cycle-related proteins. Furthermore, the binding modes of compound I-25 (MY-943) with tubulin and LSD1 were explored by molecular docking. The results of in vivo anti-gastric cancer assays using in situ tumor models showed that compound I-25 (MY-943) effectively reduced the weight and volume of gastric cancer in vivo without obvious toxicity. All these findings suggested that the N-benzylarylamide-dithiocarbamate based derivative I-25 (MY-943) was an effective dual inhibitor of tubulin polymerization and LSD1 that inhibited gastric cancers.

Local Application of Krill Oil Accelerates the Healing of Artificially Created Wounds in Diabetic Mice.

Diabetes mellitus (DM) impairs the wound healing process, seriously threatening the health of the diabetic population. To date, few effective approaches have been developed for the treatment of diabetic wounds. Krill oil (KO) contains bioactive components that have potent anti-inflammatory and anti-oxidative activities. As prolonged inflammation is a crucial contributor to DM-impaired wound healing, we speculated that the local application of KO would accelerate diabetic wound healing. Therefore, KO was applied to artificially created wounds of type 2 diabetic mice induced by streptozotocin and high-fat diet. The diabetic mice had a delayed wound healing process compared with the non-diabetic control mice, with excessive inflammation, impaired collagen deposition, and depressed neovascularization in the wound area. These effects were dramatically reversed by KO. In vitro, KO blocked the TNF-α-induced macrophage inflammation, fibroblast dysfunction, and endothelial angiogenic impairment. The present study in mice suggests that KO local application could be a viable approach in the management of diabetic wounds.

Discovery of novel coumarin-indole derivatives as tubulin polymerization inhibitors with potent anti-gastric cancer activities.

Novel coumarin-indole derivatives were designed, synthesized and evaluated as tubulin polymerization inhibitors targeting the colchicine binding site. Among these compounds, compound MY-413 displayed the most potent inhibitory activities against gastric cancer cell line MGC-803 with an IC50 value of 0.011 µM. Furthermore, the IC50 values of compound MY-413 was less than 0.1 µM for other 17 cancer cell lines and less than 0.05 µM for other 8 cancer cell lines. Compound MY-413 effectively inhibited the tubulin polymerization (IC50 = 2.46 µM) by binding to the colchicine site. Screening for the inhibitory effects of compound MY-413 on 61 kinases, it was found that compound MY-413 could inhibit MAPK pathways-related kinases. Because of the inhibitory effects of compound MY-413 on tubulin polymerization and MAPK signaling pathway, compound MY-413 induced cell apoptosis, arrested the cell cycle in the G2/M phase, induced the inhibition of cell proliferation and migration in gastric cancer cells MGC-803 and HGC-27. In addition, compound MY-413 could significantly inhibit tumor growth in MGC-803 xenograft tumor models with tumor growth inhibition (TGI) rates of 70% (15 mg/kg) and 80% (30 mg/kg) without obvious toxicity. Consistent with the in vitro results, compound MY-413 also inhibited MAPK signaling pathway, and induced apoptosis and proliferation inhibition in vivo. In conclusion, this work indicated that compound MY-413 was a promising lead compound for the further investigation as a potential anti-gastric cancer agent.

Discovery of N-benzylarylamide derivatives as novel tubulin polymerization inhibitors capable of activating the Hippo pathway.

Novel N-benzylarylamide saderivatives were designed and synthesized, and their antiproliferative activities were explored. Some of 51 target compounds exhibited potent inhibitory activities against MGC-803, HCT-116 and KYSE450 cells with IC50 values in two-digit nanomolar. Compound I-33 (MY-875) displayed the most potent antiproliferative activities against MGC-803, HCT-116 and KYSE450 cells (IC50 = 0.027, 0.055 and 0.067 µM, respectively) and possessed IC50 values ranging from 0.025 to 0.094 µM against other 11 cancer cell lines. Further mechanism studies indicated that compound I-33 (MY-875) inhibited tubulin polymerization (IC50 = 0.92 µM) by targeting the colchicine bingding site of tubulin. Compound I-33 (MY-875) disrupted the construction of the microtubule networks and affected the mitosis in MGC-803 and SGC-7901 cells. In addition, although it acted as a colchicine binding site inhibitor, compound I-33 (MY-875) also activated the Hippo pathway to promote the phosphorylation status of MST and LATS, resulting in the YAP degradation in MGC-803 and SGC-7901 cells. Due to the degradation of YAP, the expression levels of TAZ and Axl decreased. Because of the dual actions on colchicine binding site and Hippo pathway, compound I-33 (MY-875) dose-dependently inhibited cell colony formatting ability, arrested cells at the G2/M phase and induced cells apoptosis in MGC-803 and SGC-7901 cells. Moreover, compound I-33 (MY-875) could regulate the levels of cell cycle and apoptosis regulatory proteins in MGC-803 and SGC-7901 cells. Furthermore, molecular docking analysis suggested that the hydrogen bond and hydrophobic interactions made compound I-33 (MY-875) well bind into the colchicine binding site of tubulin. Collectively, compound I-33 (MY-875) is a novel anti-gastric cancer agent and deserves to be further investigated for cancer therapy by targeting the colchicine binding site of tubulin and activating the Hippo pathway.

[Study on estrogen receptors alpha and beta in the hippocampus of premenstrual syndrome model rats of gan-qi depression syndrome].

OBJECTIVE: To study the distribution pattern, the protein expressions, and changes of functional activities of estrogen receptor (ER) alpha and beta in the hippocampus of premenstrual syndrome (PMS) rats of Gan-qi depression syndrome (GDS), and to find out corresponding effect targets of Jingqianshu Granule (JG), thus providing clues for exploring the pathogenesis of PMS of GDS and the mechanisms of JG. METHODS: SD rats were randomly divided into three groups, i. e., the normal group, the model group, and the medication group, 7 in each. Resident intruder stress was used to establish the model in the model group and the medication group. JG was given to rats in the medication group at the dose of 10 mL/kg by gastrogavage while modeling. Equal volume of sterilized water was given to rats in the model group and the normal group, once daily, for 5 successive days. Then the location, protein levels, and ligand-binding capacities of ERalpha and ERbeta in the hippocampus of rats in three groups were detected using immunohistochemical assay, Western blot, and dextran-active carbon binding assay. RESULTS: There was no difference in the distribution pattern of ERalpha and ERbeta in the hippocampus of the three groups. In aspects of protein levels and estrogen-binding capacities of ERalpha and ERbeta in the hippocampus, CA1 and CA3 regions, they increased more obviously in the model group than in the normal group (P < 0.05), while they decreased more significantly in the medication group than in the model group (P < 0.05). CONCLUSION: Higher estrogen levels and enhanced expressions and activities of ERalpha and ERbeta in the hippocampus might be important mechanisms for PMS of GDS, which might also be the effect targets for JG.

Effect of Chaihu-jia-Longgu-Muli decoction on withdrawal symptoms in rats with methamphetamine-induced conditioned place preference.

Traditional Chinese medicine detoxification prescription Chaihu-jia-Longgu-Muli decoction (CLMD) relieves depressive symptoms in patients withdrawing from methamphetamine. In the present study, we assessed the effects of CLMD on methamphetamine withdrawal in rats. A methamphetamine-intoxicated rat model was established. Rats were randomly divided into the control, model, high-dosage, medium-dosage, and low-dosage groups, receiving high, medium, and low doses of CLMD, respectively. Weekly body weight measurements revealed that rats treated with methamphetamine had the lowest body weight. The conditioned place preference (CPP) experiment revealed that methamphetamine-intoxicated rats stayed significantly longer in the drug-paired chamber than the control rats. However, after administering high-dosage CLMD, the amount of time the rats spent in the drug-paired chamber was significantly less than that of the model rats. Our open-field test revealed that the model group had lower crossing and rearing scores than the control group. Additionally, rats that received CLMD treatment exhibited higher crossing and rearing scores than the model rats. Striatal dopamine (DA), 5-hydroxytryptamine (5-HT), and endorphins (ß-EP) and serum interleukin (IL)-1α and IL-2 concentrations were estimated. Rats in the model group had lower striatal DA, 5-HT, and ß-EP and higher serum IL-1α and IL-2 concentrations than those in the control group. High-dosage CLMD administration significantly changed the concentrations of these molecules, such that they approached normal concentrations. In general, CLMD could prevent the development of methamphetamine-induced withdrawal symptoms in rats by increasing the DA, 5-HT, and ß-EP and lowering the IL-1α and IL-2 concentrations.

Brain reactivity to emotional stimuli in women with premenstrual dysphoric disorder and related personality characteristics.

AIMS: Premenstrual dysphoric disorder (PMDD) is a psychiatric condition that is associated with the menstrual cycle. Elucidation of the neural regulation mechanisms of brain reactivity to emotional stimuli among women with PMDD may inform PMDD treatment. METHODS: Eighty-six women (42 PMDD, 44 healthy controls) were allocated into two groups (anger-induced group: 23 PMDD vs. 23 controls; depression-induced group: 19 PMDD vs. 21 controls). During the luteal phases of the menstrual cycle, all the women were subjected to functional magnetic resonance imaging (fMRI). fMRI resting-state scans were performed before and after the study participants had performed an emotional stimuli task. After the emotional stimuli task, emotional status of the participants were evaluated by Self-Rating Depression Scales (SDS) and Trait Anger Expression Inventory-II (STAXI-II). In addition, all the participants were requested to complete the Eysenck Personality Questionnaire (EPQ) and the Twenty-Item Toronto Alexithymia Scale (TAS-20). RESULTS: Compared to healthy controls, all women with PMDD exhibited significantly high scores in Tas-20 (p<0.001), higher neuroticism and psychoticism scores as well as significantly low extraversion and social desirability scores (p<0.05). Compared to the controls, f-MRI revealed that PMDD women had elevated ReHo in the middle frontal gyrus (BA10), temporal lobe (BA42), left cerebellum (BA37), as well as decreased activation in the precuneus (BA7), superior frontal gyrus (BA8), lobulus paracentralis (BA6), and right cerebellum (BA48) (p<0.05). Moreover, depression stimuli showed that women with PMDD had elevated ReHo levels in the middle frontal gyrus (BA11), the middle gyrus (BA47) and in the cingulate gyrus (BA23) vs. healthy controls (p<0.05). CONCLUSIONS: Women with more neuroticism and psychoticism, less extraversion and social desirability tend to report PMDD symptoms. Women with this condition experience difficulties in regulating emotions during the luteal phase of the menstrual cycle. Abnormal ReHo levels in the precuneus, superior frontal gyrus, lobulus paracentralis, and right cerebellum may contribute to anger dysregulation. Hypoactivation in the middle frontal gyrus, the middle gyrus and the cingulate gyrus may be generally associated with depression dysregulation in PMDD.

Effects of Paeonia lactiflora Extract on Estrogen Receptor ß, TPH2, and SERT in Rats with PMS Anxiety.

This study is to investigate the effect of Paeonia lactiflora extract on PMS anxiety and on expression of estrogen receptor ß (ERß), tryptophan hydroxylase-2 (TPH2), and serotonin transporter (SERT) in the premenstrual syndrome (PMS) anxiety model rats. The vaginal smear and open field test were used to screen rats in nonreception phase of estrus cycle with similar macroscopic behaviors and regular estrus cycle. PMS anxiety model rats were prepared by electrical stimulation. RT-PCR and immunofluorescence were used to measure the expression of ERß, TPH2, and SERT. Compared with normal rats, the total distance in the open field test of the model rats was significantly increased (P < 0.05). The model rats showed nervous alertness, irritability, and sensitivity to external stimuli. After treatment with the Paeonia lactiflora extract, the total distance of rats was significantly reduced (P < 0.05). In reception stage, there was no significant difference in the mRNA and protein expression of ERß, TPH2, and SERT. In nonreception stage, the expression of ERß and TPH2 in the model group was significantly decreased (P < 0.05) as compared with the control group, but not SERT. Abnormal changes of the above indicators were reversed after the administration of the Paeonia lactiflora extract. In conclusion, Paeonia lactiflora extract can increase the expression of ERß and TPH2 and decrease SERT in PMS model rats, which may be one of the mechanisms underlying the effect of Paeonia lactiflora extract on PMS.

Pharmacological Effects and Chemical Constituents of Bupleurum.

Radix Bupleuri has been used in traditional Chinese medicine for thousands of years, with confirmed curative effects. This plant is also used in healthy food and cosmetics. A recent increase in studies of Radix Bupleuri's chemical constituents (mainly comprising flavonoids, lignins, phenyl propanol derivatives, triterpenoid saponins, and volatile oils) and pharmacological effects motivates the aim of the present study: to review the chemical components and pharmacological effects of Radix Bupleuri. Our review found that Radix Bupleuri exhibits diverse pharmacological effects. More than 281 components have been isolated from Radix Bupleuri, including 15 flavonoids, 430 lignins, 12 phenyl propanol derivatives, 66 triterpenoid saponins, and 158 volatile oils.

Gene Expression in the Hippocampus in a Rat Model of Premenstrual Dysphoric Disorder After Treatment With Baixiangdan Capsules.

Objective: To explore the targets, signal regulatory networks and mechanisms involved in Baixiangdan (BXD) capsule regulation of premenstrual dysphoric disorder (PMDD) at the gene transcription level, since the etiology and pathogenesis of PMDD are not well understood. Methods: The PMDD rat model was prepared using the resident-intruder paradigm. The rats were tested for aggressive behavior, and those with scores in the lowest 30% were used as controls, while rats with scores in the highest 30% were divided into a PMDD model group, BXD administration group and fluoxetine administration group, which were evaluated with open-field tests and aggressive behavior tests. We also analyzed gene expression profiles in the hippocampus for each group, and verified differential expression of genes by real-time PCR. Results: Before and after BXD or fluoxetine administration, scores in the open-field test exhibited no significant differences. The aggressive behavior of the PMDD model rats was improved to a degree after administration of both substances. Gene chip data indicated that 715 genes were differentially expressed in the control and BXD groups. Other group-to-group comparisons exhibited smaller numbers of differentially expressed genes. The effective targets of both drugs included the Htr2c, Cdh3, Serpinb1a, Ace, Trpv4, Cacna1a, Mapk13, Mapk8, Cyp2c13, and Htr1a genes. The results of real-time PCR tests were in accordance with the gene chip data. Based on the target genes and signaling pathway network analysis, we have elaborated the impact and likely mechanism of BXD in treating PMDD and premenstrual irritability. Conclusion: Our work contributes to the understanding of PMDD pathogenesis and the mechanisms of BXD treatment. We speculate that the differentially expressed genes could participate in neuroactive ligand-receptor interactions, mitogen-activated protein kinase, calcium, and gamma-aminobutyric acid signal transduction.