Aripiprazole is a wide-used antipsychotic drug with therapeutic effects on both positive and negative symptoms of schizophrenia, and reduced side-effects. Although aripiprazole was developed as a dopamine D2 receptor (D2R) partial agonist, all other D2R partial agonists that aimed to mimic aripiprazole failed to exert therapeutic effects in clinic. The present in vivo study aimed to investigate the effects of aripiprazole on the D2R downstream cAMP-PKA and Akt-GSK3β signalling pathways in comparison with a D2R antagonist--haloperidol and a D2R partial agonist--bifeprunox. Rats were injected once with aripiprazole (0.75 mg/kg, i.p.), bifeprunox (0.8 mg/kg, i.p.), haloperidol (0.1 mg/kg, i.p.) or vehicle. Five brain regions--the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), ventral tegmental area (VTA) and substantia nigra (SN) were collected. The protein levels of PKA, Akt and GSK3β were measured by Western Blotting; the cAMP levels were examined by ELISA tests. The results showed that aripiprazole presented similar acute effects on PKA expression to haloperidol, but not bifeprunox, in the CPU and VTA. Additionally, aripiprazole was able to increase the phosphorylation of GSK3β in the PFC, NAc, CPu and SN, respectively, which cannot be achieved by bifeprunox and haloperidol. These results suggested that acute treatment of aripiprazole had differential effects on the cAMP-PKA and Akt-GSK3β signalling pathways from haloperidol and bifeprunox in these brain areas. This study further indicated that, by comparison with bifeprunox, the unique pharmacological profile of aripiprazole may be attributed to the relatively lower intrinsic activity at D2R.

Stimuli-responsive polymer-drug conjugates (PDCs) provide promising approaches in anticancer treatment. Here, we report the synthesis and biological evaluation of PDCs made of the highly potent antimitotic agent monomethyl auristatin E conjugated to dendritic polyglycerol and dendritic polyglycerol sulfate via a reductively cleavable, self-immolative disulfide linker. Cell viability assays with the human cancer cell lines A549 (lung carcinoma) and HeLa (cervix carcinoma) revealed that the drug's cytotoxicity was reduced by conjugation to the polymers, with the sulfated conjugates being more effective than the non-sulfated ones. Kinetic studies using real-time cell analysis indicated a retarded drug release from the polymers, with a much later cytotoxic response after treatment with the non-sulfated conjugates due to less cellular uptake, as confirmed by flow cytometry and confocal laser scanning microscopy. In contrast, the non-cleavable dPGS-MMAE conjugate that was synthesized for comparison was not cytotoxic under the same conditions. Overall, reductively cleavable dPGS-SS-MMAE conjugates showed promising results in vitro and good tolerability in vivo. Further in vivo studies are planned.

Prescription of antipsychotic drugs (APDs) to children has substantially increased in recent years. Whilst current investigations into potential long-term effects have uncovered some alterations to adult behaviours, further investigations into potential changes to neurotransmitter systems are required. The current study investigated potential long-term changes to the adult dopamine (DA) system following aripiprazole, olanzapine and risperidone treatment in female and male juvenile rats. Levels of tyrosine hydroxylase (TH), phosphorylated-TH (p-TH), dopamine active transporter (DAT), and D₁ and D₂ receptors were measured via Western blot and/or receptor autoradiography. Aripiprazole decreased TH and D₁ receptor levels in the ventral tegmental area (VTA) and p-TH levels in the prefrontal cortex (PFC) of females, whilst TH levels decreased in the PFC of males. Olanzapine decreased PFC p-TH levels and increased D₂ receptor expression in the PFC and nucleus accumbens (NAc) in females only. Additionally, risperidone treatment increased D₁ receptor levels in the hippocampus of females, whilst, in males, p-TH levels increased in the PFC and hippocampus, D₁ receptor expression decreased in the NAc, and DAT levels decreased in the caudate putamen (CPu), and elevated in the VTA. These results suggest that early treatment with various APDs can cause different long-term alterations in the adult brain, across both treatment groups and genders.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious dose-limiting toxicity of many anti-neoplastic agents, especially paclitaxel, and oxaliplatin. Up to 62% of patients receiving paclitaxel regimens turn out to develop CIPN. Unfortunately, there are so few agents proved effective for prevention or management of CIPN. The reason for the current situation is that the mechanisms of CIPN are still not explicit. Traditional Chinese Medicine (TCM) has unique advantages for dealing with complex diseases. Wen-Luo-Tong (WLT) is a TCM ointment for topical application. It has been applied for prevention and management of CIPN clinically for more than 10 years. Previous animal experiments and clinical studies had manifested the availability of WLT. However, due to the unclear mechanisms of WLT, further transformation has been restricted. To investigate the therapeutic mechanisms of WLT, a metabolomic method on the basis of UPLC- MS was developed in this study. Multivariate analysis techniques, such as principal component analysis (PCA) and partial least squares discriminate analysis (PLS-DA), were applied to observe the disturbance in the metabolic state of the paclitaxel-induced peripheral neuropathy (PIPN) rat model, as well as the recovering tendency of WLT treatment. A total of 19 significant variations associated with PIPN were identified as biomarkers. Results of pathway analysis indicated that the metabolic disturbance of pathways of linoleic acid (LA) metabolism and glycerophospholipid metabolism. WLT attenuated mechanical allodynia and rebalanced the metabolic disturbances of PIPN by primarily regulating LA and glycerophospholipid metabolism pathway. Further molecular docking analysis showed some ingredients of WLT, such as hydroxysafflor yellow A (HSYA), icariin, epimedin B and 4-dihydroxybenzoic acid (DHBA), had high affinity to plenty of proteins within these two pathways.

Olanzapine is the one of first line antipsychotic drug for schizophrenia and other serious mental illness. However, it is associated with troublesome metabolic side-effects, particularly body weight gain and obesity. The antagonistic affinity to histamine H1 receptors (H1R) of antipsychotic drugs has been identified as one of the main contributors to weight gain/obesity side-effects. Our previous study showed that a short term (2 weeks) combination treatment of betahistine (an H1R agonist and H3R antagonist) and olanzapine (O+B) reduced (-45%) body weight gain induced by olanzapine in drug-naïve rats. A key issue is that clinical patients suffering with schizophrenia, bipolar disease and other mental disorders often face chronic, even life-time, antipsychotic treatment, in which they have often had previous antipsychotic exposure. Therefore, we investigated the effects of chronic O+B co-treatment in controlling body weight in female rats with chronic and repeated exposure of olanzapine. The results showed that co-administration of olanzapine (3 mg/kg, t.i.d.) and betahistine (9.6 mg/kg, t.i.d.) significantly reduced (-51.4%) weight gain induced by olanzapine. Co-treatment of O+B also led to a decrease in feeding efficiency, liver and fat mass. Consistently, the olanzapine-only treatment increased hypothalamic H1R protein levels, as well as hypothalamic pAMPKα, AMPKα and NPY protein levels, while reducing the hypothalamic POMC, and UCP1 and PGC-1α protein levels in brown adipose tissue (BAT). The olanzapine induced changes in hypothalamic H1R, pAMPKα, BAT UCP1 and PGC-1α could be reversed by co-treatment of O+B. These results supported further clinical trials to test the effectiveness of co-treatment of O+B for controlling weight gain/obesity side-effects in schizophrenia with chronic antipsychotic treatment.

We report the draft genome sequence of Bacillus thuringiensis strain LM1212, which differentiates into crystal producers or spore formers during the stationary phase. Availability of this genome sequence will facilitate the study of spore formation, crystal formation, cell differentiation, and evolution of B. thuringiensis.

Ischemia reperfusion (IR) injury (IRI) is harmful to the cardiovascular system and causes mitochondrial oxidative stress. Silent information regulator 1 (SIRT1), a type of histone deacetylase, contributes to IRI. Curcumin (Cur) is a strong natural antioxidant and is the active component in Curcuma longa; Cur has protective effects against IRI and may regulate the activity of SIRT1. This study was designed to investigate the protective effect of Cur pretreatment on myocardial IRI and to elucidate this potential mechanism. Isolated and in vivo rat hearts and cultured neonatal rat cardiomyocytes were subjected to IR. Prior to this procedure, the hearts or cardiomyocytes were exposed to Cur in the absence or presence of the SIRT1 inhibitor sirtinol or SIRT1 siRNA. Cur conferred a cardioprotective effect, as shown by improved postischemic cardiac function, decreased myocardial infarct size, decreased myocardial apoptotic index, and several biochemical parameters, including the up-regulation of the antiapoptotic protein Bcl2 and the down-regulation of the proapoptotic protein Bax. Sirtinol and SIRT1 siRNA each blocked the Cur-mediated cardioprotection by inhibiting SIRT1 signaling. Cur also resulted in a well-preserved mitochondrial redox potential, significantly elevated mitochondrial superoxide dismutase activity, and decreased formation of mitochondrial hydrogen peroxide and malondialdehyde. These observations indicated that the IR-induced mitochondrial oxidative damage was remarkably attenuated. However, this Cur-elevated mitochondrial function was reversed by sirtinol or SIRT1 siRNA treatment. In summary, our results demonstrate that Cur pretreatment attenuates IRI by reducing IR-induced mitochondrial oxidative damage through the activation of SIRT1 signaling.

The present study investigates the effects and mechanisms of α-Lipoic acid (LA) on myocardial infarct size, cardiac function and cardiomyocyte apoptosis in rat hearts subjected to in vivo myocardial ischemia/reperfusion (MI/R) injury.

Prescription of second-generation antipsychotic drugs (SGAs) to childhood/adolescent has exponentially increased in recent years, which was associated with the greater risk of significant weight gain and dyslipidemia. Statin is considered a potential preventive and treatment approach for reducing SGA-induced weight gain and dyslipidemia in schizophrenia patients. However, the effect of statin treatment in children and adolescents with SGA-induced dyslipidemia is not clearly demonstrated.

HOXA cluster antisense RNA 2 (lncRNA HOXA-AS2) is a long noncoding RNA (lncRNA) that aberrantly expressed in various cancers and is closely associated with cancer progression. To overcome the limitation of small sample sizes that are inherent to single studies, a meta-analysis was conducted to explore the relationship between the expression level of HOXA-AS2 and cancer prognosis.

We aimed to identify miRNAs that were closely related to breast cancer (BRCA). By integrating several methods including significance analysis of microarrays, fold change, Pearson's correlation analysis, t test, and receiver operating characteristic analysis, we developed a decision-tree-based scoring algorithm, called Optimized Scoring Mechanism for Primary Synergy MicroRNAs (O-PSM). Five synergy miRNAs (hsa-miR-139-5p, hsa-miR-331-3p, hsa-miR-342-5p, hsa-miR-486-5p, and hsa-miR-654-3p) were identified using O-PSM, which were used to distinguish normal samples from pathological ones, and showed good results in blood data and in multiple sets of tissue data. These five miRNAs showed accurate categorization efficiency in BRCA typing and staging and had better categorization efficiency than experimentally verified miRNAs. In the Protein-Protein Interaction (PPI) network, the target genes of hsa-miR-342-5p have the most regulatory relationships, which regulate carcinogenesis proliferation and metastasis by regulating Glycosaminoglycan biosynthesis and the Rap1 signaling pathway. Moreover, hsa-miR-342-5p showed potential clinical application in survival analysis. We also used O-PSM to generate an R package uploaded on github (SuFei-lab/OPSM accessed on 22 October 2021). We believe that miRNAs included in O-PSM could have clinical implications for diagnosis, prognostic stratification and treatment of BRCA, proposing potential significant biomarkers that could be utilized to design personalized treatment plans in BRCA patients in the future.

Acute myeloid leukemia (AML) is the most refractory hematologic malignancy characterized by acute onset, rapid progression, and high recurrence rate. Here, codelivery of BCL2 (ABT199) and MCL1 (TW37) inhibitors using phenylboronic acid-functionalized polypeptide nanovehicles to achieve synergetic and potent treatment of AML is adopted. Leveraging the dynamic boronic ester bonds, BN coordination, and π-π stacking, the nanovehicles reveal remarkably efficient and robust drug coencapsulation. ABT199 can induce a series of pro-apoptotic reactions by promoting the dissociation of the pro-apoptotic protein Bim from BCL2, while the released Bim is often captured by MCL1 protein overexpressed in AML. TW37 has a strong inhibitory ability to MCL1, thereby can restrain the depletion of Bim protein. Dual inhibitor-loaded nanoparticles (NPAT) reveal excellent stability, acid/enzyme/H2 O2 -triggered drug release, and significant cytotoxicity toward MOLM-13-Luc and MV-411 AML cells with low half maximal inhibitory concentrations of 1.15 and 7.45 ng mL-1 , respectively. In mice bearing MOLM-13-Luc or MV-411 AML cancer, NPAT reveal significant inhibition of tumor cell infiltration in bone marrow and main organs, potent suppression of tumor growth, and remarkably elevated mouse survival. With facile construction, varying drug combination, superior safety, synergetic efficacy, the phenylboronic acid-functionalized smart nanodrugs hold remarkable potential for AML treatment.

Introduction: Neuroinflammation in the central nervous system, particularly the prefrontal cortex (PFC), plays a role in the pathogenesis of schizophrenia, which has been found to be associated with maternal immune activation (MIA). Recent evidence suggests that epigenetic regulation involves in the MIA-induced neurodevelopmental disturbance. However, it is not well-understood how epigenetic modulation is involved in the neuroinflammation and pathogenesis of schizophrenia. Methods: This study explored the modulation of histone acetylation in both neuroinflammation and neurotransmission using an MIA rat model induced by prenatal polyriboinosinic-polyribocytidylic acid (Poly I:C) exposure, specifically examining those genes that were previously observed to be impacted by the exposure, including a subunit of nuclear factor kappa-B (Rela), Nod-Like-Receptor family Pyrin domain containing 3 (Nlrp3), NMDA receptor subunit 2A (Grin2a), 5-HT2A (Htr2a), and GABAA subunit β3 (Gabrb3). Results: Our results revealed global changes of histone acetylation on H3 (H3ace) and H4 (H4ace) in the PFC of offspring rats with prenatal Poly I:C exposure. In addition, it revealed enhancement of both H3ace and H4ace binding on the promoter region of Rela, as well as positive correlations between Rela and genes encoding histone acetyltransferases (HATs) including CREB-binding protein (CBP) and E1A-associated protein p300 (EP300). Although there was no change in H3ace or H4ace enrichment on the promoter region of Nlrp3, a significant enhancement of histone deacetylase 6 (HDAC6) binding on the promoter region of Nlrp3 and a positive correlation between Nlrp3 and Hdac6 were also observed. However, prenatal Poly I:C treatment did not lead to any specific changes of H3ace and H4ace on the promoter region of the target genes encoding neurotransmitter receptors in this study. Discussion: These findings demonstrated that epigenetic modulation contributes to NF-κB/NLRP3 mediated neuroinflammation induced by prenatal Poly I:C exposure via enhancement of histone acetylation of H3ace and H4ace on Rela and HDAC6-mediated NLRP3 transcriptional activation. This may further lead to deficits in neurotransmissions and schizophrenia-like behaviors observed in offspring.

The long non-coding RNAs (lncRNAs) have been involved in various processes, including cancer. However, the function of many lncRNAs is still elusive in triple-negative breast cancer (TNBC).

Myocardial dysfunction is well-recognized manifestations of organ dysfunction in sepsis, which is the leading cause of death in critically ill patients. The underlying mechanisms associated with sepsis-induced myocardial injury (SIMI) include cardiac contractility, inflammatory response, oxidative stress, and apoptosis. Kudzu celery decoction (KCD) is composed of a variety of traditional Chinese medicine (TCM) such as kudzu and celery. The previous study found that the main ingredients in kudzu and celery have also been proved to have anti-inflammatory, antioxidative, and other biological activities. In this study, the therapeutic effects of KCD were evaluated in the cecal ligation and puncture (CLP) model of BALB/c mice. The effects of KCD on cardiac function, myocardium damage, inflammation, and fibrosis in CLP-injured mice were analyzed with echocardiography, histological staining, and quantitative real-time PCR. The results showed that KCD treatment improved the anal temperature, sepsis score, blood routine parameters, and blood biochemical parameters in CLP-injured mice. Then, we observed that KCD could remarkably alleviate cardiac dysfunction, myocardial fibrosis, oxidative stress, and inflammation in CLP-injured mice. In this study, we confirmed that KCD has a significant protective effect on SIMI, which may favor KCD a potential cardioprotective drug candidate to alleviate SIMI and further amplify the application of TCM prescription in clinic.

This retrospective study compared the efficacy and safety of nedaplatin-based chemoradiotherapy and cisplatin-based chemoradiotherapy in stage II-IVa nasopharyngeal carcinoma (NPC) patients. Patients treated with cisplatin-based or nedaplatin-based chemoradiotherapy between January 2012 and December 2015 were evaluated. Survival was estimated by the Kaplan‒Meier method and compared by the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. A cohort of 538 NPC patients was enrolled. There were no significant differences in the 5-year overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), or distant metastasis-free survival (DMFS) between the cisplatin and nedaplatin groups. During the whole treatment course, patients in the cisplatin group had higher incidences of grade 3‒4 vomiting and anorexia, while patients in the nedaplatin group had higher incidences of grade 3‒4 leucopenia and mucositis. In terms of late toxicities, patients in the cisplatin group had a higher incidence of xerostomia. In multivariate analysis, T stage, N stage, and clinical stage were prognostic factors for OS, PFS, and DMFS. In subgroup analyses, nedaplatin-based chemotherapy achieved comparable treatment outcomes in specific populations stratified by age, sex, ECOG PS score and clinical stage. Cisplatin and nedaplatin are effective choices for stage II-IVa NPC patients, with a different spectrum of side effects.

Background: Pyrotinib, an irreversible pan-ERBB inhibitor, has shown promising antitumour activity, and acceptable tolerability. This research was conducted to evaluate the actual use and effectiveness of pyrotinib in China, therefore, contributed to solve the problem of real-world data scarcity. Methods: In this retrospective study, 168 patients who received pyrotinib treatment for HER2-positive metastatic breast cancer (MBC) in Hunan Province from June 2018 to August 2019 were included. Progression-free survival (PFS), tumor mutation burden (TMB), and drug-related adverse events (AEs) after pyrotinib administration were analyzed. Results: The median PFS (mPFS) time in the 168 participants was 8.07 months. The mPFS times in patients with pyrotinib in second-line therapy (n = 65) and third-or-higher-line therapy (n = 94) were 8.10 months and 7.60 months, respectively. Patients with brain metastases achieved 8.80 months mPFS time. In patients with pyrotinib in third-or-higher-line therapy, patients who had previously used lapatinib still got efficacy but showed a shorter mPFS time (6.43 months) than patients who had not (8.37 months). TMB was measured in 28 patients, K-M curve (P = 0.0024) and Multivariate Cox analysis (P = 0.0176) showed a significant negative association between TMB and PFS. Diarrhea occurred in 98.2% of participants (in any grade) and 19.6% in grade 3-4 AEs. Conclusion: Pyrotinib is highly beneficial to second-or-higher-line patients or HER2-positive MBC patients with brain metastases. Pyrotinib seems to be a feasible strategy both in combination of chemotherapeutic drugs or as a replacement of lapatinib if diseases progressed. TMB could be a potential predictor for evaluating pyrotinib's effectiveness in HER2-positive MBC.

Flap necrosis, the most prevalent postoperative complication of reconstructive surgery, is significantly associated with ischaemia-reperfusion injury. Recent research indicates that exosomes derived from bone marrow mesenchymal stem cells (BMSCs) hold potential therapeutic applications in several diseases. Traditionally, BMSCs are cultured under normoxic conditions, a setting that diverges from their physiological hypoxic environment in vivo. Consequently, we propose a method involving the hypoxic preconditioning of BMSCs, aimed at exploring the function and the specific mechanisms of their exosomes in ischaemia-reperfusion skin flaps. This study constructed a 3 × 6 cm2 caudal superficial epigastric skin flap model and subjected it to ischaemic conditions for 6 h. Our findings reveal that exosomes from hypoxia-pretreated BMSCs significantly promoted flap survival, decrease MCP-1, IL-1β, and IL-6 levels in ischaemia-reperfusion injured flap, and reduce oxidative stress injury and apoptosis. Moreover, results indicated that Hypo-Exo provides protection to vascular endothelial cells from ischaemia-reperfusion injury both in vivo and in vitro. Through high-throughput sequencing and bioinformatics analysis, we further compared the differential miRNA expression profiles between Hypo-Exo and normoxic exosomes. Results display the enrichment of several pathways, including autophagy and mTOR. We have also elucidated a mechanism wherein Hypo-Exo promotes the survival of ischaemia-reperfusion injured flaps. This mechanism involves carrying large amounts of miR-421-3p, which target and regulate mTOR, thereby upregulating the expression of phosphorylated ULK1 and FUNDC1, and subsequently further activating autophagy. In summary, hypoxic preconditioning constitutes an effective and promising method for optimizing the therapeutic effects of BMSC-derived exosomes in the treatment of flap ischaemia-reperfusion injury.

Mutations in the KEAP1-NFE2L2 signaling pathway were linked to increased tumorigenesis and aggressiveness. Interestingly, not all hotspot mutations on NFE2L2 were damaging; some even were activating. However, there was conflicting evidence about the association between NFE2L2 mutation and Nrf2-activating mutation and responsiveness to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and other multiple cancers.

In this study, we investigated the effects of antipsychotic drugs, olanzapine and haloperidol, on the density of the muscarinic M2 receptors in the dorsal vagal complex (DVC) and hypoglossal nucleus (HN). Female Sprague Dawley rats were treated with olanzapine, haloperidol or vehicle (control) for 1 (short-term) or 12 weeks (long-term). Quantitative autoradiography was used to investigate the M2 receptor density in the DVC and HN using a muscarinic antagonist [(3)H] AF-DX384. Olanzapine, but not haloperidol, treatment induced a significant decrease in the binding density of M2 receptors in the DVC compared to control groups. Although the HN showed a higher density of [(3)H] AF-DX384 binding than the DVC, treatment with both olanzapine and haloperidol did not induce any significant changes in [(3)H] AF-DX384 binding in the HN. These results suggest that olanzapine-induced body weight gain may be associated with functional changes in the muscarinic neurotransmission in the DVC.