Fluoxetine mitigates depressive-like behaviors in mice via anti-inflammation and enhancing neuroplasticity.

Neuroplasticity and inflammation represent a common final pathway for effective antidepressant treatment. SSRIs are the most commonly prescribed medications for depression and have demonstrated efficacy in reducing depressive symptoms. However, the precise impact of SSRIs on neuroplasticity and inflammation remains unclear. In this study, we aimed to investigate the influence of long-term treatment with SSRIs on hippocampal neuron, inflammation, synaptic function and morphology. Our findings revealed that fluoxetine treatment significantly alleviated behavioral despair, anhedonia, and anxiety in reserpine-treated mice. Moreover, fluoxetine mitigated hippocampal neuron impairment, inhibited inflammatory release, and increased the expression of synaptic proteins markers (SYP and PSD95) in mice. Notably, fluoxetine also suppressed reserpine-induced synapse loss in the hippocampus. Based on these results, fluoxetine has been demonstrated effectively to ameliorate depressive mood and cognitive dysfunction, possibly through the enhancement of synaptic plasticity. Overall, our study contributes to a further understanding of the mechanisms underlying the therapeutic effects of fluoxetine and its potential role in improving depressive symptoms and cognitive impairments.

Design, synthesis and antifungal activities of novel triazole derivatives with selenium-containing hydrophobic side chains.

In this work, a series of novel 1,2,4-triazole derivatives with selenium-containing hydrophobic side chains were designed and synthesized based on the structure of lanosterol 14α-demethylase (CYP51). All compounds were characterized by HRMS, 1H NMR and 13C NMR. Then, their antifungal activities against eight human pathogenic fungi were evaluated in vitro by testing the minimal inhibitory concentrations. The results showed that nearly all tested compounds were found to be more potent against all tested fungal strains than control drug fluconazole. Further mechanism study demonstrated that the target compounds had fungal CYP51 inhibitory activity. Meanwhile, representative compounds revealed low cytotoxic effects toward mammalian cell lines. In addition, the docking results showed that the target compounds bound to Candida albicans CYP51 in a better pattern than fluconazole, especially in the narrow hydrophobic cleft. Overall, the novel 1,2,4-triazole derivatives with selenium-containing hydrophobic side chains can be further developed for the potential treatment of invasive fungal infections.

Discovery of novel selenium-containing azole derivatives as antifungal agents by exploiting the hydrophobic cleft of CYP51.

Herein, we report the design, synthesis and evaluation of a novel series of diselenide and selenide derivatives as potent antifungal agents by exploiting the hydrophobic cleft of CYP51. Among all synthesized compounds, the most potent compound B01 with low cytotoxic and hemolysis effect exhibited excellent activity against C.alb., C.gla., C.par. and C.kru., as well as selected fluconazole-resistant strains. Moreover, compound B01 could reduce the biofilm formation of the FCZ-resistant C.alb. Subsequently, metabolic stability assays using liver microsomes demonstrated that compound B01 showed good profiles of metabolic stability. With superior pharmacological profile, compound B01 was advanced into in vivo bioactivity evaluation. In a murine model of systemic C.alb. infection, compound B01 significantly reduced fungal load of kidneys. Furthermore, compound B01 revealed relatively low acute toxicity and subacute toxicity in mice. In addition, docking study performed into C.alb. CYP51, showed the binding mode between C.alb. CYP51 and compound B01. Collectively, diselenides compound B01 can be further developed for the potential treatment of invasive fungal infections.

Examining patterns of traditional Chinese medicine use in pediatric oncology: A systematic review, meta-analysis and data-mining study / 中西医结合学报

BACKGROUND@#Traditional Chinese medicine (TCM) is becoming a popular complementary approach in pediatric oncology. However, few or no meta-analyses have focused on clinical studies of the use of TCM in pediatric oncology.@*OBJECTIVE@#We explored the patterns of TCM use and its efficacy in children with cancer, using a systematic review, meta-analysis and data mining study.@*SEARCH STRATEGY@#We conducted a search of five English (Allied and Complementary Medicine Database, Embase, PubMed, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov) and four Chinese databases (Wanfang Data, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and VIP Chinese Science and Technology Periodicals Database) for clinical studies published before October 2021, using keywords related to "pediatric," "cancer," and "TCM."@*INCLUSION CRITERIA@#We included studies which were randomized controlled trials (RCTs) or observational clinical studies, focused on patients aged < 19 years old who had been diagnosed with cancer, and included at least one group of subjects receiving TCM treatment.@*DATA EXTRACTION AND ANALYSIS@#The methodological quality of RCTs and observational studies was assessed using the six-item Jadad scale and the Effective Public Healthcare Panacea Project Quality Assessment Tool, respectively. Meta-analysis was used to evaluate the efficacy of combining TCM with chemotherapy. Study outcomes included the treatment response rate and occurrence of cancer-related symptoms. Association rule mining (ARM) was used to investigate the associations among medicinal herbs and patient symptoms.@*RESULTS@#The 54 studies included in this analysis were comprised of RCTs (63.0%) and observational studies (37.0%). Most RCTs focused on hematological malignancies (41.2%). The study outcomes included chemotherapy-induced toxicities (76.5%), infection rate (35.3%), and response, survival or relapse rate (23.5%). The methodological quality of most of the RCTs (82.4%) and observational studies (80.0%) was rated as "moderate." In studies of leukemia patients, adding TCM to conventional treatment significantly improved the clinical response rate (odds ratio [OR] = 2.55; 95% confidence interval [CI] = 1.49-4.36), lowered infection rate (OR = 0.23; 95% CI = 0.13-0.40), and reduced nausea and vomiting (OR = 0.13; 95% CI = 0.08-0.23). ARM showed that Radix Astragali, the most commonly used medicinal herb (58.0%), was associated with treating myelosuppression, gastrointestinal complications, and infection.@*CONCLUSION@#There is growing evidence that TCM is an effective adjuvant therapy for children with cancer. We proposed a checklist to improve the quality of TCM trials in pediatric oncology. Future work will examine the use of ARM techniques on real-world data to evaluate the efficacy of medicinal herbs and drug-herb interactions in children receiving TCM as a part of integrated cancer therapy.

Discovery of 1,2,3-selenadiazole analogues as antifungal agents using a scaffold hopping approach.

With the increasing incidence of antifungal resistance, new antifungal agents having novel scaffolds hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. In this study, we reported the design, synthesis, and pharmacological evaluation of novel 1,2,3-selenadiazole analogues by scaffold hopping strategy. Preliminary results of antifungal activity demonstrated that the new class of compounds showed broad-spectrum fungistatic and fungicidal activity. Most importantly, these newly synthesized compounds can eliminate these azole-resistant fungi and inhibit the formation of C. albicans biofilm. In particular, compound S07 showed promising antifungal activity against five azole-resistant strains with MIC values ranging from 4 to 32 µg/mL. Then, further target identification and mechanistic studies indicated that representative compound S07 exert its inhibitory activity by inhibiting fungal lanosterol 14α-demethylase enzyme (CYP51). Interestingly, representative compounds showed low cytotoxicity on mammalian cell lines. In addition, the molecular docking studies elucidated the binding modes of these compounds toward CYP51. Altogether, these results suggest that compound S07 with novel skeleton is a promising CYP51 inhibitor for treatment of fungal infections.

Lead optimization generates selenium-containing miconazole CYP51 inhibitors with improved pharmacological profile for the treatment of fungal infections.

A series of selenium-containing miconazole derivatives were identified as potent antifungal drugs in our previous study. Representative compound A03 (MIC = 0.01 µg/mL against C.alb. 5314) proved efficacious in inhibiting the growth of fungal pathogens. However, further study showed lead compound A03 exhibited potential hemolysis, significant cytotoxic effect and unfavorable metabolic stability and was therefore modified to overcome these drawbacks. In this article, the further optimization of selenium-containing miconazole derivatives resulted in the discovery of similarly potent compound B17 (MIC = 0.02 µg/mL against C.alb. 5314), exhibiting a superior pharmacological profile with decreased rate of metabolism, cytotoxic effect and hemolysis. Furthermore, compound B17 showed fungicidal activity against Candida albicans and significant effects on the treatment of resistant Candida albicans infections. Meanwhile, compound B17 not only could reduce the ergosterol biosynthesis pathway by inhibiting CYP51, but also inhibited biofilm formation. More importantly, compound B17 also shows promising in vivo efficacy after intraperitoneal injection and the PK study of compound B17 was evaluated. In addition, molecular docking studies provide a model for the interaction between the compound B17 and the CYP51 protein. Overall, we believe that these selenium-containing miconazole compounds can be further developed for the potential treatment of fungal infections.

Simeprevir suppresses SARS-CoV-2 replication and synergizes with remdesivir

The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global threat to human health. Using a multidisciplinary approach, we identified and validated the hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. Simeprevir potently reduces SARS-CoV-2 viral load by multiple orders of magnitude and synergizes with remdesivir in vitro. Mechanistically, we showed that simeprevir inhibits the main protease (Mpro) and unexpectedly the RNA-dependent RNA polymerase (RdRp). Our results thus reveal the viral protein targets of simeprevir, and provide preclinical rationale for the combination of simeprevir and remdesivir for the pharmacological management of COVID-19 patients. One Sentence SummaryDiscovery of simeprevir as a potent suppressor of SARS-CoV-2 viral replication that synergizes with remdesivir.

Rapid bioluminescence assay for monitoring rat CES1 activity and its alteration by traditional Chinese medicines / 药物分析学报

In traditional Chinese medicine herbs (TCM), including Radix Salviae Miltiorrhizae (Danshen), Radix Puerariae Lobatae (Gegen), Radix Angelicae Sinensis (Danggui), and Rhizoma Chuanxiong (Chuanxiong) are widely used for the prevention and treatment of cardiovascular diseases and also often co-administered with Western drugs as a part of integrative medicine practice. Carboxylesterase 1 (CES1) plays a pivotal role in the metabolisms of pro-drugs. Since (S)-2-(2-(6-dimethylamino)-benzothiazole)-4,5-dihydro-thiazole-4-carboxylate (NLMe) has recently been identified by us as a selective CES1 bioluminescent sensor, we developed a rapid method using this substrate for the direct measurement of CES1 activity in rats. This bioluminescence assay was applied to determine CES1 activity in rat tissues after a two-week oral administration of each of the four herbs noted above. The results demonstrated the presence of CES1 enzyme in rat blood and all tested tissues with much higher enzyme activity in the blood, liver, kidney and heart than that in the small intestine, spleen, lung, pancreas, brain and stomach. In addition, the four herbs showed tissue-specific effects on rat CES1 expression. Based on the CES1 biodistribution and its changes after treatment in rats, the possibility that Danshen, Gegen and Danggui might alter CES1 ac-tivities in human blood and kidney should be considered. In summary, a selective and sensitive biolu-minescence assay was developed to rapidly evaluate CES1 activity and the effects of orally administered TCMs in rats.

Current trends in drug metabolism and pharmacokinetics

Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug-drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice.

Current understanding of ABCA1 in lipid accumulation / 基础医学与临床

ATP-binding cassette transporter A1 (ABCA1) is an membrane protein,using ATP for transferring substances,modulated by liver X receptors(LXRs), retinoic X receptors(RXRs), sterol regulatory element binding proteins(SREBPs), microRNAs and other upstream modulators.ABCA1 plays an important role in multiple pathways related to lipid accumulation.Upregulating ABCA1 expression may slow-down lipid accumulation, thus offers a promising strategy for metabolic diseases.

Effect of brain-derived neurotrophic factor on retinal Müller cells in diabetic rats / 眼科新进展

Objective To investigate the protective effect of brain derived neurotrophic factor (BDNF) on Müller cells in the retina of diabetic rats.Methods A total of 54 healthy male SD rats were recruited and randomly divided into control group,diabetic group and BDNF group.Then a diabetic model was established by intraperitoneal injection of streptozotocin in rats of diabetic and BDNF groups.Preparation of BDNF injection was performed using PBS balanced salt solution containing 0.1 g · L 1 BSA.The BDNF group was given BDNF injection,while the control and diabetic group were injected with equal dose of PBS balanced salt solution 4 weeks after successful modeling.And after 8 weeks,the expression of L-glutamate/L-aspartate transporter (GLAST),glutamine synthetase (GS) and synaptophysin (SYN) were detected by immunofluorescence technique and Western blot,and the content of glutamic acid in retina was determined by glutamic acid determination kit.Results Compared with the control group,the expression of GLAST,GS and SYN were significantly decreased in diabetic group,and the content of glutamic acid was increased significantly (all P ＜ 0.01).Compared with the diabetic group,the expression of GLAST,GS and SYN were increased in BDNF group,and the glutamate level was decreased significantly (all P ＜0.01).Conclusion In the early stage of diabetic retinopathy,administration of exogenous BDNF can unregulated the expression of GLAST,SYN and GS and improve the function of Müller cells to protect RGC against damage,suggesting that BDNF has neuroprotective effects on Müller cells in retina of rats with diabetic retinopathy.

Design, synthesis and antiproliferative activities of artemisinin derivatives substituted by N-heterocycles / 药学学报

Increasing attention has been focused on the antitumor activity of artemisinin derivatives in recent years, for artemisinin had been reported to have cytotoxic effects against HL-60, P388 and MCF-7 tumor cells. We report here the synthesis and evaluation for antitumor activity of a series of artemisinin-ether derivatives bearing tetrahydropyrrole, morpholine, piperidine, substituted piperidines and azoles with various linkers. Sixteen 10-O-substituted dihydroartemisinin derivatives were designed and synthesized, all of which have never been reported in literatures and whose antiproliferative effects on human breast cancer MCF-7, MCF-7/Adr and HL-60 cells were determined by MTT assay or direct cell counting. Each of these artemisinin derivatives possessed better effects than dihydroartemisinin evidently against HL-60 and MCF-7 cells growth, while less potent than doxorubicin. All target compounds exhibited significantly improved potency compared to DHA and doxorubicin on the doxorubicin-resistant MCF-7/Adr cells, so did they in their sensitive counterparts MCF-7 cells. Among them, compounds GF02, GH04 and ZH04 showed strong activity against these three cell lines growth. Further research is undergoing.

Thermoelastic damping in optical waveguide resonators with the bolometric effect.

Incorporating the bolometric effect, the thermoelastic damping in a nanowaveguide resonator driven by an optical gradient force is investigated in this paper. Based on the Euler-Bernoulli beam theory, the governing equation of the optowaveguide resonator is derived by considering the complex distribution of injected optical power, which has significant influence on the thermoelastic damping. By solving the heat diffusion equation, the theoretical model of the thermoelastic damping is presented. In this model, the effects of injected optical power, representative temperatures, waveguide material, and geometries on the thermoelastic damping are studied and discussed respectively. The results show that the peak value of thermoelastic damping increases as the injected optical power is increasing within a low range. Hardly any changes exist for the intrinsic energy dissipation of different materials at higher injected optical power. When the environmental temperature falls in the range of 293-500 K, the thermoelastic damping increases slowly, and then drops down quickly as a function of the dimensionless frequency. However, the thermoelastic damping monotonically decreases when the representative temperature drops to lower than 293 K. In addition, the thermoelastic damping is found to be scale dependent, particularly with the effect of injected optical power.

A de-illumination scheme for face recognition based on fast decomposition and detail feature fusion.

Almost all the face recognition algorithms are unsatisfied due to illumination variation. Feature with high frequency represents the face intrinsic structure according to the common assumption that illumination varies slowly and the face intrinsic feature varies rapidly. In this paper, we will propose an adaptive scheme based on FBEEMD and detail feature fusion. FBEEMD is a fast version of BEEMD without time-consuming surface interpolation and iteration computation. It can decompose an image into sub-images with high frequency matching detail feature and sub-images with low frequency corresponding to contour feature. However, it is difficult to determine by quantitative analysis that which sub-images with high frequency can be used for reconstructing an illumination-invariant face. Thus, two measurements are proposed to calculate weights for quantifying the detail feature. With this fusion technique, one can reconstruct a more illumination-neutral facial image to improve face recognition rate. Verification experiments using classical recognition algorithms are tested with Yale B, PIE and FERET databases. The encouraging results show that the proposed scheme is very effective when dealing with face images under variable lighting condition.

Role of prostaglandin E2 receptors in H9c2 cardiomyocyte hypertrophy induced by prostaglandin E2 / 中华麻醉学杂志

Objective To evaluate the role of prostaglandin E2 (EP) receptors in H9c2 cardiomyocyte hypertrophy induced by prostaglandin E2 (PGE2).Methods Primary cultured H9c2 cardiomyocytes were seeded in culture flasks (3 ml/flask) or in 24-well plate (1 ml/hole) or 6-well plate (2 ml/hole) with density of 4 × 104/ml.The cells were randomly divided into 4 groups (n=24 each): control group (group C),PGE2 group,AH6809 (EP1 and EP2 receptor antagonist) group (group A) and GW627368X (EP4 receptor antagonist) group (group G).The cells were continuously cultured for 48 h.PGE2 (final concentration 1 μmol/L) was added to the culture medium in PGE2 group.PGE2 (final concentration 1 μmol/L) and A H6809 (final concentration 10 μmol/L) were added to the culture medium in group A.PGE2 (final concentration 1 μmol/L) and GW627368X (final concentration 10 μmol/L) were added to the culture medium.The cells were then cultured for 48 h in groups PGE2,A and G.Then the cell morphology was observed by using fluorescent microscope.The cell diameter was measured by using the Image J medical image analysis system.Total protein content in the cells was measured with BCA method.The expression of atrial natriuretic peptide (ANP) mRNA and brain natriuretic peptide (BNP) mRNA in the cytoplasm was determined using RT-PCR.Results Compared with group C,the total protein in the cells and cell diameter were significantly increased,and the expression of ANP mRNA and BNP mRNA in the cytoplasm was up-regulated in groups PGE2,A and G (P ＜ 0.05).Compared with group PGE2,the total protein in the cells and cell diameter were significantly decreased,and the expression of ANP mRNA and BNP mRNA in the cytoplasm was downregulated in group G (P ＜ 0.05),and no significant change was found in the parameters mentioned above in group A (P ＞ 0.05).Conclusion EP4 receptor mediates H9c2 cardiomyocyte hypertrophy induced by PGE2 and the effect is not related to EP1 and EP2.

Exploring on the standardized training model for residents in the department of cardiology / 中华医学教育探索杂志

The standardized training is an indispensible stage for the improvement of residents' comprehensive quality and for the training of high-qualified talents.The article preliminarily explored the standardized training model for residents,which was in accordance with the characteristics of the department of cardiology mainly from four aspects:the set-up of reasonable training program,the training of practical skills,the training of humanistic quality and the training of life-long learning ability.

The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine.

The lipophilicity and solubility profiles of bis(12)-hupyridone (B12H) and bis(7)-tacrine (B7T), two novel acetylcholinesterase inhibitors dimerized from huperzine A fragments and tacrine, respectively, were investigated over a broad pH range. Lipophilicity was assessed by both shake flask method with 1-octanol-water system and a reverse-phase HPLC system with methanol-water as mobile phase. The former method was used for determining the lipophilicities of the ionized forms (log D) of the dimers while the latter method was used for that of the neutral forms (log P). The log P values for B12H and B7T were found to be 5.4 and 8.2, respectively, indicating that the two dimers are highly lipophilic. The solubilities of both dimers were found to be affected by pH. The solubility of B12H was >1.41 mg/ml when the pH was <7, but <0.06 mg/ml when the pH was >8. The solubility of B7T was >0.26 mg/ml when the pH was <9, but <0.005 mg/ml when the pH was >12. The ionic strength of a solution could affect the solubilities considerably (11.16 mg/ml for B12H and 12.71 mg/ml for B7T in water; 2.07 mg/ml for B12H and 0.36 mg/ml for B7T in saline). The ionization constants (pK(a)) of the two dimers were determined by UV spectrophotometry. Both dimers were found to have two pK(a) values: 7.5+/-0.1 (pK(a1)) and 10.0+/-0.2 (pK(a2)) for B12H; and 8.7+/-0.1 (pK(a1)) and 10.7+/-0.4 (pK(a2)) for B7T. Furthermore, an in vivo pharmacological assay conducted in mice showed that a maximum AChE inhibition occurred 15 min after the single-dose and intraperitoneal administration of either dimer. This indicates that the two dimers may easily cross the blood-brain barrier. In summary, these physiochemical characteristics suggest that the two dimers may be promising candidates for the development of better drugs for Alzheimer's disease.

Selective and sensitive determination of bis(7)-tacrine, a high erythrocyte binding acetylcholinesterase inhibitor, in rat plasma by high-performance liquid chromatography-tandem mass spectrometry.

The current study aims to develop a specific and sensitive LC-MS/MS method for determination of bis(7)-tacrine (B7T) in rat plasma. A 100 microL plasma sample was extracted with ethyl acetate. B7T and the internal standard (IS), pimozide, in the samples were then analyzed with LC-MS/MS in positive electrospray ionization condition. Chromatographic separation of B7T and IS was achieved in a C(18) reversed-phase HPLC column (150 x 2.1 mm i.d.) by isocratic elution with a mobile phase consisting of 0.05% formic acid in water and acetonitrile (1:1, v/v) at a flow rate of 0.35 mL/min. Multiple-reaction monitoring (MRM) mode was employed to measure the ion transitions: m/z 247 to 197 for B7T and m/z 462 to m/z 328 for IS, respectively. The method was linear over the studied ranges of 100-5000 and 10-100 ng/mL. The intra-day and inter-day variations of the analysis were less than 6.8% with standard errors less than 9.0%. The detection limit of B7T in rat plasma was 1 ng/mL. The developed method was successfully applied to the pharmacokinetic study of B7T after intravenous administration of 1 mg/kg B7T and further proved to be readily utilized for determination of B7T in rat plasma samples.

Inhibition of human cytochrome P-450 CYP1A2 by flavonoids: a quantitative structure-activity relationship study / 药学学报

The inhibition activity of 36 flavonoids against CYP1A2 was determined by our previously developed in vitro method. The Comparative Molecular Similarity Indexes Analysis (CoMSJA) approach was used to probe the quantitative relationships between the flavonoids' molecular structural descriptors and their inhibitory activities. A reliable CoMSIA model with the combined electrostatic and hydrophobic fields was derived with the regression coefficient R2 of 0.948 and the cross-validation regression coefficient q2 of 0.630, separately, which is capable of elucidating the quantitative relationship between the 3D structural descriptors of the flavones and their bioactivities. Comparing with flavone, the larger pi-pi conjugated system of alpha-naphthoflavone significantly improved the biologically inhibitory ability. Based on the core structure of the latter, either electropositive substituents or hydrophobic groups at the 6, 3', and 4' ring positions or electronegative counterparts at the 5 ring position, can enhance the inhibitory potency against CYP1 A2 according to the CoMSIA contour maps.