-
Neuropsychopharmacology : Official... Jun 2023This study is the first randomized controlled trial to test the effects of ketamine in Borderline Personality Disorder (BPD). BPD remains undertreated in the community... (Randomized Controlled Trial)
Randomized Controlled Trial
This study is the first randomized controlled trial to test the effects of ketamine in Borderline Personality Disorder (BPD). BPD remains undertreated in the community and no medication has FDA approval for this indication. People with BPD experience chronic mood disturbances with depressed mood, suicidal ideation, and severe social difficulties. In this double-blind, randomized controlled pilot study, we tested the effects of one infusion of ketamine (0.5 mg/kg, n = 10) or the psychoactive comparator drug midazolam (0.04 mg/kg, n = 12) in adults with BPD. Infusions were well tolerated in both groups. Dissociative symptoms during infusion were more intense with ketamine than midazolam (t(12.3) = 3.61, p = 0.01), but they resolved by 40 min after infusion in both groups. Post-infusion adverse events were at the expected low levels in both groups. For our primary outcome measure of suicidal ideation and our secondary outcome measure of depression, we found numerical reduction but not significant group or group x timepoint difference (p > 0.05). For our secondary outcome measures of anxiety and BPD symptoms, we did not observe group or group x timepoint differences. There was a group x timepoint effect for socio-occupational functioning (F(1,20.12) = 5.16, p = 0.03, at Day 14, ketamine group showed more improvement than midazolam group). An exploratory analysis revealed that improvement in socio-occupational functioning was correlated with improvement in depression in the ketamine group (r(8) = 0.65, p = 0.04) but not midazolam group (r(9) = 0.41, p = 0.216). This pilot study provides the first randomized controlled evidence of the effects of antidepressant-dosed ketamine in people with BPD. Our results provide reason for optimism that antidepressant-dosed ketamine will be well-tolerated in larger studies and may provide clinical benefit for mood symptoms and related impairments in people with BPD.
Topics: Adult; Humans; Ketamine; Pilot Projects; Borderline Personality Disorder; Midazolam; Antidepressive Agents; Double-Blind Method
PubMed: 36804489
DOI: 10.1038/s41386-023-01540-4 -
Journal of Gastrointestinal Oncology Dec 2022This paper aims to explore the effects of plasminogen activator, urokinase (PLAU) expression on the migration, invasion, and proliferation of colorectal cancer (CRC)...
BACKGROUND
This paper aims to explore the effects of plasminogen activator, urokinase (PLAU) expression on the migration, invasion, and proliferation of colorectal cancer (CRC) cells and to preliminarily analyze its possible mechanism, thereby laying a foundation for the research on potential biological targets of CRC.
METHODS
CRC-related mRNA was screened in Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/gds/). Differentially expressed genes (DEGs) were obtained for functional enrichment analysis. The enriched pathway and key involved functional gene were screened for further and analysis CRC cells were transfected with PLAU-NC (negative control), PLAU-mimic, and PLAU-inhibitor for 48 h and divided into the above groups for later studies. The migration, invasion, and proliferation capacities of CRC cells were detected using wound healing, Transwell, and colony formation assays, respectively. The Src inhibitor saracatinib (AZD0530) was added to the PLAU-NC and PLAU-mimic groups, and the expression levels of Src/extracellular signal-regulated kinase (ERK) pathway-, migration-, invasion-, and proliferation-related proteins were detected by Western blotting.
RESULTS
The results showed that after upregulation of PLAU, the number of CRC cells (SW480) that migrated to the center of the wound significantly increased, the number of cells that migrated and invaded through the basement membrane increased in the PLAU-mimic group, and the number of colonies also increased. These results suggest that increasing PLAU expression promotes the migration, invasion, and proliferation of CRC cells. At the same time, the molecular mechanism of PLAU in CRC cells was investigated by downregulating the protein expression of Src combined with the results of the bioinformatics analysis. Western blotting revealed that the protein expressions of phosphorylated Src (p-Src) and phosphorylated ERK (p-ERK) in SW480 and SW620 cells increased significantly in the PLAU-mimic group compared with the PLAU-NC group, while the results were the opposite in the PLAU-inhibitor group. After being treated with saracatinib, we observed significantly decreased protein levels of p-ERK, matrix metallopeptidase 2 (MMP-2), MMP-3, MMP-9, Cyclin D1, and Cyclin A2 in the SW480 cells.
CONCLUSIONS
In conclusion, PLAU affects the migration, invasion, and proliferation of CRC cells by activating the Src/ERK pathway.
PubMed: 36636041
DOI: 10.21037/jgo-22-1215 -
Journal of Ethnopharmacology Apr 2023Jiawei Taohe Chengqi Decoction (JTCD) is a Traditional Chinese Medicine (TCM) formula modified from Taohe Chengqi Decoction in the classic ancient literature of TCM...
ETHNOPHARMACOLOGICAL RELEVANCE
Jiawei Taohe Chengqi Decoction (JTCD) is a Traditional Chinese Medicine (TCM) formula modified from Taohe Chengqi Decoction in the classic ancient literature of TCM "Treatise on Febrile Diseases". Clinical and pharmacological studies have shown that JTCD has a therapeutic effect on hepatic encephalopathy, non-alcoholic fatty liver, cirrhotic ascites, and can alleviate acute liver injury in rats. Our previous studies confirmed that JTCD could alleviate hepatic fibrosis and activation of hepatic stellate cells (HSCs). However, its mechanism remains unclear.
AIM OF THE STUDY
This study aimed to elucidate the mechanism of Src Signal on hepatic fibrosis and HSCs activation, and whether JTCD inhibited hepatic fibrosis and HSCs activation through affecting Src Signal.
MATERIALS AND METHODS
In vivo, sixty specific pathogen free male C57/BL6 mice were divided into following six groups: Control group, Model group, SARA group, JTCD low dose group, JTCD medium dose group and JTCD high dose group. Then we established a carbon tetrachloride (CCL)-induced hepatic fibrosis mice model, each JTCD group was given the corresponding dose of JTCD by gavage, the SARA group was given Saracatinib and the control group was given saline, once a day for 4 consecutive weeks. UPLC-Q-TOF-MS analyzed chemical components of JTCD. Pathological examination including Hematoxylin and Eosin (H&E), Masson and Sirius red staining was used to observe the characteristic of hepatic fibrosis. Automatic biochemical analyzer detected the levels of alanine aminotransfease (ALT), and aspartate transaminase (AST) in serum. Western-blot and immunohistochemical staining (IHC) detected protein expression. In vitro, we used shRNA to knock down the expression of Src in immortalized human hepatic stellate cell line (LX-2), then intervened with ERK1/2 agonists/inhibitors and JTCD-containing serum after transforming growth factor β1 (TGF-β1) treatment. Immunofluorescence and western-blot detected protein expression. The migratory characteristic of HSCs was assessed by wound-healing assay.
RESULTS
We identified 135 chemical components in the water extract of JTCD, and the water extract of JTCD contains a variety of anti-hepatic fibrosis components. Compared to the model group, hepatic fibrosis performance was significantly improved, the serum levels of ALT and AST were significantly decreased in JTCD groups and SARA group, IHC staining and western blot results indicated that JTCD decreased the expressions of α-smooth muscle actin (α-SMA), phospho-Src (Tyr416), phospho-ERK1/2 and phospho-Smad3. In vitro, JTCD-containing serum could significantly decrease the protein expressions of α-SMA, phospho-Src (Tyr416), phospho-ERK1/2 and phospho-Smad3 according to the results of western-blot and immunofluorescence, in addition, JTCD-containing serum inhibited the mobility and activation of LX-2. What's more, after intervening with Src-shRNA, ERK1/2 agonists/inhibitors and JTCD-containing serum, the western-blot results showed that Src/ERK/Smad3 signal has an important role in hepatic fibrosis and HSCs, and JTCD attenuates hepatic fibrosis by preventing activation of HSCs through regulating Src/ERK/Smad3 signal pathway.
CONCLUSIONS
The results showed that Src kinase promoted hepatic fibrosis and HSCs activation through the ERK/Smad3 signal pathway. More importantly, the mechanism by which JTCD attenuated hepatic fibrosis and HSCs activation was by inhibiting the Src/ERK/Smad3 signal pathway.
Topics: Animals; Humans; Male; Mice; Carbon Tetrachloride; Hepatic Stellate Cells; Liver; Liver Cirrhosis; MAP Kinase Signaling System; RNA, Small Interfering; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta1
PubMed: 36549368
DOI: 10.1016/j.jep.2022.116059 -
EBioMedicine Dec 2022Niemann-Pick disease type C (NPC) is a rare prematurely fatal lysosomal lipid storage disease with limited therapeutic options. The prominent neuropathological hallmarks...
BACKGROUND
Niemann-Pick disease type C (NPC) is a rare prematurely fatal lysosomal lipid storage disease with limited therapeutic options. The prominent neuropathological hallmarks include hypomyelination and cerebellar atrophy. We previously demonstrated the efficacy of recombinant human heat shock protein 70 (rhHSP70) in preclinical models of the disease. It reduced glycosphingolipid levels in the central nervous system (CNS), improving cerebellar myelination and improved behavioural phenotypes in Npc1 (Npc1) mice. Furthermore, treatment with arimoclomol, a well-characterised HSP amplifier, attenuated lysosomal storage in NPC patient fibroblasts and improved neurological symptoms in Npc1 mice. Taken together, these findings prompted the investigation of the effects of HSP amplification on CNS myelination.
METHODS
We administered bimoclomol daily or rhHSP70 6 times per week to Npc1 (BALB/cNctr-Npc1/J, also named Npc1) mice by intraperitoneal injection from P7 through P34 to investigate the impact on CNS myelination. The Src-kinase inhibitor saracatinib was administered with/without bimoclomol twice daily to explore the contribution of Fyn kinase to bimoclomol's effects.
FINDINGS
Treatment with either bimoclomol or rhHSP70 improved myelination and increased the numbers of mature oligodendrocytes (OLs) as well as the ratio of active-to-inactive forms of phosphorylated Fyn kinase in the cerebellum of Npc1 mice. Additionally, treatment with bimoclomol preserved cerebellar weight, an effect that was abrogated when co-administered with saracatinib, an inhibitor of Fyn kinase. Bimoclomol-treated mice also exhibited increased numbers of immature OLs within the cortex.
INTERPRETATION
These data increase our understanding of the mechanisms by which HSP70 regulates myelination and provide further support for the clinical development of HSP-amplifying therapies in the treatment of NPC.
FUNDING
Funding for this study was provided by Orphazyme A/S (Copenhagen, Denmark) and a Pathfinder Award from The Wellcome Trust.
Topics: Animals; Humans; Mice; Cerebellum; Disease Models, Animal; Heat-Shock Proteins; Mice, Inbred BALB C; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Pyridines; HSP70 Heat-Shock Proteins; Nerve Fibers, Myelinated; Myelin Sheath
PubMed: 36455410
DOI: 10.1016/j.ebiom.2022.104374 -
Discover Oncology Dec 2022Bladder cancer (BCa) is one of the most common malignant tumors in the urogenital system, characterized by the high recurrence rate, mortality rate and poor prognosis....
PURPOSE
Bladder cancer (BCa) is one of the most common malignant tumors in the urogenital system, characterized by the high recurrence rate, mortality rate and poor prognosis. Based on cuproptosis-related long noncoding RNAs (CRLs), this study set out to create a prediction signature to evaluate the prognosis of patients with BCa.
METHODS
RNA-seq data including CRLs and related clinicopathological data were gathered from The Cancer Genome Atlas (TCGA) database (n = 428). The predictive signature was constructed after correlation analysis. Subsequently, relying on the analyzed data from the TCGA database and our sample collection, we examined and verified the connections between CRLs model and important indexes included prognosis, route and functional enrichment, tumor immune evasion, tumor mutation, and treatment sensitivity.
RESULTS
Patients in the high-risk group had lower overall survival (OS) than that of low-risk group. Compared with clinicopathological variables, CRLs features have better predictive value according to receiver operating characteristic (ROC) curve. The expression level of CRLs was highly associated with the tumor progress, tumor microenvironment and tumor immune escape. Additionally, we identified that the mutation of TP53, TTN, KMT2D and MUC16 gene were founded in patients with BCa. Lapatinib, pazopanib, saracatinib, gemcitabine, paclitaxel and palenolactone had good antitumor effects for BCa patients in the high-risk group (all P < 0.001).
CONCLUSION
This study revealed the effects of CRLs on BCa and further established CRLs model, which can be used in clinic for predicting prognosis, immunological response and treatment sensitivity inpatient with BCa.
PubMed: 36454396
DOI: 10.1007/s12672-022-00596-w -
The Medical Clinics of North America Jan 2023Post-traumatic stress disorder (PTSD) is characterized by symptoms of re-experiencing, avoidance, negative alterations in cognition and mood, and marked alterations in... (Review)
Review
Post-traumatic stress disorder (PTSD) is characterized by symptoms of re-experiencing, avoidance, negative alterations in cognition and mood, and marked alterations in arousal and reactivity following exposure to a traumatic event. PTSD can be assessed by structured interviews and screening measures in psychiatric and nonpsychiatric settings. Evidence-based psychotherapies are the first-line treatment of PTSD, with cognitive behavioral therapies, such as prolonged exposure, cognitive processing therapy, and eye movement desensitization and reprocessing having the largest body and highest quality of evidence. Serotonin reuptake inhibitors are the first-line pharmacologic treatments for PTSD and are often used in conjunction with other therapeutic interventions.
Topics: Humans; Stress Disorders, Post-Traumatic; Cognitive Behavioral Therapy; Cognition
PubMed: 36402502
DOI: 10.1016/j.mcna.2022.04.003 -
Cells Nov 2022The communication between calcitonin gene-related peptide (CGRP) and cytokines plays a prominent role in maintaining trigeminal ganglion (TG) and trigeminovascular...
The communication between calcitonin gene-related peptide (CGRP) and cytokines plays a prominent role in maintaining trigeminal ganglion (TG) and trigeminovascular sensitization. However, the underlying regulatory mechanism is elusive. In this study, we explored the hypothesis that Src family kinases (SFKs) activity facilitates the crosstalk between CGRP and cytokines in sensitizing TG. Mouse TG tissue culture was performed to study CGRP release by enzyme-linked immunosorbent assay, cytokine release by multiplex assay, cytokine gene expression by quantitative polymerase chain reaction, and phosphorylated SFKs level by western blot. The results demonstrated that a SFKs activator, pYEEI (YGRKKRRQRRREPQY(PO3H2)EEIPIYL) alone, did not alter CGRP release or the inflammatory cytokine interleukin-1β (IL-1β) gene expression in the mouse TG. In contrast, a SFKs inhibitor, saracatinib, restored CGRP release, the inflammatory cytokines IL-1β, C-X-C motif ligand 1, C-C motif ligand 2 (CCL2) release, and IL-1β, CCL2 gene expression when the mouse TG was pre-sensitized with hydrogen peroxide and CGRP respectively. Consistently with this, the phosphorylated SFKs level was increased by both hydrogen peroxide and CGRP in the mouse TG, which was reduced by a CGRP receptor inhibitor BIBN4096 and a protein kinase A (PKA) inhibitor PKI (14-22) Amide. The present study demonstrates that SFKs activity plays a pivotal role in facilitating the crosstalk between CGRP and cytokines by transmitting CGRP receptor/PKA signaling to potentiate TG sensitization and ultimately trigeminovascular sensitization.
Topics: Rats; Mice; Animals; Receptors, Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide; Trigeminal Ganglion; Cytokines; src-Family Kinases; Hydrogen Peroxide; Ligands; Neurons; Rats, Sprague-Dawley
PubMed: 36359895
DOI: 10.3390/cells11213498 -
Frontiers in Pharmacology 2022Gastric cancer is one of the most important malignancies with poor prognosis. Ferroptosis and cuproptosis are newly discovered metal-dependent types of programmed cell...
Gastric cancer is one of the most important malignancies with poor prognosis. Ferroptosis and cuproptosis are newly discovered metal-dependent types of programmed cell death, which may directly affect the outcome of gastric cancer. Long noncoding RNAs (lncRNAs) can affect the prognosis of cancer with stable structures, which could be potential prognostic prediction factors for gastric cancer. Differentially expressed metal-dependent programmed cell death (PCD)-related lncRNAs were identified with DESeq2 and 's correlation analysis. Through GO and KEGG analyses and GSEA , we identified the potential effects of metal-dependent PCD-related lncRNAs on prognosis. Using Cox regression analysis with the LASSO method, we constructed a 12-lncRNA prognostic signature model. Also, we evaluated the prognostic efficiency with Kaplan-Meier (K-M) survival curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) methods. The sensitivities for antitumor drugs were then predicted with the pRRophetic method. Also, we discuss Chinese patent medicines and plant extracts that could induce metal-dependent programmed cell death. We constructed a metal-dependent PCD-related lncRNA-gene co-expression network. Also, a metal-dependent PCD-related gastric cancer prognostic signature model including 12 lncRNAs was constructed. The K-M survival curve revealed a poor prognosis in the high-risk group. ROC curve analysis shows that the AUC of our model is 0.766, which is better than that of other published models. Moreover, the half-maximum inhibitory concentration (IC50) for dasatinib, lapatinib, sunitinib, cytarabine, saracatinib, and vinorelbine was much lower among the high-risk group. Our 12 metal-dependent PCD-related lncRNA prognostic signature model may improve the OS prediction for gastric cancer. The antitumor drug sensitivity analysis results may also be helpful for individualized chemotherapy regimen design.
PubMed: 36339625
DOI: 10.3389/fphar.2022.1039499 -
Current Pharmaceutical Design 2022Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. The symptoms of PD are characterized not only by motor alterations but also by a... (Review)
Review
BACKGROUND
Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. The symptoms of PD are characterized not only by motor alterations but also by a spectrum of nonmotor symptoms. Some of these are psychiatric manifestations such as sleep disorders; depression; cognitive difficulties that can evolve into dementia; and symptoms of psychosis, which include hallucinations, illusions, and delusions. Parkinson's disease psychosis (PDP) occurs in 18-50% of patients with PD. Treating PDP is challenging because antipsychotic drugs tend to be inefficient or may even worsen the disease's motor symptoms.
OBJECTIVE
This review aims to summarize the current understanding of the molecular mechanisms involved in PDP and recent innovative alternatives for its treatment.
METHODS
This is a narrative review in which an extensive literature search was performed on the Scopus, EMBASE, PubMed, ISI Web of Science, and Google Scholar databases from inception to August 2021. The terms "Parkinson's disease psychosis", "Parkinson psychosis," "neurodegenerative psychosis", and "dopamine psychosis" were among the keywords used in the search.
RESULTS
Recently, views on the etiology of hallucinations and illusions have evolved remarkably. PDP has been cemented as a multifactorial entity dependent on extrinsic and novel intrinsic mechanisms, including genetic factors, neurostructural alterations, functional disruptions, visual processing disturbances, and sleep disorders. Consequently, innovative pharmacological and biological treatments have been proposed. Pimavanserin, a selective 5-HT2A inverse agonist, stands out after its approval to treat PDP-associated hallucinations and illusions.
CONCLUSION
Future results from upcoming clinical trials should further characterize the role of this drug in the management of PDP as well as other treatment options with novel mechanisms of action, such as saracatinib, SEP-363856, cannabidiol, electroconvulsive therapy, and transcranial magnetic stimulation.
Topics: Humans; Parkinson Disease; Dopamine; Illusions; Psychotic Disorders; Hallucinations; Antipsychotic Agents; Urea; Sleep Wake Disorders
PubMed: 36321314
DOI: 10.2174/1381612828666220428102802 -
Biological Psychiatry Feb 2023The presentation, etiology, and relative risk of psychiatric disorders are strongly influenced by biological sex. Neuroticism is a transdiagnostic feature of psychiatric...
BACKGROUND
The presentation, etiology, and relative risk of psychiatric disorders are strongly influenced by biological sex. Neuroticism is a transdiagnostic feature of psychiatric disorders displaying prominent sex differences. We performed genome-wide association studies of neuroticism separately in males and females to identify sex-specific genetic and transcriptomic profiles.
METHODS
Neuroticism scores were derived from the Eysenck Personality Inventory Neuroticism scale. Genome-wide association studies were performed in 145,669 females and 129,229 males from the UK Biobank considering autosomal and X chromosomal variation. Two-sided z tests were used to test for sex-specific effects of discovered loci, genetic correlates (n = 673 traits), tissue and gene transcriptomic profiles, and polygenic associations across health outcomes in the Vanderbilt University Biobank (39,692 females and 31,268 males).
RESULTS
The single nucleotide polymorphism heritability of neuroticism was not statistically different between males (h = 10.6%) and females (h = 11.85%). Four female-specific (rs10736549-CNTN5, rs6507056-ASXL3, rs2087182-MMS22L, and rs72995548-HSPB2) and 2 male-specific (rs10507274-MED13L and rs7984597) neuroticism risk loci reached genome-wide significance. Male- and female-specific neuroticism polygenic scores were most significantly associated with mood disorders (males: odds ratio = 1.11, p = 1.40 × 10; females: odds ratio = 1.14, p = 6.05 × 10). They also associated with sex-specific laboratory measurements related to erythrocyte count, distribution, and hemoglobin concentration. Gene expression variation in the pituitary was enriched for neuroticism loci in males (male: b = 0.026, p = .002), and genetically regulated transcriptomic changes highlighted the effect of SHISHA9, TEX26, and NCOA6.
CONCLUSIONS
Through a comprehensive assessment of genetic risk for neuroticism and the associated biological processes, this study identified several molecular pathways that can partially explain the known sex differences in neurotic symptoms and their psychiatric comorbidities.
Topics: Female; Humans; Male; Genetic Predisposition to Disease; Genome-Wide Association Study; HSP27 Heat-Shock Proteins; Mental Disorders; Neuroticism; Phenotype; Polymorphism, Single Nucleotide; Transcription Factors; Transcriptome
PubMed: 36244801
DOI: 10.1016/j.biopsych.2022.07.019