Efficacy and safety of venlafaxine hydrochloride combined with tandospirone citrate for patients with vascular depression accompanied by somatic symptoms: An open-labeled randomized control trial.

AIMS: To explore the pharmacological treatment of vascular depression (VaDep) and whether the blood levels of neurotransmitters can reflect the VaDep severity. METHODS: VaDep patients with somatic symptoms were enrolled and randomly received venlafaxine + tandospirone (Combined Group) or venlafaxine (Monotherapy Group). The treatment efficacy was assessed by Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Patient Health Questionnaire-15 (PHQ-15). The levels of blood monoamine neurotransmitters were measured by enzyme-linked immunosorbent assay. RESULTS: Both groups reported a progressive decrease in HAMD, HAMA, and PHQ-15 scores to below the baseline after the respective treatment. Compared with the Monotherapy Group, the Combined Group reported a significant decrease in HAMD score at week 2 and markedly lower HAMA and PHQ-15 scores at weeks 1, 2, 4, and 8. Both groups showed a decrease in the levels of blood monoamine neurotransmitters at weeks 4 and 8 when compared with the baseline. A strong positive association was evident between the plasma 5-HT levels and the HAMD score. CONCLUSION: The combined therapy rapidly acts on VaDep comorbid with anxiety and somatic symptoms and significantly alleviates the anxiety and somatic symptoms. The plasma levels of 5-HT may serve as potential objective candidates in evaluating VaDep severity and the efficacy of the undertaken treatment regimen.

Objective Sleep Duration and All-Cause Mortality Among People With Obstructive Sleep Apnea.

Importance: The association between sleep duration and all-cause mortality remains unclear among people with obstructive sleep apnea (OSA). Objective: To explore whether there is an association between sleep duration and all-cause mortality among people with OSA. Design, Setting, and Participants: This cohort study investigated participants with OSA from the Sleep Heart Health Study (SHHS) in which participants were enrolled between 1995 and 1998 with questionnaires and polysomnography (PSG) assessment and followed up for a median of 11.8 years. SHHS was a multicenter community-based study; 2574 participants with OSA defined by apnea-hypopnea index (AHI) greater than or equal to 15 from SHHS were found; all of them had all-cause mortality data and were included in the study. Data were analyzed from November 2022 to October 2023. Exposures: Participants were divided into 4 groups with objective sleep duration of (1) at least 7 hours, (2) 6 to less than 7 hours, (3) 5 to less than 6 hours, and (4) less than 5 hours, which was determined by total sleep time on PSG at baseline. Main Outcomes and Measures: All-cause mortality was defined as deaths from any cause and its risk was compared among 4 OSA groups using Cox regression models. Results: A total of 2574 participants with OSA were included (1628 [63.2%] men and 946 [36.8%] women; mean [SD] age, 65.4 [10.7] years; 211 [8.2%] Black, 2230 [86.6%] White, 133 [5.2%] other race). Overall, 688 all-cause deaths were observed in participants. Compared with the group sleeping at least 7 hours, the groups sleeping 6 to less than 7 hours (hazard ratio [HR], 1.53 [95% CI, 1.13-2.07]), 5 to less than 6 hours (HR, 1.40 [95% CI, 1.03-1.90]), and less than 5 hours (HR, 1.64 [95% CI, 1.20-2.24]) had significantly higher risks of all-cause mortality independent of AHI. Sensitivity analyses were performed among participants with available data of positive airway pressure treatment during follow-up and the finding was mostly consistent, albeit the HR for the group of 5 to less than 6 hours was not statistically significant. Conclusions and Relevance: In this cohort study of 2574 participants with OSA, those with shorter objective sleep duration had higher risk of all-cause mortality independent of AHI compared with those sleeping at least 7 hours. Further studies would be needed to investigate health benefits of extending sleep length among people with OSA with short sleep duration.

Cyclic Diguanylate G-Quadruplex Inducer-Nitric Oxide Donor Conjugate as a Bifunctional Antibiofilm Agent and Antibacterial Synergist against Pseudomonas aeruginosa with a Hyperbiofilm Phenotype.

Antibiotic resistance caused by biofilm formation is a clinical challenge. Nitric oxide (NO) can effectively disperse a mature biofilm and can also synergistically influence the level of cyclic diguanylate (c-di-GMP), a universal secondary messenger that plays an important role in biofilm formation in bacteria. Based on our previous finding that c-di-GMP G-quadruplex inducers are effective biofilm formation inhibitors, we designed and synthesized a c-di-GMP G-quadruplex inducer-NO donor conjugate (A11@NO) as a bifunctional antibiofilm agent after obtaining the c-di-GMP G-quadruplex inducer (A11), which has an amino group capable of binding to a nitroso group (NO donor). The conjugate A11@NO showed better biofilm inhibition efficiency than A11, and it can also eradicate mature biofilm. Additionally, it exhibited good antimicrobial synergism against Pseudomonas aeruginosa and helped elevate the bactericidal efficiency of tobramycin against biofilm-formed bacteria. In combination with tobramycin, A11@NO also improved the survival rate of Caenorhabditis elegans in a hyperbiofilm environment.

Schisandrin A ameliorates airway inflammation in model of asthma by attenuating Th2 response.

Asthma is a persistent respiratory ailment that displays periodicity and is linked to the equilibrium of T cells. Several compounds obtained from Chinese herbal medicines display beneficial impacts on T cell regulation and the attenuation of inflammatory mediator synthesis. Schisandrin A, an active lignan derived from the Schisandra fruit, exhibits anti-inflammatory characteristics. In the present study, the network analysis conducted revealed that the nuclear factor-kappaB (NF-κB) signaling pathway is likely a prominent contributor to the anti-asthmatic effects of schisandrin A. In addition, it has been established that the inhibition of cyclooxygenase 2 (COX-2/PTGS2) is likely a significant factor in this process. The results of in vitro experiments have substantiated that schisandrin A can effectively lower the expression of COX-2 and inducible nitric oxide synthase (iNOS) in 16 HBE cells and RAW264.7 cells in a manner that is dependent on the dosage administered. It was able to effectively reduce the activation of the NF-κB signaling pathway while simultaneously improving the injury to the epithelial barrier function. Furthermore, an investigation utilizing immune infiltration as a metric revealed an inequity in Th1/Th2 cells and a surge in Th2 cytokines in asthma patients. In the OVA-induced asthma mice model, it was observed that schisandrin A treatment effectively suppressed inflammatory cell infiltration, reduced the Th2 cell ratio, inhibited mucus secretion, and prevented airway remodeling. To summarize, the administration of schisandrin A has been found to effectively alleviate the symptoms of asthma by impeding the production of inflammation, which includes reducing the Th2 cell ratio and improving the integrity of the epithelial barrier function. These findings offer valuable insights into the potential therapeutic applications of schisandrin A for the treatment of asthma.

Augmentation therapy with tandospirone citrate in vascular depression patients with mild cognitive impairment: A prospective randomized clinical trial.

Cognitive impairment is a prominent clinical manifestation of vascular depression (VaDep). The current study aimed to assess the efficacy of tandospirone citrate in VaDep cases with mild cognitive impairment (VaDep-MCI) as well as the role of plasma monoamine neurotransmitters during the treatment. In this single-blind, randomized controlled study, 116 participants were randomly assigned to the tandospirone (tandospirone citrate-escitalopram) and control (escitalopram) groups. The primary endpoints were changes in cognitive test scores from baseline to Week 8, including the Rey Auditory Verbal Learning Test (RAVLT), Semantic Verbal Fluency (SVF) test, Trail Making Test (TMT), Digital Span Test (DST) and Clock Drawing Test (CDT) scores. Generalized estimating equation models were used to examine repeated measures. The results showed that compared with the changes in the control group from baseline to Week 8, the tandospirone group showed more significant changes in SVF score at Weeks 4 (p < 0.05) and 8 (p < 0.001), and TMT (B-A) score at Week 8 (p < 0.05). RAVLT, DST and DCT scores were relatively stable in both groups during the study period. Moreover, mediation analysis showed that these results were not mediated by the alleviation of depression symptoms. Partial Spearman correlation analysis showed that only plasma 5-hydroxytryptamine (5-HT) was positively correlated with Hamilton Depression Rating Scale score after Bonferroni correction (r = 0.347, p < 0.001). Augmentation therapy with tandospirone citrate improved the executive and language functions of VaDep-MCI patients. Additionally, plasma 5-HT levels may serve as a potential biomarker of VaDep severity. These findings may provide clinical insights into the treatment of vascular depression.

Design, Synthesis and Biological Evaluation of Novel and Potent Protein Arginine Methyltransferases 5 Inhibitors for Cancer Therapy.

Protein arginine methyltransferases 5 (PRMT5) is a clinically promising epigenetic target that is upregulated in a variety of tumors. Currently, there are several PRMT5 inhibitors under preclinical or clinical development, however the established clinical inhibitors show favorable toxicity. Thus, it remains an unmet need to discover novel and structurally diverse PRMT5 inhibitors with characterized therapeutic utility. Herein, a series of tetrahydroisoquinoline (THIQ) derivatives were designed and synthesized as PRMT5 inhibitors using GSK-3326595 as the lead compound. Among them, compound 20 (IC50: 4.2 nM) exhibits more potent PRMT5 inhibitory activity than GSK-3326595 (IC50: 9.2 nM). In addition, compound 20 shows high anti-proliferative effects on MV-4-11 and MDA-MB-468 tumor cells and low cytotoxicity on AML-12 hepatocytes. Furthermore, compound 20 possesses acceptable pharmacokinetic profiles and displays considerable in vivo antitumor efficacy in a MV-4-11 xenograft model. Taken together, compound 20 is an antitumor compound worthy of further study.

Anti-inflammatory activities of natural cyclopeptide RA-XII in colitis-associated colon cancer mouse model and its effect on gut microbiome.

Colorectal cancer (CRC), the third most common cancer globally, is associated with intestinal inflammation that leads to poor prognosis. RA-XII, a natural cyclopeptide, has previously been reported to possess anti-tumor activities. Here, the anti-inflammatory activities of RA-XII were investigated in colitis-associated colon cancer mice and a co-culture in vitro model, in which colon cancer cells HCT116 and macrophages RAW264.7 were grown together to mimic the inflammatory microenvironment of CRC. Changes of inflammatory-related molecules and protein expressions in cells were evaluated after RA-XII incubation. Besides, azoxymethane and dextran sulfate sodium-induced colitis-associated colon cancer mice were treated with RA-XII for 24 days, inflammatory parameters and gut microbiome alterations were studied. Our results showed that RA-XII reversed the inflammatory responses of RAW264.7 cells induced by LPS and modulated the protein expressions of AKT, STAT3/p-STAT3, P70S6K, NF-κB and GSK3ß and suppressed the expression of LC3A/B in HCT116 cells in co-culture system. RA-XII treatment restored the colitis damage in colon, reduced colon tumors numbers and decreased inflammatory factors (IL-6, IL-10 and TNF-α). The role of RA-XII on regulating gut microbiome was also demonstrated for the first time. In conclusion, our findings provided new scientific evidence for developing RA-XII as a potent anti-inflammatory agent for CRC.

Design, synthesis and mechanism studies of novel dual PARP1/BRD4 inhibitors against pancreatic cancer.

Inducing the deficiency of homologous recombination (HR) repair is an effective strategy to broaden the indication of PARP inhibitors in pancreatic cancer treatment. Repression of BRD4 has been reported to significantly elevate HR deficiency and sensitize cancer cells to PARP1/2 inhibitors. Inspired by the concept of synthetic lethality, we designed, synthetized and optimized a dual PARP1/BRD4 inhibitor III-7, with a completely new structure and high selectivity against both targets. III-7 repressed the expression and activity of PARP1 and BRD4 to synergistically inhibit the malignant growth of pancreatic cancer cells in vitro and in vivo. Based on the results of bioinformatic analysis, we found that Olaparib induced the acceleration of mitosis and recovery of DNA repair to cause the generation of drug resistance. III-7 reversed Olaparib-induced adaptive resistance and induced cell cycle arrest and DNA damage by perturbing PARP1 and BRD4-involved signaling pathways. We believe that the PARP1/BRD4 dual inhibitors are novel and promising antitumor agents, which provide an efficient strategy for pancreatic cancer treatment.

FDI-6 and olaparib synergistically inhibit the growth of pancreatic cancer by repressing BUB1, BRCA1 and CDC25A signaling pathways.

Inducing homologous recombination (HR) deficiency is a promising strategy to broaden the indication of PARP1/2 inhibitors in pancreatic cancer treatment. In addition to inhibition kinases, repression of the transcriptional function of FOXM1 has been reported to inhibit HR-mediated DNA repair. We found that FOXM1 inhibitor FDI-6 and PARP1/2 inhibitor Olaparib synergistically inhibited the malignant growth of pancreatic cancer cells in vitro and in vivo. The results of bioinformatic analysis and mechanistic study showed that FOXM1 directly interacted with PARP1. Olaparib induced the feedback overexpression of PARP1/2, FOXM1, CDC25A, CCND1, CDK1, CCNA2, CCNB1, CDC25B, BRCA1/2 and Rad51 to promote the acceleration of cell mitosis and recovery of DNA repair, which caused the generation of adaptive resistance. FDI-6 reversed Olaparib-induced adaptive resistance and inhibited cell cycle progression and DNA damage repair by repressing the expression of FOXM1, PARP1/2, BUB1, CDC25A, BRCA1 and other genes-involved in cell cycle control and DNA damage repair. We believe that targeting FOXM1 and PARP1/2 is a promising combination therapy for pancreatic cancer without HR deficiency.

Discovery of Potent and Novel Dual PARP/BRD4 Inhibitors for Efficient Treatment of Pancreatic Cancer.

Targeting poly(ADP-ribose) polymerase1/2 (PARP1/2) is a promising strategy for the treatment of pancreatic cancer with breast cancer susceptibility gene (BRCA) mutation. Inducing the deficiency of homologous recombination (HR) repair is an effective way to broaden the indication of PARP1/2 inhibitor for more patients with pancreatic cancer. Bromodomain-containing protein 4 (BRD4) repression has been reported to elevate HR deficiency. Therefore, we designed, synthetized, and optimized a dual PARP/BRD4 inhibitor III-16, with a completely new structure and high selectivity against PARP1/2 and BRD4. III-16 showed favorable synergistic antitumor efficacy in pancreatic cancer cells and xenografts by arresting cell cycle progression, inhibiting DNA damage repair, and promoting autophagy-associated cell death. Moreover, III-16 reversed Olaparib-induced acceleration of cell cycle progression and recovery of DNA repair. The advantages of III-16 over Olaparib suggest that dual PARP/BRD4 inhibitors are novel and promising agents for the treatment of advanced pancreatic cancer.

Design and Synthesis of Novel c-di-GMP G-Quadruplex Inducers as Bacterial Biofilm Inhibitors.

The formation of biofilms by clinical pathogens typically leads to chronic and recurring antibiotic-resistant infections. High cellular levels of cyclic diguanylate (c-di-GMP), a ubiquitous secondary messenger of bacteria, have been proven to be associated with a sessile biofilm lifestyle of pathogens. A promising antibiofilm strategy involving the induction of c-di-GMP to form dysfunctional G-quadruplexes, thereby blocking the c-di-GMP-mediated biofilm regulatory pathway, was proposed in this study. In this new strategy, a series of novel c-di-GMP G-quadruplex inducers were designed and synthesized for development of therapeutic biofilm inhibitors. Compound 5h exhibited favorable c-di-GMP G-quadruplex-inducing activity and 62.18 ± 6.76% biofilm inhibitory activity at 1.25 µM without any DNA intercalation effect. Moreover, the favorable performance of 5h in interfering with c-di-GMP-related biological functions, including bacterial motility and bacterial extracellular polysaccharide secretion, combined with the reporter strain and transcriptome analysis results confirmed the c-di-GMP signaling-related action mechanism of 5h.

Selection and Validation of Appropriate Reference Genes for Quantitative RT-PCR Analysis in Rubia yunnanensis Diels Based on Transcriptome Data.

Real-time quantitative polymerase chain reaction (RT-qPCR) has been widely applied in gene expression and transcription abundance analysis because of its high sensitivity, good repeatability, and strong specificity. Selection of relatively stable reference genes is a precondition in order to obtain the reliable analysis results. However, little is known about evaluation of a set of reference genes through scientific experiments in Rubia plants. Here, 15 candidate reference genes were selected from R. yunnanensis transcriptome database and analyzed under abiotic stresses, hormone treatments, and different tissues. Among these 15 candidate reference genes, heterogeneous nuclear ribonucleoprotein (hnRNP), TATA binding protein (TBP), ribosomal protein L5 (RPL5), malate dehydrogenase (MDH), and elongation factor 1-alpha (EF-1α) were indicated as the five most stable reference genes by four statistical programs (geNorm, NormFinder, BestKeeper, and RefFinder). Ultimately, the validity of reference genes was confirmed by normalizing the expression of o-succinylbenzoate-CoA ligase (OSBL) and isochorismate synthase (ICS) involved in the anthraquinone biosynthesis pathway in different tissues and hormone treatments. Meanwhile, four other putative genes involved in the anthraquinone biosynthesis pathway were also normalized with the selected reference genes, which showed similar expression levels with those given by transcriptome data. This work is the first research that aims at a systematic validation on the stability of reference genes selected from R. yunnanensis transcriptome data and will be conducive to analyze gene expression in R. yunnanensis or other Rubia species.

A controlled study of the efficacy and safety of tandospirone citrate combined with escitalopram in the treatment of vascular depression: A pilot randomized controlled trial at a single-center in China.

Vascular depression can respond poorly to antidepressants. This study aimed to explore the efficacy and safety of tandospirone plus escitalopram for treating vascular depression with anxiety. This pilot randomized controlled trial included consecutive inpatients/outpatients with vascular depression/anxiety at the Department of Neurology, Fujian Medical University Union Hospital, China (January 2014 to December 2016). Among 157 patients screened, 100 were randomly divided into the tandospirone + escitalopram (combination therapy) and escitalopram (monotherapy) groups equally, and then followed for 8 weeks. Efficacy was evaluated using the Hamilton Depression (HAMD), Hamilton Anxiety (HAMA), Clinical Global Impression (CGI) and Mini-Mental State examination (MMSE) scales. Adverse events (AEs) were assessed with the Treatment Emergent Symptom Scale (TESS). HAMD and HAMA scores decreased progressively, showing reductions versus baseline at 1, 2, 4 and 8 weeks in both groups (P < 0.001). HAMD and HAMA scores were lower in the tandospirone + escitalopram group than those in the escitalopram group at 1 and 2 weeks (P < 0.001), but not at 4 and 8 weeks. Improvements in CGI scores (severity, improvement and efficacy indexes) were greater in the tandospirone + escitalopram group than that in the escitalopram group at 1 and 2 weeks (P < 0.01), but not at 4 and 8 weeks. The tandospirone + escitalopram group had higher MMSE scores than that in the escitalopram group at 4 and 8 weeks (P < 0.01). All AEs were mild, and the rates were comparable between groups. Augmentation of escitalopram with tandospirone accelerates the onset of anti-depressive and anxiolytic effects and improves cognitive function in patients with vascular depression and anxiety.

Effects of separate or combined exposure of nonylphenol and octylphenol on central 5-HT system and related learning and memory in the rats.

This study evaluated toxic effects of nonylphenol (NP) and octylphenol (OP) on central 5-hydroxytryptamine (5-HT) system and related learning and memory in the rats. Male Sprague-Dawley rats were exposed to NP (30, 90, or 270 mg/kg), OP (40, 120, or 360 mg/kg), or a mixture of NP and OP [(mixed with the corresponding NP, OP alone exposed low, medium and high dose according to the natural environment exists NP:OP = 4:1; NOL (24 mg/kg NP+8 mg/kg OP), NOM (72 mg/kg NP+24 mg/kg OP), NOH (216 mg/kg NP+72 mg/kg OP)] by gavage every other day for 30 d. Learning and memory were assessed using a passive-avoidance test. Levels of estrogen receptor ß (ERß), 5-HT, tryptophan hydroxylase 2 (TPH2), monoamine oxidase (MAOA) enzyme, serotonin transporter (SERT), the vesicular monoamine transporter 2 (VMAT2), 5-hydroxytryptamine 1 A (5-HT1A), 5-hydroxytryptamine 3 A (5-HT3A), 5-hydroxytryptamine 3B (5-HT3B), 5-hydroxytryptamine 4 A (5-HT4A) and 5-hydroxytryptamine 6 A (5-HT6A) were measured using ELISA kits. Levels of ERß, MAOA, SERT, VMAT2, 5-HT1A, 5-HT3A, 5-HT3B, 5-HT4A and 5-HT6A in rat hippocampal reduced by a high dose of NP and/or OP. Levels of TPH2 in rat midbrain and 5-HT in rat hippocampal increased by a high dose of NP and/or OP. In addition, latency was significantly shorter and errors were significantly greater in the high dose NP and NP+OP (NO) groups. Taken together, these results suggest that NP and/or OP may affect learning and memory in rats by inhibiting levels of ERß, which could then lead to decreases in levels of 5-HT1A, 5-HT3A, 5-HT3B, 5-HT4A, and 5-HT6A in the rat hippocampus. These findings suggested that separate and combined exposure to NP and OP could produce toxic effects on central 5-HT system and related learning and memory in the rats.

Ambient PM2.5 exposure exacerbates severity of allergic asthma in previously sensitized mice.

OBJECTIVE: Epidemiological studies have shown that elevated concentrations of ambient particulate matter (aerodynamic diameter ≤2.5 µm; PM2.5) correlates with increased incidence of asthma. The aim of this study was to determine whether PM2.5 participates in the exacerbation of asthma. METHODS: Effects of 1, 10 and 100 µg PM2.5 instilled intratracheally in ovalbumin (OVA)-sensitized or asthmatic mice were compared. RESULTS: PM2.5 exposure in the OVA-sensitized and especially asthmatic groups increased Mch responsiveness in a dose-dependent manner. In OVA-sensitized groups, exposure to 1 µg of PM2.5 caused no detectable lung inflammation, while 10 and 100 µg of PM2.5 resulted in a slightly increased trend in numbers of neutrophils and macrophages. Compared with the asthmatic control group, both 10 and 100 µg of PM2.5 provoked a significant increase in eosnophils and neutrophils whereas only 100 µg of PM2.5 noticeably enhanced lymphocytes. In asthmatic groups, administration of 100 µg of PM2.5 greatly increased levels of the pro-inflammatory cytokine TNF-α and Th2-related cytokines IL-4 and IL-10 in bronchoalveolar lavage fluid, but it decreased Th1-related INF-γ. In addition, 10 and 100 µg of PM2.5 exacerbated inflammatory infiltration, goblet cell metaplasia and lung ultrastructure lesions in asthmatic mice. CONCLUSIONS: Our results suggested that acute exposure of PM2.5 could synergize with allergens in the subsequent challenge to aggravate the severity of asthma in sensitized mice, possibly by promoting a Th2-biased immune response.