Efficacy of non-invasive brain stimulation combined with antidepressant medications for depression: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Antidepressants, noninvasive brain stimulation (NIBS), and their combination are commonly used in routine clinical practice. Nevertheless, there is a continuous dispute regarding whether the effectiveness of NIBS in combination with antidepressants exceeds that of antidepressants alone. This meta-analysis aimed to evaluate the existing evidence and draw a definitive conclusion on this issue. METHODS: We conducted a comprehensive search of five databases: Embase, PubMed, Web of Science, SinoMed, and the Cochrane Database of Randomized Controlled Trials. The search was conducted until October 6, 2023. The primary outcomes were the pre- and post-intervention depression and anxiety scores. Secondary outcomes included dropout rates, response rates, and certain levels of neurotransmitters [ 5-hydroxytryptamine (5-HT), dopamine (DA), and gamma-aminobutyric acid (GABA)] at the end of the intervention. Subgroup, meta-regression, and sensitivity analyses were performed to explore the sources of heterogeneity. The data were analysed using R 4.2.2. RESULTS: We included 18 RCTs [1357 participants; 11 studies used repetitive transcranial magnetic stimulation (rTMS) and 7 studies used transcranial direct current stimulation (tDCS)]. The follow-up duration varied from two weeks to three months. Overall, whether in combination with rTMS or tDCS, antidepressants proved more effective in alleviating depressive symptoms compared to when used as monotherapy. However, this advantage was not evident during the follow-up period. (p > 0.05). And the combination's efficacy in improving anxiety was found to be lacking. Post-treatment serum levels of 5-HT, DA, and GABA were higher in the rTMS group were higher than antidepressant medication group (p < 0.05). Furthermore, subgroup analysis results indicated that only the rTMS + antidepressant medication treatment significantly improved remission and remission rates. The meta-regression results showed that the type of antidepressant and the sex of the participants had a significant association with the depression score. CONCLUSION: Combination treatment with NIBS was significantly more effective in improving depression symptoms than medication alone. rTMS combined with antidepressants appears to be more effective in improving response and remission rates. However, efficacy may be influenced by the type of medicine used in combination, and long-term efficacy data is lacking. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023388259.

Accumulation and glucocorticoid signaling suppression by four emerging perfluoroethercarboxylic acids based on animal exposure and cell testing.

Various perfluoroethercarboxylic acids (PFECA) have emerged as next-generation replacements of legacy per- and polyfluoroalkyl substances (PFAS). However, there is a paucity of information regarding their bioaccumulation ability and hazard characterization. Here, we explored the accumulation and hepatotoxicity of four PFECA compounds (HFPO-DA, HFPO-TA, PFO4DA, and PFO5DoDA) in comparison to perfluorooctanoic acid (PFOA) after chronic low-dose exposure in mice. Except for HFPO-DA, the levels of all tested PFAS in the liver exceeded that in serum. High molecular weight PFECA compounds (PFO5DoDA and HFPO-TA) showed stronger accumulation capacity and longer half-lives (t1/2) than low molecular weight PFECA compounds (HFPO-DA and PFO4DA) and even legacy PFOA. Although hepatomegaly is a common apical end point of PFAS exposure, the differentially expressed gene (DEG) profiles in the liver suggested significant differences between PFOA and the four PFECA compounds. Gene enrichment analysis supported a considerable inhibitory effect of PFECA, but not PFOA, on the glucocorticoid receptor (GR) signaling pathway. Both HFPO-TA and PFO5DoDA demonstrated a more pronounced ability to perturb RNA expression profiles in vivo and to suppress GR signaling in vitro compared to HFPO-DA and PFO4DA. Calculated reference doses (RfDs) emphasized the potential hazard of PFECA to human health. Overall, our findings indicate that PFECA alternatives do not ease the concerns raised from legacy PFAS pollution.

Environmentally relevant concentrations of fipronil selectively disrupt venous vessel development in zebrafish embryos/larvae.

The pesticide fipronil is widely dispersed in aquatic environments and frequently detected in the general population. Although the adverse effects on embryonic growth by fipronil exposure have been extensively documented, the early responses for its developmental toxicity are largely unknown. In the present study, we explored the sensitive targets of fipronil, focusing on vascular injury using zebrafish embryos/larvae and cultured human endothelial cells. Exposure to 5-500 µg/L fipronil at the early stage impeded the growth of sub-intestinal venous plexus (SIVP), caudal vein plexus (CVP), and common cardinal veins (CCV). The damages on venous vessels occurred at exposure to the environmentally relevant concentration as low as 5 µg/L fipronil, whereas no significant change was observed in general toxicity indexes. In contrast, vascular development of the dorsal aorta (DA) or intersegmental artery (ISA) was not affected. In addition, the mRNA levels of vascular markers and vessel type-specific function genes exhibited significant decreases in venous genes, including nr2f2, ephb4a, and flt4, but no appreciable change in arterial genes. Likewise, the more pronounced changes in cell death and cytoskeleton disruption were shown in human umbilical vein endothelial cells as compared with human aortic endothelial cells. Furthermore, molecular docking supported a stronger affinity of fipronil and its metabolites to the proteins correlated with venous development, such as BMPR2 and SMARCA4. These results reveal the heterogeneity in developing vasculature responsive to fipronil's exposure. The preferential impacts on the veins confer higher sensitivity, allowing them to be appropriate targets for monitoring fipronil's developmental toxicity.

Molecular characterization and prognosis of mutant TP53 acute myeloid leukemia and myelodysplastic syndrome with excess blasts.

INTRODUCTION: Myeloid tumors typically harbor TP53 mutations, which are linked to a dismal prognosis. There are fewer studies on whether TP53-mutated acute myeloid leukemia (AML) and myelodysplastic syndrome with excess blasts (MDS-EB) differ in molecular characteristics and should be considered as separate entities. METHODS: Between January 2016 and December 2021, a retrospective analysis was done on a total of 73 newly diagnosed AML patients and 61 MDS-EB patients from the first affiliated hospital of Soochow University. We described a survival profile and a thorough characterization of newly found TP53-mutant AML and MDS-EB and investigated the relationship between these characteristics and overall survival (OS). RESULTS: 38 (31.1%) were mono-allelic, and 84 (68.9%) were bi-allelic. There is no significant difference between TP53-mutated AML and MDS-EB (median OS 12.9 verse 14.4 months; p = .558). Better overall survival was linked to mono-allelic TP53 than bi-allelic TP53(HR = 3.030, CI:1.714-5.354, p < .001). However, the number of TP53 mutations and comutations were not significantly associated with OS. TP53 variant allele frequency cutoff of 50% is significant correlation with OS (HR: 2.177, 95% CI: 1.142-4.148; p = .0063). CONCLUSION: Our data revealed that allele status and allogeneic hematopoietic stem cell transplant independently affect the prognostic of AML and MDS-EB patients, with a concordance of molecular features and survival between these two disease entities. Our analysis favors considering TP53-mutated AML/MDS-EB as a distinct disorder.

PFO5DoDA disrupts hepatic homeostasis primarily through glucocorticoid signaling inhibition.

Legacy per- and polyfluoroalkyl substances (PFASs) are a worldwide health concern due to their potential bioaccumulation and toxicity in humans. A variety of perfluoroether carboxylic acids (PFECAs) have been developed as next-generation replacements of legacy PFASs. However, information regarding their possible environmental and human health risks is limited. In the present study, we explored the effects of PFECAs on mice based on long-term exposure to environmentally relevant doses of perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoDA). Results showed that PFECAs exposure suppressed many cellular stress signals and resulted in hepatomegaly. PFO5DoDA acted as an agonist of the peroxisome proliferator-activated receptor (PPAR) in vitro and modulated PPAR-dependent gene expression in the liver. Importantly, PFECAs had an inhibitory effect on the glucocorticoid receptor (GR), which may contribute to the extensive suppression of stress signals. Of note, the GR suppression induced by PFECAs was not reported by legacy perfluorooctanoic acid (PFOA). PFO5DoDA-induced changes in both GR and PPAR signals remodeled hepatic metabolic profiles, including decreased fatty acids and amino acids and increased ß-oxidation. Mechanistically, PFO5DoDA inhibited GR transactivation by degradation of GR proteins. Our results emphasize the potential risk of PFECAs to human health, which were introduced to ease concerns regarding legacy PFASs.

Clinical characteristics and prognostic analysis of acute myeloid leukemia patients with PTPN11 mutations.

OBJECTIVES: Little is known about the clinical impact of germline/somatic mutations of PTPN11 in acute leukemia. The aim of this study was to investigate the clinical characteristics and prognostic impact of PTPN11 mutations in patients with acute myeloid leukemia (AML). METHODS: Seventy-four patients with PTPN11 mutation-positive AML treated at our institution were enrolled in this study. The prevalence of PTPN11 mutations was examined using targeted next-generation sequencing technology, and patients with AML and PTPN11 mutations were screened. Clinical characteristics, prognostic impact, and association between PTPN11 mutations and other mutations were analyzed retrospectively. RESULTS: PTPN11 mutations co-occurred more commonly with DNMT3A, NPM1, and FLT3 internal tandem duplication mutations. Compared with PTPN11 wild-type (WT) patients, PTPN11 mutation-positive AML patients presented with higher white blood cell (WBC) and platelet (PLT) counts. In 74 PTPN11 positive AML patients, PTPN11 mutations had an adverse effect on overall survival (OS) (62.5%) and a negative prognostic effect on event-free survival (EFS) (50%). Allo-hematopoietic stem cell transplantation (HSCT) abrogated the negative effect of mutations in PTPN11; the OS and EFS of AML patients with PTPN11 mutations who received transplantation were longer than those of AML patients with PTPN11 mutations who did not undergo allo-HSCT (P = 0.001, EFS; P < 0.001, OS). Discussion: Newly diagnosed PTPN11 mutation-positive AML patients with high WBC and PLT counts or presenting no remission after first induction chemotherapy suffer from high mortality rates. CONCLUSION: Given the lack of targeted therapies for PTPN11 mutations, timely HSCT is necessary for patients.

Psychological status of patients with amputation injury and effects of psychological interventions based on magnetic resonance imaging and X-ray characteristics.

BACKGROUND: To explore the psychological status of patients with amputation injury and to evaluate the effects of psychological interventions based on magnetic resonance imaging (MRI) and X-ray characteristics. METHODS: Two hundred patients admitted from June 2016 to May 2019 were randomly assigned into control and observation groups (n=100). Routine care was performed for both groups, based on which observation group was given psychological interventions. Coping style, compliance to examinations, mental stress, degree of perceived control, degree of anxiety, degree of depression, incidence rate of adverse events, and satisfaction with nursing services were compared. RESULTS: After interventions, the score of positive coping, score of compliance to examinations and Control Attitudes Scale-Revised (CAS-R) score were significantly higher, whereas the score of negative coping, Chinese perceived stress scale (CPSS) score, self-rating anxiety scale (SAS) score and self-rating depression scale (SDS) score were lower in observation group than those in control group. The score of positive coping, score of compliance to examinations and CAS-R score were significantly elevated, while the score of negative coping, CPSS score, SAS score and SDS score reduced in both groups (p<0.05). The satisfaction rate was significantly higher in observation group than that in control group (p<0.05). The incidence rate of these adverse events was significantly lower in observation group than that in control group (p<0.05). CONCLUSION: Psychological interventions before MRI and X-ray examinations are conducive to adjustment of the mental state of patients receiving replantation of a severed limb, thus improving the compliance to examinations, completion rate and image quality.

AGTR2, One Possible Novel Key Gene for the Entry of SARS-CoV-2 Into Human Cells.

Recently, it was confirmed that ACE2 is the receptor of SARS-CoV-2, the pathogen causing the recent outbreak of severe pneumonia around the world. It is confused that ACE2 is widely expressed across a variety of organs and is expressed moderately but not highly in lung, which, however, is the major infected organ. Therefore, we hypothesized that there could be some other genes playing key roles in the entry of SARS-CoV-2 into human cells. Here we found that AGTR2 (angiotensin II receptor type 2), a G-protein coupled receptor, has interaction with ACE2 and is highly expressed in lung with a high tissue specificity. More importantly, simulation of 3D structure based protein-protein interaction reveals that AGTR2 shows a higher binding affinity with the Spike protein of SARS-CoV-2 than ACE2 (energy: -8.2 vs. -5.1 [kcal/mol]). A number of compounds, biologics and traditional Chinese medicine that could decrease the expression level of AGTR2 were predicted. Finally, we suggest that AGTR2 could be a putative novel gene for the entry of SARS-CoV-2 into human cells, which could provide different insight for the research of SARS-CoV-2 proteins with their receptors.

Bioactivities of serotonin transporter mediate antidepressant effects of Acorus tatarinowii Schott.

ETHNOPHARMACOLOGICAL RELEVANCE: Acrorus tatarinowii Schott has been widely used in the treatments of neuropsychiatric and digestive disorders in clinical practices of traditional Chinese medicine for thousands of years. Both clinical and preclinical studies demonstrated antidepressant effects of A. tatarinowii. However, the possible action mechanisms of antidepressant effects of A. tatarinowii remain unraveled. AIM OF THE STUDY: The present study aimed to investigate the roles of serotonin transporter (SERT) in antidepressant effects of A. tatarinowii. MATERIALS AND METHODS: Antidepressant effects of water extract of A. tatarinowii were evaluated by forced swimming test (FST), tail suspension test (TST) and locomotor activity test. The water extract was analyzed by ultra high performance liquid chromatography (UPLC) method. Two major fractions of A. tatarinowii, petroleum ether extract and water extract after petroleum ether processed, were prepared and analyzed by UPLC method. Further, volatile oil extracted by ether extraction, solid phase micro-extraction (SPME) and hydro-distillation were compared and analyzed by gas chromatography-mass spectrometer (GC-MS) method. Finally, major constituents of water extract of A. tatarinowii were isolated by preparative high performance liquid chromatography (HPLC) and identified by extensive spectroscopic analyses. Effects of all of the above mentioned samples on SERT activity were tested by a high content assay (HCA). RESULTS: Results of FST, TST and locomotor activity confirmed that water extract of A. tatarinowii significantly decreased mice immobility time but did not change mice locomotor activity. UPLC analysis results revealed that the water extract contained trace amount of ß-asarone (0.0004206%) and α-asarone (0.0001918%). HCA results demonstrated that the water extract significantly enhanced SERT activity at 100 µg/mL. Further, GC-MS and UPLC analyses revealed that petroleum ether extract contained high content of ß-asarone (45.63%) and α-asarone (12.50%). GC-MS analysis results demonstrated that the volatile oil extracted by ether extraction, SPME and hydro-distillation contained similar major components. HCA results verified that the petroleum ether extract significantly enhanced SERT activity at 1.56 µg/mL. Moreover, UPLC analysis of water extract after petroleum ether processed did not show any characteristic peaks. HCA results demonstrated that this extract significantly inhibited SERT activity at 50-100 µg/mL. Finally, phytochemistry investigation on the water extract of A. tatarinowii afforded seven constituents including veratric acid (9), anisic acid (7), 3,4,5-trimethoxybenzoic acid (3), trans-isoferulic acid (2), 2,4,5-trimethoxybenzoic acid (11), 4-hydroxybenzoic acid (6) and syringic acid (13). Their structures were established on the basis of nuclear magnetic resonance (NMR) and mass spectrometer (MS) data and comparative UPLC analyses. HCA results demonstrated the major components of the water extract of A. tatarinowii demonstrated SERT enhancement/inhibition activities. CONCLUSIONS: This study first systematically demonstrated the roles of SERT activity in antidepressant effects of A. tatarinowii, including water extract, major fractions and main constituents. These results revealed that A. tatarinowii could regulate SERT activities in bidirectional ways.

Evaluation of Daphne genkwa diterpenes: fingerprint and quantitative analysis by high performance liquid chromatography.

Daphne genkwa contains a novel class of anticancer diterpene esters that inhibit DNA topoisomerase I. Fingerprint and quantitative analysis by HPLC were performed in order to characterise and evaluate D. genkwa. A standard fingerprint of Daphne diterpene esters from the root extract was first established by HPLC-UV, and the major peaks in the fingerprint profile were preliminarily determined using HPLC-MS. The principal Daphne diterpene esters, yuanhuacine (1), yuanhuadine (2), yuanhuajine (3) and yuanhuagine (4), were isolated and identified using a combination of UV, IR, MS, 1H-NMR and 13C-NMR spectral data. Quantitative analysis indicated that 1 was the principal component in the root, and that 2 was the major component in the buds. The average extraction rates of 1 and 2 were 0.0151 and 0.0033% (n=10) from the root, respectively, and 0.0020 and 0.0078% (n=3) from the buds, respectively.

Preparation of yuanhuacine and relative daphne diterpene esters from Daphne genkwa and structure-activity relationship of potent inhibitory activity against DNA topoisomerase I.

Two new daphne diterpene esters Yuanhuajine (2) and Yuanhuagine (4), together with three known daphne diterpene esters yuanhuacine (1), yuanhuadine (3), and yuanhuapine (5), were isolated and identified from Daphne genkwa, a traditional Chinese medicine. Their structures were elucidated by a combination of UV, IR, MS and NMR ((1)H NMR, (13)C NMR, HSQC, and HMBC) spectra. In order to explore the structure-activity relationship, three compounds 6, 7, and 8 were prepared as three derivatives of 1. Inhibitory activities against DNA topoisomerase I (topo I) were assessed for the compounds 1-8. These compounds, except for 8, exhibited potent inhibitory activities against DNA topo I at IC(50) levels of 11.1-53.4 microM and they are new type of topo I inhibitors bearing different structures compared with the known topo I inhibitors. The agarose-gel electrophoresis experiments showed that the orthoester group of daphne diterpene esters was necessary for the inhibitory activity against DNA topo I, and the inhibition against DNA topo I is probably one of the anti-tumor mechanisms of daphne diterpene esters.