Reverse-QTY code design of active human serum albumin self-assembled amphiphilic nanoparticles for effective anti-tumor drug doxorubicin release in mice.

Human serum albumin (HSA) is a highly water-soluble protein with 67% alpha-helix content and three distinct domains (I, II, and III). HSA offers a great promise in drug delivery with enhanced permeability and retention effect. But it is hindered by protein denaturation during drug entrapment or conjugation that result in distinct cellular transport pathways and reduction of biological activities. Here we report using a protein design approach named reverse-QTY (rQTY) code to convert specific hydrophilic alpha-helices to hydrophobic to alpha-helices. The designed HSA undergo self-assembly of well-ordered nanoparticles with highly biological actives. The hydrophilic amino acids, asparagine (N), glutamine (Q), threonine (T), and tyrosine (Y) in the helical B-subdomains of HSA were systematically replaced by hydrophobic leucine (L), valine (V), and phenylalanine (F). HSArQTY nanoparticles exhibited efficient cellular internalization through the cell membrane albumin binding protein GP60, or SPARC (secreted protein, acidic and rich in cysteine)-mediated pathways. The designed HSArQTY variants displayed superior biological activities including: i) encapsulation of drug doxorubicin, ii) receptor-mediated cellular transport, iii) tumor cell targeting, and iv) antitumor efficiency compare to denatured HSA nanoparticles. HSArQTY nanoparticles provided superior tumor targeting and antitumor therapeutic effects compared to the albumin nanoparticles fabricated by antisolvent precipitation method. We believe that the rQTY code is a robust platform for specific hydrophobic modification of functional hydrophilic proteins with clear-defined binding interfaces.

Morphometric and volumetric analysis of the posterior cranial fossa in adult Chiari malformation type I with and without group B basilar invagination.

BACKGROUND: The frequent association of basilar invagination (BI) makes the understanding of the pathogenesis of Chiari malformation type I (CMI) difficult. The influence of group B type of BI (the BI without obvious atlantoaxial instability) on the skeletal morphology has not been thoroughly studied. The objective of this study is to evaluate the skeletal alterations in the posterior cranial fossa (PCF) of adult CMI cases with and without group B BI. METHODS: Fifty-four adult CMI without BI cases (CMI-only group) and 30 adult CMI with group B BI cases (CMI-BI group) were retrospectively studied. Fifty-six adult patients with unruptured intracranial aneurysms were included as the controls. Several linear and angular variables, and the bony volume of the PCF were analyzed based on thin-slice computed tomography data. RESULTS: Morphological analysis revealed a significant difference in several variables from controls compared to CMI-only, and CMI-BI patients. The clivus and occipital bone, shortened and elevated in CMI-only patients, were further flattened in BI-associated CMI patients. Furthermore, although out of the scope for the diagnostic threshold of BI, the CMI-only cases also had a tendency to form BI. The association of BI modified several variables, without further reducing the bony PCF volume. CONCLUSIONS: These findings indicate that the variables associated with group B BI tend to be a continuum of the same pathological abnormalities that originate from the same pathological alterations in CMI patients.

Preparation of the Key Dolutegravir Intermediate via MgBr2-Promoted Cyclization.

A novel approach for synthesizing the key dolutegravir intermediate is described via MgBr2-promoted intramolecular cyclization. Condensation of commercially available methyl oxalyl chloride and ethyl 3-(N,N-dimethylamino)acrylate afforded the vinylogous amide in an excellent yield. Subsequent substitution by aminoacetaldehyde dimethyl acetal and methyl bromoacetate gave rise to the expected precursor for cyclization, which was promoted by MgBr2 to highly selectively convert into pyridinone diester. The key dolutegravir intermediate was finally prepared by the selective hydrolysis of the corresponding diester via LiOH.

Intraneural Injection of ATP Stimulates Regeneration of Primary Sensory Axons in the Spinal Cord.

Injury to the peripheral axons of sensory neurons strongly enhances the regeneration of their central axons in the spinal cord. It remains unclear on what molecules that initiate such conditioning effect. Because ATP is released extracellularly by nerve and other tissue injury, we hypothesize that injection of ATP into a peripheral nerve might mimic the stimulatory effect of nerve injury on the regenerative state of the primary sensory neurons. We found that a single injection of 6 µl of 150 µm ATP into female rat sciatic nerve quadrupled the number of axons growing into a lesion epicenter in spinal cord after a concomitant dorsal column transection. A second boost ATP injection 1 week after the first one markedly reinforced the stimulatory effect of a single injection. Single ATP injection increased expression of phospho-STAT3 and GAP43, two markers of regenerative activity, in sensory neurons. Double ATP injections sustained the activation of phospho-STAT3 and GAP43, which may account for the marked axonal growth across the lesion epicenter. Similar studies performed on P2X7 or P2Y2 receptor knock-out mice indicate P2Y2 receptors are involved in the activation of STAT3 after ATP injection or conditioning lesion, whereas P2X7 receptors are not. Injection of ATP at 150 µm caused little Wallerian degeneration and behavioral tests showed no significant long-term adverse effects on sciatic nerve functions. The results in this study reveal possible mechanisms underlying the stimulation of regenerative programs and suggest a practical strategy for stimulating axonal regeneration following spinal cord injury.SIGNIFICANCE STATEMENT Injury of peripheral axons of sensory neurons has been known to strongly enhance the regeneration of their central axons in the spinal cord. In this study, we found that injection of ATP into a peripheral nerve can mimic the effect of peripheral nerve injury and significantly increase the number of sensory axons growing across lesion epicenter in the spinal cord. ATP injection increased expression of several markers for regenerative activity in sensory neurons, including phospho-STAT3 and GAP43. ATP injection did not cause significant long-term adverse effects on the functions of the injected nerve. These results may lead to clinically applicable strategies for enhancing neuronal responses that support regeneration of injured axons.

[Evaluation on contribution rate of each component total salvianolic acids and characterization of apparent oil/water partition coefficient].

The difference between three representative components of total salvianolic acids in pharmacodynamic activity were compared by three different pharmacological experiments: HUVECs oxidative damage experiment, 4 items of blood coagulation in vitro experiment in rabbits and experimental myocardial ischemia in rats. And the effects of contribution rate of each component were calculated by multi index comprehensive evaluation method based on CRITIC weights. The contribution rates of salvianolic acid B, rosmarinic acid and Danshensu were 28.85%, 30.11%, 41.04%. Apparent oil/water partition coefficient of each representative components of total salvianolic acids in n-octyl alcohol-buffer was tested and the total salvianolic acid components were characterized based on a combination of the approach of self-defined weighting coefficient with effects of contribution rate. Apparent oil/water partition coefficient of total salvianolic acids was 0.32, 1.06, 0.89, 0.98, 0.90, 0.13, 0.02, 0.20, 0.56 when in octanol-water/pH 1.2 dilute hydrochloric acid solution/ pH 2.0, 2.5, 5.0, 5.8, 6.8, 7.4, 7.8 phosphate buffer solution. It provides a certain reference for the characterization of components.

Modification of nitrilase based on computer screening and efficient biosynthesis of 4-cyanobenzoic acid.

4-cyanobenzoic acid serves as a crucial intermediate for the synthesis of various high-value organic compounds. The enzymatic hydrolysis of terephthalonitrile to produce 4-cyanobenzoic acid using nitrilase offers the advantages of a simple reaction pathway, environmental friendliness, and easy product separation. In order to efficiently develop nitrilases that meet industrial production requirements, the virtual screening method used in the study is established and mature. From a total of 371 amino acids in the nitrilase AfNIT, which exhibits activity in terephthalonitrile hydrolysis, three candidate sites (F168, S192, and T201) were identified, and a "small and accurate" mutant library was constructed. The triple mutant F168V/T201N/S192F was screened from this small mutant library with a specific activity of 227.3 U mg-1 , which was 3.8 times higher than that of the wild-type AfNIT. Using the whole-cell biocatalyst containing the mutant F168V/T201N/S192F, terephthalonitrile was successfully hydrolyzed at a concentration of 150 g L-1 to produce 4-cyanobenzoic acid with a final yield of 170.3 g L-1 and a conversion rate of 98.7%. The obtained nitrilase mutant F168V/T201N/S192F in this study can be effectively applied in the biomanufacturing of 4-cyanobenzoic acid using terephthalonitrile as a substrate. Furthermore, the results also demonstrate the significant improvement in predictive accuracy achieved through the latest AI-assisted computer simulation methods. This approach represents a promising and feasible new technological pathway for assisting enzyme engineering research, laying a theoretical foundation for other related studies.

Synthesis of telmisartan impurity B.

Telmisartan is an antihypertensive drug and is a specific angiotensin II receptor (AT1) antagonist. According to European Pharmacopoeia 7 Edition 2008 telmisartan quality standard, there are seven impurities in telmisartan. Impurity B which is not available commercially and no synthetic method is published so far. We report herein the first synthesis of impurity B. The structure of impurity B was confirmed by 1H NMR, 13C NMR and MS data. These findings should be important for quality control purposes in the manufacture and quality control of telmisartan.

[Polybasic research on the biopharmaceutical characteristics of 20 (S)-protopanaxadiol].

In this study, the biopharmaceutical properties of 20 (S)-protopanaxadiol (PPD) were studied. Firstly, the equilibrium solubility and apparent oil/water partition coefficient of PPD were used to predict the absorption in vivo. Meanwhile the membrane permeability and absorption window were studied by Caco-2 cell model and single-pass intestinal perfusion model. Furthermore, the bioavailability and metabolism were combined to study the absorption properties and metabolic properties in vivo. All of them were used to provide theoretical and practical foundation for designing PPD preparation. The results showed that PPD is poorly water-soluble, and the equilibrium solubility in water is only 35.24 mg x L(-1). The oil-water partition coefficient is 46.21 (logP = 1.66). By Caco-2 cell model, the results showed PPD uptake in general, and it also has efflux. By in situ intestinal perfusion model, the results showed that the absorption of PPD in the intestine is good, and the effective permeability coefficient were duodenum > jejunum > ileum > colon. The oral bioavailability of PPD was 29.39%. It was not well. Metabolic studies showed PPD in vivo presented a wide spread metabolism. So the main factors that restricted oral bioavailability of PPD were the poor solubility and first-pass effect.

[Study on dosage form design for improving oral bioavailability of traditional Chinese medicines].

Both chemical drugs and traditional Chinese medicines have the problem of low bioavailability. However, as traditional Chinese medicines are a multi-component complex, their dosage forms are required to be designed in line with their characteristics, in order to improve the bioavailability of traditional Chinese medicines. Traditional Chinese medicines are mostly prepared into pill, powder, paste, elixir and decoction, but with such drawbacks as high administration dose and poor efficacy. With the process of modernization of traditional Chinese medicines, new-type preparations have be developed and made outstanding achievements. However, they fail to make an organic integration between traditional Chinese medicine theories and modern preparation theories. Characteristics of traditional Chinese medicines are required to be taken into account during the development of traditional Chinese medicines. In the article, multi-component preparation technology was adopted to establish a multi-component drug release system of traditional Chinese medicines on the basis of multiple components of traditional Chinese medicines.

[Establishment of modern multi-component sustained-release preparations of oral traditional Chinese medicines].

Traditional Chinese medicines have a long history, with a large quantity of efficient traditional Chinese medicines and prescriptions. However, the vast majority of pharmaceutical dose forms remain common preparations, with very few efficient, long-lasting and low-dose preparations. The sustain-release preparation allows sustained drug release in a longer period of time, maintains blood drug concentration, reduces the toxic effect and medication frequency, and improves medication compliance. Unlike monomer drugs, the material base of traditional Chinese medicine and compounds is multi-component, instead of single or several active monomers. Therefore, under the guidance of the Chinese medicine theories, modern multi-component sustained-release preparations were developed for oral traditional Chinese medicines, with the aim of finally improving the clinical efficacy of traditional Chinese medicines.

C1-2 Fusion in Atlantoaxial Dislocation and Basilar Invagination with and without Chiari Malformation: Clinical/Radiological and Craniometric Results.

OBJECTIVE: Patients with Chiari malformation (CM) associated with atlantoaxial dislocation (AAD) and basilar invagination (BI) may present with a small posterior cranial fossa, but data on the volumetric analysis are lacking. Additionally, whether additional foramen magnum decompression (FMD) is needed together with atlantoaxial fusion remains controversial. This study evaluated the volumetric alterations of the posterior cranial fossa in these patients and analyzed the radiological and clinical outcomes after posterior C1-C2 reduction and fixation plus C1 posterior arch resection. METHODS: Thirty-two adult CM patients with AAD and BI (CM-AAD/BI group) and 21 AAD and BI patients without CM (AAD/BI-only group) who received posterior atlantoaxial fusion plus C1 posterior arch resection were retrospectively studied. The clinical and radiological outcomes and volumetric measurements of the posterior cranial fossa were evaluated. RESULTS: The majority of CM-AAD/BI patients (94%) improved clinically and radiologically at 12 mo postoperatively, and none required additional FMD. Morphological analysis revealed a significant reduction in the bony posterior cranial fossa volumes of the CM-AAD/BI group (P < 0.01) and the AAD/BI-only group (P < 0.01) relative to those of the CM group. No significant differences were observed between the CM-AAD/BI and AAD/BI groups. CONCLUSIONS: Compared with patients with simple CM, patients with AAD/BI with or without CM demonstrated a considerably and equally reduced bony posterior cranial fossa volume. No additional FMD is needed in the treatment of CM-AAD/BI patients after posterior reduction and fusion plus C1 posterior arch resection.

A survival nomogram model constructed with common clinical characteristics to assist clinical decisions for diffuse low-grade gliomas: A population analysis based on SEER database.

Background: The prognosis of diffuse low-grade gliomas (DLGGs, WHO grade 2) is highly variable, making it difficult to evaluate individual patient outcomes. In this study, we used common clinical characteristics to construct a predictive model with multiple indicators. Methods: We identified 2459 patients diagnosed with astrocytoma and oligodendroglioma from 2000 to 2018 in the SEER database. After removing invalid information, we randomly divided the cleaned patient data into training and validation groups. We performed univariate and multivariate Cox regression analyses and constructed a nomogram. Receiver operating characteristic (ROC) curve, c-index, calibration curve, and subgroup analyses were used to assess the accuracy of the nomogram by internal and external validation. Results: After univariate and multivariate Cox regression analyses, we identified seven independent prognostic factors, namely, age (P<0.001), sex (P<0.05), histological type (P<0.001), surgery (P<0.01), radiotherapy (P<0.001), chemotherapy (P<0.05) and tumor size (P<0.001). The ROC curve, c-index, calibration curve, and subgroup analyses of the training group and the validation group showed that the model had good predictive value. The nomogram for DLGGs predicted patients' 3-, 5- and 10-year survival rates based on these seven variables. Conclusions: The nomogram constructed with common clinical characteristics has good prognostic value for patients with DLGGs and can help physicians make clinical decisions.

Genome-Wide Association Study Reveals the Genetic Basis of Total Flavonoid Content in Brown Rice.

Flavonoids have anti-inflammatory, antioxidative, and anticarcinogenic effects. Breeding rice varieties rich in flavonoids can prevent chronic diseases such as cancer and cardio-cerebrovascular diseases. However, most of the genes reported are known to regulate flavonoid content in leaves or seedlings. To further elucidate the genetic basis of flavonoid content in rice grains and identify germplasm rich in flavonoids in grains, a set of rice core collections containing 633 accessions from 32 countries was used to determine total flavonoid content (TFC) in brown rice. We identified ten excellent germplasms with TFC exceeding 300 mg/100 g. Using a compressed mixed linear model, a total of 53 quantitative trait loci (QTLs) were detected through a genome-wide association study (GWAS). By combining linkage disequilibrium (LD) analysis, location of significant single nucleotide polymorphisms (SNPs), gene expression, and haplotype analysis, eight candidate genes were identified from two important QTLs (qTFC1-6 and qTFC9-7), among which LOC_Os01g59440 and LOC_Os09g24260 are the most likely candidate genes. We also analyzed the geographic distribution and breeding utilization of favorable haplotypes of the two genes. Our findings provide insights into the genetic basis of TFC in brown rice and could facilitate the breeding of flavonoid-rich varieties, which may be a prevention and adjuvant treatment for cancer and cardio-cerebrovascular diseases.

Computational identification of immune-related lncRNA signature for predicting the prognosis and immune landscape of human glioblastoma multiforme.

Emerging evidence shows immune-related long noncoding RNAs (ir-lncRNAs) perform critical roles in tumor progression and prognosis assessment. However, the identification of ir-lncRNAs and their clinical significance in human glioblastoma multiforme (GBM) remain largely unexplored. Here, a designed computational frame based on immune score was used to identify differentially expressed ir-lncRNAs (DEir-lncRNAs) from The Cancer Genome Atlas (TCGA) GBM program. The immune-related lncRNA signature (IRLncSig) composed of prognosis-related DEir-lncRNAs selected by Cox regression analysis and its clinical predictive values were verified, which was further validated by another dataset from the Gene Expression Omnibus database (GEO). Subsequently, the association between IRLncSig and immune cell infiltration, immune checkpoint inhibitor (ICI) biomarkers, O6-methylguanine-DNA methyltransferase (MGMT) gene expression, and biological function were also analyzed. After calculation, five prognosis-related ir-lncRNAs were included in the establishment of IRLncSig. The risk assessment based on IRLncSig indicated that the high-IRLncSig-score group was significantly associated with poor prognosis (p < 0.001), significant aggregation of macrophages (p < 0.05), higher ICI biomarker expression, and MGMT gene expression (p < 0.05). Signature-related lncRNAs may be involved in immune activities in the tumorigenesis and progression of GBM. In summary, the novel IRLncSig shows a promising clinical value in predicting the prognosis and immune landscape of GBM.

Chromobox Homolog 8 (CBX8) in Human Tumor Carcinogenesis and Prognosis: A Pancancer Analysis Using Multiple Databases.

Some emerging studies have suggested that chromobox homolog 8 (CBX8) may play a critical role in carcinogenesis and prognosis in human cancer. Based on The Cancer Genome Atlas (TCGA)'s available data and the Gene Expression Omnibus (GEO) database, we conducted a systematic analysis of the carcinogenic effects of the CBX8 gene. We used TIMER2, GEPIA2, UALCAN, cBioPortal, Kaplan-Meier plotter, OncoLnc, STRING, HPA, and Oncomine data analysis websites and R data analysis software to analyze available data. The results show that the level of expression of CBX8 was significantly different among 27 different types of tumors and adjacent normal tissues. Moreover, we found that CBX8 expression had a close relationship with prognosis in some kinds of cancers. The phosphorylation level of some protein sites (such as S256) was significantly increased in tumors. CD8 + T-cell, B-cell and cancer-associated fibroblast infiltration levels were associated with CBX8 expression. The results of enrichment analysis indicated that the main biological activities of CBX8 are connected to gene transcription and repair of DNA damage. In conclusion, the level of expression of CBX8 was closely related to carcinogenesis and prognosis of some kinds of tumors, which needs further experimental verification.

Diabetes increases the risk of meningioma: A systematic review and meta-analysis of observational studies.

BACKGROUND: Increasing epidemiological evidence suggests that diabetes may be associated with meningioma risk, but the evidence supporting this association is still inconclusive. Therefore, we performed a meta-analysis of all eligible observational studies to evaluate the potential association of diabetes with meningioma risk. METHODS: A comprehensive literature search was performed in the PubMed, Web of Science and Cochrane Library databases up to November 30, 2020. A random-effects model was applied to calculate the pooled effect size (ES) and its 95 % confidence interval (CI). RESULTS: Eight studies were included in this study. In a random-effects pooled analysis, the results showed that DM (diabetes mellitus) increased the risk of meningioma (ES 1.17, 95 % CI: 1.02-1.35, P = 0.027). In subgroup analyses, DM increased the risk of meningioma in women (ES: 1.19, 95 % CI: 1.02-1.40, P = 0.027) and men (ES: 1.53, 95 % CI: 1.25-1.88, P = 0.000). This effect was not observed in the postmenopausal group (ES: 1.18, 95 % CI: 0.64-2.18, P = 0.597). CONCLUSION: Our meta-analysis showed that DM increases the risk of meningioma, but the association was only present in some subgroups. This conclusion should be further confirmed.

Sporadic Solid/Cystic Hemangioblastomas in the Cerebellum: Retrospective Study of More Than Ten Years of Experience in a Single Center.

BACKGROUND: Solid/cystic hemangioblastomas are rare, and they lack a systematic description. We clarify the epidemiology, clinical features, imaging characteristics, and surgical outcomes of sporadic solid/cystic hemangioblastomas in the cerebellum. METHODS: A total of 75 patients with sporadic hemangioblastomas from 2006 to 2018 were enrolled in this retrospective study and divided into solid (26/75), cystic (40/75), and solid/cystic (9/75) groups according to the imaging findings. All patients underwent microsurgical resection and had a definite 31 pathologic diagnosis. RESULTS: The age at diagnosis in the solid/cystic group was the highest among the 3 groups (P < 0.05). The solid/cystic group showed the shortest symptom duration (P < 0.05), which was related to obvious peritumoral brain edema (P < 0.05). The combination of computed tomography angiography and magnetic resonance imaging helped with the differential diagnosis. The solid/cystic group showed the lowest rate of gross total resection (P < 0.05) as a result of the obscure brain-tumor interface, and the guidance of intraoperative ultrasonography helped with the microsurgical procedures to a certain extent. Patients in the solid/cystic group showed greater intraoperative blood loss (P < 0.05), a lower ratio of symptom improvement (P < 0.05), and a longer mean hospital stay (P < 0.05) than did patients in the cystic group. CONCLUSIONS: Cerebellar sporadic solid/cystic hemangioblastomas are rare and usually affect elderly people. The combination of computed tomography angiography and magnetic resonance imaging may improve the preoperative diagnosis. Solid/cystic hemangioblastomas showed the lowest rate of gross total resection as a result of the obscure brain-tumor interface.

ASK1 phosphorylation regulates astrocytic reactive gliosis in vitro and in vivo.

Apoptosis signal-regulating kinase 1 (ASK1) may play a pivotal role in reactive gliosis. To assess the role of ASK1 in trauma-induced reactive gliosis, we examined the phosphorylation of ASK1 and the expression of glial fibrillary acidic protein (GFAP) and vimentin after scratch injury in cultured astrocytes and spinal cord injury (SCI) in rats. Enhanced phosphorylation of ASK1 was detected during reactive gliosis both in vitro and in vivo, and P38 MAPK relayed the signal from phosphorylated ASK1 to the activation of astrocytes. Immunoprecipitation analyses suggested that 14-3-3 was dissociated from ASK1 during astrocyte activation. Finally, treatment with thioredoxin reduced ASK1 phosphorylation and reactive gliosis and promoted hindlimb locomotion recovery in SCI rats. These results indicated that ASK1 may play an important role in mechanical-injury-induced reactive gliosis.

Medulloblastomas in cerebellopontine angle: Epidemiology, clinical manifestations, imaging features, molecular analysis and surgical outcome.

Cerebellopontine angle (CPA) medulloblastoma is rare and short of system description. We attempted to clarify its epidemiology, clinical manifestations, imaging features, pathological and molecular types, and surgical outcomes. 8 patients from 7 to 52 years old were enrolled in this retrospective study, with mean age 21.6 ±â€¯16.4 years. The most frequent symptoms were raised intracranial pressure (100%), followed by cerebellar signs (50%), decreased hearing (50%), facial paralysis (50%), abducent paralysis (50%), and facial paresthesia (37.5%). MRI demonstrated a solid CPA lesion with heterogeneously weak or significant enhancement after gadolinium administration, accompanied with peritumoral oedema (75%), cystic change (62.5%) and dural tail sign (50%), while CT showed petrous bone and internal auditory canal intact. All cases received tumor excision, with 6 (75%) cases undergoing gross total resection, and the remaining (25%) getting partial excision. Pathological examination confirmed 5 (62.5%) classic, 2 (25%) desmoplastic, and 1 (12.5%) anaplastic. Further molecular analysis identified 5 (62.5%) WNT and 3 (37.5%) SHH. Immediately after the primary surgery, 7 (87.5%) cases gained improvement of the symptoms and signs and 1 (12.5%) kept the preoperative status stable. Follow up was available ranged from 5 to 34 months, during that period 5 cases kept symptom free and 3 cases recurred/progressed. In conclusion, CPA medulloblastoma is rare and lacking of special clinical manifestations and radiological features, and should be considered in the differential diagnosis of CPA lesions. In this series the most frequent pathological and molecular type is classic and WNT. Microsurgery excision is effective to prevent progressive decline of neurological status.

Antidepressant effect of venlafaxine in chronic unpredictable stress: Evidence of the involvement of key enzymes responsible for monoamine neurotransmitter synthesis and metabolism.

A number of studies have linked abnormalities in the function of the serotonergic and noradrenergic systems to the pathophysiology of depression. It has been reported that selective serotonin reuptake inhibitors promote the expression of tryptophan hydroxylase (TPH), which is involved in the synthesis of serotonin. However, limited evidence of TPH alteration has been found in selective serotonin and noradrenaline reuptake inhibitors (SNRIs), and more key enzymes need to be investigated. The aim of the present study was to determine whether venlafaxine (VLX; a classical SNRI) regulates TPH and other key enzymes responsible for the synthesis and metabolism of monoaminergic transmitters in rats with chronic unpredictable stress (CUS). The present results suggested that CUS­exposed rats exhibited decreased locomotor activity in the open­field test and increased immobility time in the forced swim test, as compared with the controls. Pretreatment with VLX (20 mg/kg) significantly increased locomotor activity and reduced immobility time in the CUS­exposed rats. In addition, VLX (20 mg/kg) treatment prevented the CUS­induced reduction in tyrosine hydroxylase and TPH expression in the cortex and hippocampus. Furthermore, VLX alleviated the CUS­induced oxidative stress in the serum, cortex and hippocampus. However, VLX administration did not have an effect on indoleamine­2,3­dioxygenase overexpression in the hippocampus. It was therefore concluded that the regulation of abnormalities in the synthesis and metabolism of monoaminergic transmitters may be associated with the antidepressant effects of VLX, suggesting that multimodal pharmacological treatments can efficiently treat depression.