Transcriptomic congruence analysis for evaluating model organisms.

Model organisms are instrumental substitutes for human studies to expedite basic, translational, and clinical research. Despite their indispensable role in mechanistic investigation and drug development, molecular congruence of animal models to humans has long been questioned and debated. Little effort has been made for an objective quantification and mechanistic exploration of a model organism's resemblance to humans in terms of molecular response under disease or drug treatment. We hereby propose a framework, namely Congruence Analysis for Model Organisms (CAMO), for transcriptomic response analysis by developing threshold-free differential expression analysis, quantitative concordance/discordance scores incorporating data variabilities, pathway-centric downstream investigation, knowledge retrieval by text mining, and topological gene module detection for hypothesis generation. Instead of a genome-wide vague and dichotomous answer of "poorly" or "greatly" mimicking humans, CAMO assists researchers to numerically quantify congruence, to dissect true cross-species differences from unwanted biological or cohort variabilities, and to visually identify molecular mechanisms and pathway subnetworks that are best or least mimicked by model organisms, which altogether provides foundations for hypothesis generation and subsequent translational decisions.

Ethnoracial Identity and Cognitive Impairment: A Community Study.

BACKGROUND: Identifying potentially modifiable risk factors associated with MCI in different ethnoracial groups could reduce MCI burden and health inequity in the population. METHODS: Among 2845 adults aged 65+ years, we investigated potential risk exposures including education, physical and mental health, lifestyle, and sensory function, and their cross-sectional associations with MCI. We compared proportions of exposures between Black and White participants and explored relationships among race, MCI, and exposures. Logistic regression modeled MCI as a function of each exposure in the overall sample adjusting for age, sex, educational level, and race, and investigating race*exposure interactions. RESULTS: Compared with White participants, Black participants had greater odds of MCI (OR 1.53; 95% CI, 1.13 to 2.06) and were more likely to report depressive symptoms, diabetes, and stroke, to have high blood pressure and BMI, and to be APOE - 4 carriers. Exposures associated with higher odds of MCI were diabetes, stroke, lifetime smoking, sleep disturbances, social isolation, loneliness, depression and anxiety symptoms, and vision and hearing loss. There were no significant interactions between race and any exposure. CONCLUSIONS: Black participants had 53% higher odds of MCI adjusting for age, sex, and education. The same exposures were associated with MCI in Black and White participants.

Association of plasma biomarkers of Alzheimer's disease and related disorders with cognition and cognitive decline: The MYHAT population-based study.

INTRODUCTION: Plasma biomarkers of Alzheimer's disease and related dementias predict global cognitive performance and decline over time; it remains unclear how they associate with changes in different dementia syndromes affecting distinct cognitive domains. METHODS: In a prospective study with repeated assessments of a randomly selected population-based cohort (n = 787, median age 73), we evaluated performance and decline in different cognitive domains over up to 8 years in relation to plasma concentrations of amyloid beta 42/40 (Aß42/40) ratio, phosphorylated tau181 (p-tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). RESULTS: Cross-sectionally, memory showed the strongest associations with p-tau181, and attention, executive, and visuospatial functions with NfL. Longitudinally, memory decline was distinguishable with all biomarker profiles dichotomized according to data-driven cutoffs, most efficiently with Aß42/40. GFAP and Aß42/40 were the best discriminators of decline patterns in language and visuospatial functions, respectively. DISCUSSION: These relatively non-invasive tests may be beneficial for clinical screening after replication in other populations and validation through neuroimaging or cerebrospinal fluid analysis. HIGHLIGHTS: We performed a prospective study with up to 8 years of repeated domain-specific cognitive assessments and baseline plasma Alzheimer's disease and related dementias biomarker measurements in a randomly selected population-based cohort. We considered distinct growth curves of trajectories of different cognitive domains and survival bias induced by missing data by adding quadratic time and applying joint modeling technique. Cross-sectionally, memory showed the strongest associations with plasma phosphorylated tau181, while attention, executive, and visuospatial functions were most strongly associated with neurofilament light chain. Longitudinally, memory and visuospatial declines were most efficiently distinguished by dichotomized amyloid beta 42/40 profile among all plasma biomarkers, while language was by dichotomized glial fibrillary acidic protein. These relatively non-invasive tests may be beneficial for clinical screening; however, they will need replication in other populations and validation through neuroimaging and/or cerebrospinal fluid assessments.

A Novel High Entropy Hydroxide Electrode Material for Promoting Energy Density of Supercapacitors and Its Efficient Synthesis Strategy.

In this work, a novel high entropy hydroxide NiCoMoMnZn-layered double hydroxide(LDH) is synthesized as an electrode material for supercapacitors using a novel template re-etching method to promote the energy density. As a positive electrode material for supercapacitors, NiCoMoMnZn-LDH has the advantage of a uniform distribution of elements, high specific surface area, porous and stable structure. More importantly, the specific capacitance can reach 1810.2 F g-1 at the current density of 0.5 A g-1 , and the NiCoMoMnZn-LDH//AC HSC assembled from the material has an energy density of up to 62.1 Wh kg-1 at a power density of 475 W kg-1 . Moreover, the influence of different compositions on their morphological, structural, and electrochemical properties is investigated based on the characterization results. Then, the synergistic mechanism among the components of the high entropy NiCoMoMnZn-LDH is revealed in detail by DFT calculations. In addition, the synthesis strategy proposed in this work for high-entropy hydroxides exhibits universality. Experimental results show that the proposed strategy successfully avoids not only phase separation and element aggregation in the formation of high entropy materials, but also reduces structural distortion, which is beneficial for efficient and large-scale synthesis of high entropy hydroxides.

It goes both ways: The relationship between anxiety and mild cognitive impairment.

OBJECTIVE: To investigate the relationship between anxiety and mild cognitive impairment (MCI), and whether it is mediated by perceived stress, at the population level. METHOD AND DESIGN: In a longitudinal study of 368 adults aged 65+ from a population-based cohort, we annually assessed anxiety symptoms (GAD-7), perceived stress (PSS-4), and ratings on the Clinical Dementia Rating (CDR®), where CDR = 0.5 was operationalized as MCI. Examining data from three consecutive assessment waves, we first determined the associations between anxiety at the first wave with MCI at the third wave, and vice versa. We then used mediation analyses to determine whether the pathways in both directions were mediated by perceived stress at the second wave, adjusting for demographics and other relevant covariates. RESULTS: We confirmed significant bidirectional longitudinal associations between anxiety and MCI. Perceived stress was detected as a significant mediator for both pathways between anxiety and MCI, explaining 37.1% of the total effect (TE) of anxiety on incident MCI while conversely explaining 27.1% of the TE of MCI on anxiety. CONCLUSIONS: A bidirectional relationship with a 2-year lag between anxiety and MCI was mediated through perceived stress. Clinicians should be sensitive both to potential consequent anxiety when patients present with cognitive impairment, and to potential incipient MCI when the presenting complaint is anxiety. Managing stress may help mitigate adverse outcomes.

Plasma biomarkers identify older adults at risk of Alzheimer's disease and related dementias in a real-world population-based cohort.

INTRODUCTION: Plasma biomarkers-cost effective, non-invasive indicators of Alzheimer's disease (AD) and related disorders (ADRD)-have largely been studied in clinical research settings. Here, we examined plasma biomarker profiles and their associated factors in a population-based cohort to determine whether they could identify an at-risk group, independently of brain and cerebrospinal fluid biomarkers. METHODS: We measured plasma phosphorylated tau181 (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid beta (Aß)42/40 ratio in 847 participants from a population-based cohort in southwestern Pennsylvania. RESULTS: K-medoids clustering identified two distinct plasma Aß42/40 modes, further categorizable into three biomarker profile groups: normal, uncertain, and abnormal. In different groups, plasma p-tau181, NfL, and GFAP were inversely correlated with Aß42/40, Clinical Dementia Rating, and memory composite score, with the strongest associations in the abnormal group. DISCUSSION: Abnormal plasma Aß42/40 ratio identified older adult groups with lower memory scores, higher dementia risks, and higher ADRD biomarker levels, with potential implications for population screening. HIGHLIGHTS: Population-based plasma biomarker studies are lacking, particularly in cohorts without cerebrospinal fluid or neuroimaging data. In the Monongahela-Youghiogheny Healthy Aging Team study (n = 847), plasma biomarkers associated with worse memory and Clinical Dementia Rating (CDR), apolipoprotein E ε4, and greater age. Plasma amyloid beta (Aß)42/40 ratio levels allowed clustering participants into abnormal, uncertain, and normal groups. Plasma Aß42/40 correlated differently with neurofilament light chain, glial fibrillary acidic protein, phosphorylated tau181, memory composite, and CDR in each group. Plasma biomarkers can enable relatively affordable and non-invasive community screening for evidence of Alzheimer's disease and related disorders pathophysiology.

Influence of Vacancy Defects of the Calcium Oxide Surface on the Nonequilibrium Phase Transition of Alkali Metal Salts.

Molten alkali metal salt effectively promotes the performance of calcium looping (CaL). Deep insight into the nonequilibrium phase-transition characteristic of alkali metal salt is better for the control of the temperature in CaL, which not only ensures the complete melting of metal salt but also prevents the reaction from inhibiting caused by higher temperatures. In this work, therefore, the molecular dynamics simulation method is used to explore the nonequilibrium phase-transition characteristic of Na2SO4. The results show that the equilibrium melting temperature of nanosodium sulfate on the calcium oxide surface is 810 K, which is lower than the macroscopic melting temperature. Meanwhile, the high heating rates led to the atoms in Na2SO4 unable to break through the thermal stability limit, resulting in overheating of the crystal. Both the surface premelting and overheating melting temperature of the crystal are increased. When the heating rates are 0.25, 0.5, and 1.0 K/ps, the overheating melting temperatures are 845, 885, and 930 K, respectively. More than that, the surface defects enhance the interaction between CaO and Na2SO4 because of the surface being charged. The increases in the interaction not only effectively break the stability of the crystal lattice of Na2SO4 on the defective surfaces but also promote the energy transport inside Na2SO4. Therefore, as the defect concentration increases from 0 to 3% and 5%, the overheating melting temperature of Na2SO4 gradually decreases from 845 to 836 and 815 K.

Influence of Vacancy Defect of Calcium Oxide Surface on the Wettability of Molten Alkali Metal Salt in Calcium Looping Process.

The influence of the vacancy defect of the CaO surface on the wettability of molten alkali metal salt was studied by molecular dynamics simulations. The results indicated that in the temperature range of 800-1100 K, the molten Na2SO4 on both VDcalcium and VDoxygen defect surfaces presented a poor wettability compared to that on the complete surface. Measurement of the density profile and the contact angle of the molten Na2SO4 showed that the higher the temperature and defect concentration, the worse the wettability. The micromechanism was revealed by calculating the polarization intensity that the vacancy defect surface led to the formation of the induced dipole moment in the molten Na2SO4. Induced polarization caused by defect surfaces reduces the wettability of Na2SO4. More importantly, as the temperature and defect concentration increase, various defect surfaces form loose and local weak liquidity structures. These structures are beneficial for the diffusion of carbon dioxide into the solid, but the reduction in the spreading area caused by poor wettability causes the efficiency of the CaL to decline. The vibration difference between Na2SO4 and CaO increases with the increased temperature and defect concentration. This means that the thermal energy transportability at the interface is suppressed by poor wettability.

Effects of Temperature and Ionic Concentration on Nanodroplet Electrocoalescence.

Droplet electrocoalescence is of interest for various applications such as petroleum dehydration, electrospray ionization, and surface self-cleaning. Here, the effects of temperature and ionic concentration on nanodroplet electrocoalescence are investigated by molecular dynamics simulation. The results show that low ionic concentration rapidly drives ions towards water clusters and leads to dipole polarization of droplets. With an increase of ionic concentration, the particle-particle interaction is enhanced, but the mobility of free water molecules and salt ions is curbed by hydration and ion pairs, which then slows the electrocoalescence. Low temperature accelerates the rotation of water molecules but does not enhance the mobility of ions. Alternatively, high temperature not only breaks the self-assembly of water molecules along the electric field direction but also helps ions to overcome the electrostatic barrier between particles. The latter effect promotes dipole polarization to compensate for the shortcoming of less orientation polarization. The combined effects of ion concentration and temperature are investigated and unified by droplet conductivity from the microscopic point of view. The conductivity increases with the increase in temperatures and ionic concentrations. We confirm that the accurate control of droplet electrocoalescence can be achieved by a suitable combination of temperature and ionic concentration.

[Effect of jianpi-jiedu formula on tumor angiogenesis-relevant genes expression in colorectal cancer].

OBJECTIVE: To investigate the effect of the jianpi-jiedu formula (JPJD) on the expression of angiogenesis-relevant genes in colon cancer.
 Methods: Crude extract was obtained from JPJD by water extract method. The effect of JPJD crude extract on colon cancer cell proliferation capacity was determined by MTT assays. The IC50 value was calculated by GraphPad Prism5 software. Affymetrix gene expression profiling chip was used to detect significant differences in expressions of genes after JPJD intervention, and pathway enrichment analysis was performed to analyze the differentially expressed genes. Ingenuity Pathway Analysis software was applied to analyze differentially expressed genes relevant to tumor angiogenesis based on mammalian target of rapamycin (mTOR) signaling pathway and then the network diagram was built. Western blot was used to verify the protein levels of key genes related to tumor angiogenesis.
 Results: JPJD crud extract inhibited the proliferation capacity in colon cancer cells. The IC50 values in 24, 48, and 72 hours after treatment were 13.060, 9.646 and 8.448 mg/mL, respectively. The results of chip showed that 218 genes significantly upgraded, and 252 genes significantly downgraded after JPJD treatment. Most of the genes were related to the function of biosynthesis, metabolism, cell apoptosis, antigen extraction, angiogenesis and so on. There were 12 differentially expressed angiogenesis genes. IPA software analysis showed that the JPJD downregulated expression of sphingomyelin phosphodiesterase 3 (SMPD3), VEGF, vascular endothelial growth factor A (VEGFA), integrin subunit alpha 1 (ITGA1), cathepsin B (CTSB), and cathepsin S (CTSS) genes, while upregulated expressions of GAB2 and plasminogen activator, urokinase receptor (PLAUR) genes in the colorectal cancer cell. Western blot results demonstrated that JPJD obviously downregulated expressions of phospho-mTOR (P-mTOR), signal transducer and activator of transcription 3 (STAT3), hypoxia inducible factor-1α (HIF-1α), and VEGF proteins, while obviously upregulated the level of phospho-P53 (P-P53) protein.
 Conclusion: JPJD may inhibit colorectal tumor angiogenesis through regulation of the mTOR-HIF-1α-VEGF signal pathway.

[Inhibitory effect of jianpi-jiedu prescription-contained serum on colorectal cancer SW48 cell proliferation by mTOR-P53-P21 signalling pathway].

OBJECTIVE: To investigate the effect of jianpi-jiedu (JPJD) prescription-contained serum on colorectal cancer SW48 cell proliferation and the underlying mechanisms.
 Methods: Crude extract from JPJD was made by water extract method and the main components of crude extract from JPJD were analyzed by ultra-performance liquid phase high resolution time of flight mass spectrometry (UPLC-Q-TOF/MS). The low, medium, and high-concentration of JPJD-contained serum were prepared by the serum pharmacological method. The effect of serum containing JPJD on SW48 cell proliferation was determined by MTT assay. The cell cycle was detected by flow cytometric method. The protein levels of mammalian target of rapamycin (mTOR), phospho-mTOR, P-P53, and -P21, and the mRNA level of mTOR were examined by Western blot and RT-PCR, respectively.
 Results: Seven compounds including calycosin-7-glucoside, astragaloside, ginsenoside-Re, ginsenoside-Rb1, glycyrrhizinic acid, apigenin, atractylenolide-II were identified. MTT assays demonstrated that the SW48 cell proliferation was inhibited by medium and high concentration of JPJD-contained serum and the percentages of cells at G1 phase in SW48 cell cultured in the medium and high concentration of JPJD serum group were significantly higher than those in the control group (P<0.05). Meanwhile, the levels of mTOR mRNA and phospho-mTOR protein in the medium and high concentration of JPJD serum groups were substantially lower than those in the control group (P<0.05). Conversely, the expressions of phospho-P53 and P21 protein were significantly increased in the medium and high concentration of JPJD serum group compared with those in the control group.
 Conclusion: JPJD prescription-contained serum can inhibit SW48 cell proliferation, which may be related to mTOR-P53-P21 signaling pathways.

Covalent drugs based on small molecules and peptides for disease theranostics.

Biomacromolecules, such as proteins, nucleic acids and polysaccharides, are widely distributed in the human body, and some of them have been recognized as the targets of drugs for disease theranostics. Drugs typically act on targets in two ways: non-covalent bond and covalent bond. Non-covalent bond-based drugs have some disadvantages, such as structural instability and environmental sensitivity. Covalent interactions between drugs and targets have a longer action time, higher affinity and controllability than non-covalent interactions of conventional drugs. With the development of artificial intelligence, covalent drugs have received more attention and have been developed rapidly in pharmaceutical research in recent years. From the perspective of covalent drugs, this review summarizes the design methods and the effects of covalent drugs. Finally, we discuss the application of covalent peptide drugs and expect to provide a new reference for cancer treatment.

The involvement of AMPA-ERK1/2-BDNF pathway in the mechanism of new antidepressant action of prokinetic meranzin hydrate.

It was recently discovered that ketamine can relieve depression in a matter of hours through an action on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This is much more rapid than the several weeks required for the available antidepressants to show therapeutic efficacy. However, ketamine has negative side effects. The aim of this study was to determine whether the natural prokinetic drug meranzin hydrate (MH) has a fast-acting antidepressant effect mediated by AMPA receptors. By means of in vivo and in vitro experiments, we found that (1) treatment of rats with MH at 9 mg/kg decreased immobility time in a forced swimming test (FST), as did the popular antidepressant fluoxetine and the AMPA receptor positive modulator aniracetam. Pretreatment of rats with NBQX (10 mg/kg), an antagonist of AMPA receptors, blocked this effect of MH. (2) MH increased number of crossings of forced swimming rats in the open field test. (3) FST enhanced hippocampal ERK1/2, p-ERK1/2 and BDNF expression levels. MH (9 mg/kg) treatment further up-regulated hippocampal p-ERK1/2 and BDNF expression levels, and this effect was prevented by NBQX. (4) MH-increased BDNF expression corresponded with MH-decreased immobility time in the FST. (5) In vitro experiments, we found that incubation of rats hippocampus slices with MH (10, 20 µM respectively) increased concentrations of BDNF and p-ERK1/2. This effect of MH (20 µM) were prevented by NBQX. In conclusion, in animals subjected to acute stress, the natural prokinetic drug MH produced a rapid effect mediated by AMPA receptors and involving BDNF modulation through the ERK1/2 pathway.

Effect of tribulus terrestris saponins on behavior and neuroendocrine in chronic mild stress depression rats.

OBJECTIVE: To observe the effect of tribulus terrestris saponins (TTS) on behavior and neuroendocrine of chronic mild stress (CMS) depression rats. METHODS: Thirty male Sprague-Dawley rats were randomly allocated to six groups: vehicle group, CMS group, CMS + fluoxetine group and CMS + TTS of low-dosage (0.375 g/kg), medium-dosage (0.75 g/kg) and high-dosage (2.25 g/kg) groups. All rats except the vehicle group singly housed and exposed an unpredicted sequence of mild stressors. The behavior of rats was detected by open-field test (OFT) and sucrose preference test (SPT). The concentration of corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH) in serum of the rats were detected by radioimmunoassay. The concentration of cortisol (CORT) in serum was detected by enzyme immunoassay. RESULTS: CMS procedure not only significantly decreased the scores of crossing, rears and grooming in OFT and the sucrose preference in SPT (all P < 0.01), but also markedly increased serum CRH and CORT levels (both P < 0.05). Treatment with TTS (0.75 and 2.25 g/kg) could significantly prevent all of these abnormalities induced by CMS (P < 0.05, P < 0.01). CONCLUSION: CMS can affect rat behavior and neuroendocrine and cause depression. TTS has the antagonism on CMS and produce antidepressive effects.

Comparative proteomic and radiobiological analyses in human lung adenocarcinoma cells.

In clinic, many non-small cell lung cancer (NSCLC) patients receive radiation therapy after chemotherapy failure. However, whether the multidrug resistance (MDR) can elevate the radioresistance (RDR) remains unclear. To evaluate the MDR's effect on the RDR, screen MDR- and RDR-related proteins in human lung adenocarcinoma (HLA) cells and tissues A549, and A549/DDP cells after irradiation were analyzed by colony-forming assay and flow cytometry. Two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) were utilized to identify differentially expressed proteins (DEPs) between them. The value of D0, Dq, and SF2 increased, the mean percentage in G2 phase and apoptosis rate significantly decreased in A549/DDP cells compared with A549 cells. 40 DEP points were found, and among them 27 were identified through proteomics. Four up-regulated proteins (HSPB1, Vimentin, Cofilin-1, and Annexin A4) in MDR cells compared with non-MDR cells, were confirmed by Western blot. Immuno-histochemistry showed that they were also over-expressed in MDR tissues compared with non-MDR counterparts of HLA. These results proved that the MDR in HLA cells and tissues increased the RDR. HSPB1, Vimentin, Cofilin-1, and Annexin A4 are potential biomarkers for predicting HLA response to MDR and RDR, and novel treatment targets of HLA.

Ethnopharmacokinetic- and activity-guided isolation of a new antidepressive compound from fructus aurantii found in the traditional chinese medicine chaihu-shugan-san: a new approach and its application.

Aims. We aimed to identify an antidepressive compound found in traditional Chinese medicine (TCM) by a new approach called ethnopharmacokinetic- and activity-guided isolation (EAGI). Methods. The new approach targets an unknown chromatographic peak produced by an absorbed compound found in oral Chaihu-Shugan-San (CSS) taken by patients with depression. Once the compound was isolated from Fructus Aurantii (FA), spectral data was employed to identify the compound. The effects of this compound, FA, and CSS on depressive behaviors were investigated. Results. The identified compound was merazin hydrate (MH) according to the new approach. MH, FA, and CSS significantly reduced immobility time and increased locomotor activity. The effects of MH, FA and CSS were similar to Fluoxetine at high doses. Conclusion. MH, a compound whose antidepressive effect is similar to FA and CSS, was isolated for the first time from FA via targeting its corresponding unknown chromatographic peak, and its antidepressive effect was compared with FA or CSS. These findings highlight the potential for drug R&D and pharmacological research of ∼100,000 TCMs.

Irisin: A bridge between exercise and neurological diseases.

Exercise plays a beneficial regulating role on each organ of the body through different mechanisms and is a powerful weapon to prevent disease. Irisin is released from muscle and widely distributed in the human body, participating in the physiological processes of multiple human systems and playing a protective role in multiple human organs. The protective effect of irisin on the nervous system is particularly remarkable, which can improve cognitive function, reduce the risk of ischemic stroke and improve its prognosis. Irisin also plays a guiding role in the prevention and treatment of neurodegenerative diseases and ischemic cerebrovascular diseases. Exercise is the driving factor promoting irisin secretion, and different exercise modes, intensity, frequency, and time all affect the level of serum irisin. As a result of analyzing the effects of various exercise modes on irisin secretion, we proposed an exercise program with a higher level of irisin secretion.

Shuganjieyu capsule increases neurotrophic factor expression in a rat model of depression.

Shuganjieyu capsule has been approved for clinical treatment by the State Food and Drug Ad-ministration of China since 2008. In the clinic, Shuganjieyu capsule is often used to treat mild to moderate depression. In the rat model of depression established in this study, Shuganjieyu capsule was administered intragastrically daily before stress. Behavioral results confirmed that depressive symptoms lessened after treatment with high-dose (150 mg/kg) Shuganjieyu capsule. Immunohistochemistry results showed that high-dose Shuganjieyu capsule significantly increased phosphorylation levels of phosphorylation cyclic adenosine monophosphate response element binding protein and brain-derived neurotrophic factor expression in the medial prefrontal cortex and hippocampal CA3 area. Overall, our results suggest that in rats, Shuganjieyu capsule effec-tively reverses depressive-like behaviors by increasing expression levels of neurotrophic factors in the brain.

Meranzin hydrate exhibits anti-depressive and prokinetic-like effects through regulation of the shared α2-adrenoceptor in the brain-gut axis of rats in the forced swimming test.

BACKGROUND: In recent years, the brain-gut axis theory has received increasing attention in studies of depression. However, most studies separately address potential antidepressant and prokinetic treatments. Investigations of drugs that could potentially treat comorbid depression and gastrointestinal (GI) dysfunction via a common mechanism of action have not yet been performed in detail. AIM: To find a common mechanism of action of our patented drug, meranzin hydrate (MH), in the antidepressant and prokinetic treatment. METHODS: The forced swimming test (FST) model of depression, plasma ghrelin measurement, and in vivo and in vitro measurements of GI motility were used. RESULTS: 1. Administration of MH (9 mg/kg) decreased the immobility time during the FST after acute treatment; this effect was inhibited by the alpha 2-adrenoceptor antagonist, yohimbine, but not by the alpha 1-adrenoceptor antagonist, prazosin. 2. After chronic treatment, the immobility time of rats during the FST was decreased significantly by MH (2.25 mg/kg). 3. MH (9 mg/kg) increased plasma ghrelin levels in rats subjected to the FST; this increase was enhanced by the ghrelin receptor agonist, GHRP-6. 4. MH (9 mg/kg) also promoted gastric emptying and intestinal transit in rats with or without FST. 5. In vitro, MH (10 µM) increased jejunal contractions in rats subjected to the FST; this effect was inhibited by yohimbine. Furthermore, the inhibitory effect of yohimbine was partly reversed by the ghrelin receptor agonist, GHRP-6. CONCLUSION: Our study revealed that MH from natural resources exhibits antidepressive and prokinetic-like effects through the regulation of the common mediator, the alpha 2-adrenoceptor.

Fructus Aurantii induced antidepressant effect via its monoaminergic mechanism and prokinetic action in rat.

Depression could hardly get a satisfactory effect from the currently available antidepressants. To get a more effective treatment, antidepressant effect and monoaminergic mechanism of Fructus Aurantii (FRA) in the rat forced swimming test (FST) and open field test (OFT), and its prokinetics were examined. FST and OFT were respectively used to evaluate the antidepressant effect and locomotor activity of FRA. We observed the effects of monoamine receptor antagonists on FRA-induced antidepressant effect in rat. The effects of FRA on intestinal transit, gastric emptying and in vitro jejunum contractile activity were assessed. FRA decreased significantly the immobility time (32.6±8.5, 30.3±5.2 vs 56.4±9.4, all p<0.01) in FST, dose-dependent increased the locomotor activity (102±17.5, 120±18.5 vs 89±9.8, p<0.05 or 0.01), significantly accelerated gastric emptying (GE: 48.1±6.3, 39.5±5.7 vs 19.5±3.8, p<0.01) and intestinal transit (IT: 67.3±9.1, 64.2±6.3 vs 49.1±8.2, p<0.01) of the semi-liquid meal, compared with vehicle. And FRA (1 µM, 10 µM) significantly increased the mean amplitude (0.24±0.021 and 0.281±0.015) of contraction in jejunum of rat compared with vehicle (0.149±0.011) in vitro. FRA (10 µM) could induce a largest amplitude (0.281±0.015) of contraction in jejunum. The anti-immobility effect of FRA in FST was prevented by pre-treatment of rat with p-chlorophenylalanine methyl ester, WAY100635, ketanserin, haloperidol, SCH233390, sulpiride, yohimbine, but not prazosin. FRA could simultaneously induce prokinetics and antidepressant effect, deserves further to investigate.