The ion channel TRPA1 is a modulator of the cocaine reward circuit in the nucleus accumbens.

Drug addiction therapies commonly fail because continued drug use promotes the release of excessive and pleasurable dopamine levels. Because the connection between pleasure and drug use becomes hard-wired in the nucleus accumbens (NAc), which interfaces motivation, effective therapies need to modulate this mesolimbic reward system. Here, we report that mice with knockdown of the cation channel TRPA1 (transient receptor potential ankyrin 1) were resistant to the drug-seeking behavior and reward effects of cocaine compared to their wildtype litter mates. In our study, we demonstrate that TRPA1 inhibition in the NAc reduces cocaine activity and dopamine release, and conversely, that TRPA1 is critical for cocaine-induced synaptic strength in dopamine receptor 1-expressing medium spiny neurons. Taken together, our data support that cocaine-induced reward-related behavior and synaptic release of dopamine in the NAc are controlled by TRPA1 and suggest that TRPA1 has therapeutic potential as a target for drug misuse therapies.

Gba1 E326K renders motor and non-motor symptoms with pathologic α-syn, tau and glial activation.

Mutations in the GBA1 gene are common genetic risk factors for Parkinson's disease (PD), disrupting enzymatic activity and causing lysosomal dysfunction, leading to elevated α-synuclein (α-syn) levels. While GBA1's role in synucleinopathy is well-established, recent research underscores neuroinflammation as a significant pathogenic mechanism in GBA1 deficiency. This study investigates neuroinflammation in Gba1 E326K knock-in mice, a model associated with increased PD and dementia risk. At 9 and 24 months, we assessed GBA1 protein and activity, α-synuclein pathology, neurodegeneration, motor deficits, and gliosis in the ventral midbrain and hippocampus using immunohistochemistry (IHC), Western blot (WB), and GCase assays. Additionally, primary microglia from WT and GBA1E326K/E326K mice were treated with α-syn preformed fibrils (PFF) to study microglia activation, pro-inflammatory cytokines, reactive astrocyte formation, and neuronal death through qPCR, WB, and immunocytochemistry analyses. We also evaluated the effects of gut inoculation of α-syn PFF in Gba1 E326K mice at 7 months and striatal inoculation at 10 months, assessing motor/non-motor symptoms, α-syn pathology, neuroinflammation, gliosis, and neurodegeneration via behavioural tests, IHC, and WB assays. At 24 months, Gba1 E326K knock-in mice showed reduced GCase enzymatic activity and glucosylceramide build-up in the ventral midbrain and hippocampus. Increased pro-inflammatory cytokines and reactive astrocytes were observed in microglia and astrocytes from Gba1 E326K mice treated with pathologic α-syn PFF. Gut inoculation of α-syn PFF increased Lewy body accumulation in the hippocampal dentate gyrus, with heightened microglia and astrocyte activation and worsened non-motor symptoms. Intrastriatal α-syn preformed fibril injection induced motor deficits, reactive glial protein accumulation, and tauopathy in the prefrontal cortex and hippocampus of Gba1 E326K mice. GBA1 deficiency due to the Gba1 E326K mutation exacerbates neuroinflammation and promotes pathogenic α-synuclein transmission, intensifying disease pathology in PD models. This study enhances our understanding of how the Gba1 E326K mutation contributes to neuroinflammation and the spread of pathogenic α-syn in the brain, suggesting new therapeutic strategies for PD and related synucleinopathies.

Advances in targeted therapy for pulmonary arterial hypertension in children.

Pulmonary arterial hypertension (PAH) is a rare and devastating disease of the pulmonary vasculature with a high morbidity and mortality rate in infants and children. Currently, treatment approaches are mostly based on adult guidelines and pediatrician clinical experience, focusing on specific pulmonary antihypertensive therapy and conventional supportive care. The advent of targeted drugs has led to significant advances in the treatment of PAH in children, including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins, which have been studied and proven to improve hemodynamics and functional class in children PAH. A new targeted drug, riociguat, is assessing its safety and efficacy in clinical trials. However, more randomized controlled studies are needed to evaluate the combination of drugs, treatment strategies, and clinical endpoints of targeted therapy in children PAH. In this review, we summarize the research advances of PAH-targeted therapy in children over the last decade in order to provide a theoretical basis for future studies. CONCLUSION: Pulmonary arterial hypertension (PAH) is a rare and devastating pulmonary vascular disease that is associated with a variety of diseases of any age in childhood onset. WHAT IS KNOWN: • Therapeutic strategies for targeted drugs for PAH in children are based almost exclusively on data from adult studies and clinical experience of pediatric specialists. • Due to the complex etiology of PAH in children and the relative lack of clinical trial data, the selection of appropriate targeted drug therapy remains difficult. WHAT IS NEW: • We redefine the definition of pulmonary arterial hypertension in children and summarize the progress of targeted therapy of pulmonary arterial hypertension in children in the past ten years. • The dosage and adverse reactions were summarized, and the mechanism of action was drawn according to the available targeted drugs. It can provide theoretical support for the development of guidelines and treatment strategies for the diagnosis and treatment of pulmonary arterial hypertension in children.

Complement and Coagulation Cascades are Potentially Involved in Dopaminergic Neurodegeneration in α-Synuclein-Based Mouse Models of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder that results in motor dysfunction and, eventually, cognitive impairment. α-Synuclein protein is known as a central protein to the pathophysiology of PD, but the underlying pathological mechanism still remains to be elucidated. In an effort to understand how α-synuclein underlies the pathology of PD, various PD mouse models with α-synuclein overexpression have been developed. However, systemic analysis of the brain proteome of those mouse models is lacking. In this study, we established two mouse models of PD by injecting α-synuclein preformed fibrils (PFF) or by inducing overexpression of human A53T α-synuclein to investigate common pathways in the two different types of the PD mouse models. For more accurate quantification of mouse brain proteome, the proteins were quantified using the method of stable isotope labeling with amino acids in mammals . We identified a total of 8355 proteins from the two mouse models; ∼6800 and ∼7200 proteins from α-synuclein PFF-injected mice and human A53T α-synuclein transgenic mice, respectively. Through pathway analysis of the differentially expressed proteins common to both PD mouse models, it was discovered that the complement and coagulation cascade pathways were enriched in the PD mice compared to control animals. Notably, a validation study demonstrated that complement component 3 (C3)-positive astrocytes were increased in the ventral midbrain of the intrastriatal α-synuclein PFF-injected mice and C3 secreted from astrocytes could induce the degeneration of dopaminergic neurons. This is the first study that highlights the significance of the complement and coagulation pathways in the pathogenesis of PD through proteome analyses with two sophisticated mouse models of PD.

New designer phenethylamines 2C-C and 2C-P have abuse potential and induce neurotoxicity in rodents.

2C (2C-x) is the general name for the family of phenethylamines containing two methoxy groups at the 2 and 5 positions of the benzene ring. The abuse of 2C family drugs has grown rapidly, although the abuse potential and neurotoxic properties of 2C drugs have not yet been fully investigated. In this study, we investigated the abuse potential and neurotoxicity of 4-chloro-2,5-dimethoxyphenethylamine (2C-C) and 2,5-dimethoxy-4-propylphenethylamine (2C-P). We found that 2C-C and 2C-P produced conditioned place preference in a dose-dependent manner in mice, and increased self-administration in rats, suggesting that 2C-C and 2C-P have abuse potential. To investigate the neurotoxicity of 2C-C and 2C-P, we examined motor performance and memory impairment after high doses of 2C-C and 2C-P. High doses of 2C-C and 2C-P decreased locomotor activity, rota-rod performance, and lower Y-maze test, novel objective recognition test, and passive avoidance test scores. We also observed that 2C-C and 2C-P affected expression levels of the D1 dopamine receptor, D2 dopamine receptor, dopamine transporter, and phospho-dopamine transporter in the nucleus accumbens and the medial prefrontal cortex, and increased c-Fos immuno-positive cells in the nucleus accumbens. Moreover, high doses of 2C-C and 2C-P induced microglial activation, which is involved in the inflammatory reaction in the striatum. These results suggest that 2C-C and 2C-P have abuse potential by affecting dopaminergic signaling and induce neurotoxicity via initiating neuroinflammation at high doses.

25C-NBF, a new psychoactive substance, has addictive and neurotoxic potential in rodents.

The use of new psychoactive substances (NPSs) as a substitute for illegal drugs is increasing rapidly and is a serious threat to public health. 25C-NBF is a newly synthesized phenethylamine-type NPS that acts as a 5-hydroxyindoleacetic acid (5-HT) receptor agonist, but little is known about its pharmacological effects. Considering that NPSs have caused unexpected harmful effects leading to emergency and even death, scientific confirmation of the potential adverse effects of 25C-NBF is essential. In the present study, we investigated whether 25C-NBF has addictive and neurotoxic potential and causes neurochemical changes. In addictive potential assessments, high conditioned place preference (CPP) scores and stable self-administration (SA) were observed in the 25C-NBF groups (CPP [3 mg kg-1]; SA [0.01, 0.03, 0.1 mg kg-1]), suggesting the addictive liability of 25C-NBF. In neurotoxic potential assessments, 25C-NBF treatment (single super-high dose [1 × 15, 30, 40 mg kg-1]; repeated high dose [4 × 8, 15, 30 mg kg-1]) resulted in reduced motor activity (open field test), abnormal motor coordination (rota-rod test) and impaired recognition memory (novel object recognition test), suggesting that 25C-NBF is neurotoxic leading to motor impairment and memory deficits. Subsequently, immunohistochemistry showed that 25C-NBF treatment decreased tyrosine hydroxylase (TH) expression and increased ionized calcium-binding adapter molecule 1 (Iba-1) expression in the striatum. Taken together, our results clearly demonstrate the dangers of recreational use of 25C-NBF, and we suggest that people stop using 25C-NBF and other NPSs whose pharmacological effects are not precisely known.

The new designer drug buphedrone produces rewarding properties via dopamine D1 receptor activation.

Substituted cathinones are synthetic analogs of the active components of natural products and are widely abused worldwide. However, the rewarding properties of these agents have not yet been evaluated. In this study, we investigated the abuse potential of buphedrone [2-(methylamino)-1-phenylbutan-1-one, α-methylamino-butyrophenone] and its effects on the mesolimbic dopaminergic system in mice using conditioned place preference (CPP) analysis, a self-administration test, a locomotor activity test, a behavioral sensitization test and Western blot analysis. Treatment with buphedrone supported CPP and self-administration, enhanced locomotor activity and produced behavioral sensitization when mice were challenged with methamphetamine. SCH23390, a D1 dopamine antagonist, prevented buphedrone-induced CPP, whereas raclopride, a D2 dopamine antagonist, had no effect. SCH23390 also blocked locomotor activity increase by buphedrone, while raclopride partially attenuated locomotor activation. Western blot analysis revealed that repeated buphedrone treatment increased D1 dopamine receptor expression in the dorsal striatum and nucleus accumbens in mice. Collectively, these findings suggest the abuse potential of buphedrone and demonstrate the involvement of the dopaminergic system in the establishment of its rewarding properties.

Let7b modulates the Wnt/ß-catenin pathway in liver cancer cells via downregulated Frizzled4.

Let7 microRNA implicated in many cellular processes and participated in the progress of various tumors. Similarly, Wnt signaling pathway plays an important role in morphogenesis, differentiation, cell survival, and proliferation. However, there is little research focusing on the relevance between Let7b and Wnt/ß-catenin signaling pathway, especially in liver cancer cell. To study this, human liver cancer cells HUH7 and MHCC97H were cultured, enhanced, or inhibited the expression of Let7b in two cell lines. Western blotting was used to measure the expression of Wnt signaling-related protein ß-catenin and Frizzled family receptor. CD24+133+ was used as a cancer stem cell marker, and the proportion of CD24+133+ in liver cancer cell lines was observed by flow cytometry. The proliferation, invasiveness, and migration of liver cancer cells were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, transwell, and wound healing assays. The research revealed that enhanced expression of Let7b decreased the expression of Frizzled4, while inhibited Let7b expression increased Frizzled4 expression. Enhanced Let7b expression reduced the proportion of cancer stem cell in liver cancer cell; meanwhile, Let7b inhibition increased the proportion of cancer stem cell. Upregulated Let7b expression repressed the proliferation, invasion, and migration of liver cancer cell. This study showed that Let7b modulates the proliferation, invasiveness, and migration of liver cancer cell and reduces the proportion of cancer stem cells in liver cancer cell by inhibiting Wnt/ß-catenin signaling pathway via downregulated Frizzled4.

Clinicopathological significance of c-MYC in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma is one of the most common malignant tumors. The oncogene c-MYC is thought to be important in the initiation, promotion, and therapy resistance of cancer. In this study, we aim to investigate the clinicopathologic roles of c-MYC in esophageal squamous cell carcinoma tissue. This study is aimed at discovering and analyzing c-MYC expression in a series of human esophageal tissues. A total of 95 esophageal squamous cell carcinoma samples were analyzed by the western blotting and immunohistochemistry techniques. Then, correlation of c-MYC expression with clinicopathological features of esophageal squamous cell carcinoma patients was statistically analyzed. In most esophageal squamous cell carcinoma cases, the c-MYC expression was positive in tumor tissues. The positive rate of c-MYC expression in tumor tissues was 61.05%, obviously higher than the adjacent normal tissues (8.42%, 8/92) and atypical hyperplasia tissues (19.75%, 16/95). There was a statistical difference among adjacent normal tissues, atypical hyperplasia tissues, and tumor tissues. Overexpression of the c-MYC was detected in 61.05% (58/95) esophageal squamous cell carcinomas, which was significantly correlated with the degree of differentiation (p = 0.004). The positive rate of c-MYC expression was 40.0% in well-differentiated esophageal tissues, with a significantly statistical difference (p = 0.004). The positive rate of c-MYC was 41.5% in T1 + T2 esophageal tissues and 74.1% in T3 + T4 esophageal tissues, with a significantly statistical difference (p = 0.001). The positive rate of c-MYC was 45.0% in I + II esophageal tissues and 72.2% in III + IV esophageal tissues, with a significantly statistical difference (p = 0.011). The c-MYC expression strongly correlated with clinical staging (p = 0.011), differentiation degree (p = 0.004), lymph node metastasis (p = 0.003), and invasion depth (p = 0.001) of patients with esophageal squamous cell carcinoma. The c-MYC was differentially expressed in a series of human esophageal tissues, and the aberrant c-MYC expression could be a potential factor in carcinogenesis and progression of esophageal squamous cell carcinoma. There was a statistical signification for c-MYC in esophageal squamous cell carcinoma patients to analyze clinicopathological features. It possibly becomes a new diagnostic indicator of esophageal squamous cell carcinoma.

Impairment of opiate-mediated behaviors by the selective TRPV1 antagonist SB366791.

Transient receptor potential vanilloid type 1 (TRPV1), the archetypal member of the vanilloid TRP family, was initially identified as the receptor for capsaicin, the pungent ingredient in hot chili peppers. We previously demonstrated that TRPV1 in the dorsal striatum significantly contributes to morphine reward by using the conditioned place preference paradigm in mice; however, it is unknown whether TRPV1 has the same effect in other reward models. In this study, we investigated the role of TRPV1 in morphine reward by using a self-administration paradigm in rats. We found that treatment with a selective TRPV1 antagonist, SB366791, significantly decreased morphine self-administration on a fixed-ratio 1 schedule or a progressive ratio schedule of reinforcement. In addition, treatment with another selective TRPV1 antagonist, AMG9810, not only significantly prevented morphine self-administration but also prevented morphine-induced c-fos expression in the nucleus accumbens. Furthermore, administration of SB366791 decreased an anxiolytic-like effect during the morphine abstinence period. Moreover, treatment with SB366791 significantly decreased morphine-priming reinstatement. Taken together, our findings suggest that blockade of TRPV1 receptors could provide an approach to limiting morphine addiction.

The new stimulant designer compound pentedrone exhibits rewarding properties and affects dopaminergic activity.

Cathinone derivatives are new recreational drugs known to produce psychostimulant effects. However, unlike other psychostimulants, the addictive potential of cathinone derivatives has not been widely studied. Here, we investigated the effects of pentedrone, a type of cathinone derivative, on the dopaminergic system using reverse transcription polymerase chain reaction and Western blot. We also evaluated the addictive potential of pentedrone using conditioned place preference and self-administration. We found that pentedrone increased the mRNA expression of dopamine 1 receptor, dopamine 2 receptor and dopamine transporter, as well as induced phosphorylation of cAMP response element-binding protein in PC-12 cells. Additionally, pentedrone at 3 and 10 mg/kg significantly increased conditioned place preference in mice, while pentedrone at 0.3 mg/kg/infusion significantly increased self-administration in rats. Finally, we found that acute administration of pentedrone enhanced locomotor activity in a dose-dependent manner. Collectively, these data suggest that the addictive properties of pentedrone may be due to its effects on the dopaminergic system.

Quercetin inhibited cadmium-induced autophagy in the mouse kidney via inhibition of oxidative stress.

The objective of the current study was to explore the inhibitory effects of quercetin on cadmium-induced autophagy in mouse kidneys. Mice were intraperitoneally injected with cadmium and quercetin once daily for 3 days. The LC3-II/ß-actin ratio was used as the autophagy marker, and autophagy was observed by transmission electron microscopy. Oxidative stress was investigated in terms of reactive oxygen species, total antioxidant capacity, and malondialdehyde. Cadmium significantly induced typical autophagosome formation, increased the LC3-II/ß-actin ratio, reactive oxygen species level, and malondialdehyde content, and decreased total antioxidant capacity. Interestingly, quercetin markedly decreased the cadmium-induced LC3-II/ß-actin ratio, reactive oxygen species levels, and malondialdehyde content, and simultaneously increased total antioxidant capacity. Cadmium can inhibit total antioxidant capacity, produce a large amount of reactive oxygen species, lead to oxidative stress, and promote lipid peroxidation, eventually inducing autophagy in mouse kidneys. Quercetin could inhibit cadmium-induced autophagy via inhibition of oxidative stress. This study may provide a theoretical basis for the treatment of cadmium injury.

[Effect of colon cancer cell-derived IL-1α on the migration and proliferation of vascular endothelial cells].

OBJECTIVE: To explore the effect of colon cancer cell-derived interleukin-1α on the migration and proliferation of human umbilical vein endothelial cells as well as the role of IL-1α and IL-1ra in the angiogenesis process. METHODS: Western blot was used to detect the expression of IL-1α and IL-1R1 protein in the colon cancer cell lines with different liver metastatic potential. We also examined how IL-1α and IL-1ra influence the proliferation and migration of umbilical vascular endothelial cells assessed by PreMix WST-1 assay and migration assay, respectively. Double layer culture technique was used to detect the effect of IL-1α on the proliferation and migration of vascular endothelial cells and the effect of IL-1ra on the vascular endothelial cells. RESULTS: Western blot analysis showed that IL-1α protein was only detected in highly metastatic colon cancer HT-29 and WiDr cells, but not in the lowly metastatic CaCo-2 and CoLo320 cells.Migration assay showed that there were significant differences in the number of penetrated cells between the control (17.9±3.6) and 1 ng/ml rIL-1α group (23.2±4.2), 10 ng/ml rIL-1α group (31.7±4.5), and 100 ng/ml rIL-1α group (38.6±4.9), showing that it was positively correlated with the increasing concentration of rIL-1α (P<0.01 for all). The proliferation assay showed that the absorbance values were 1.37±0.18 in the control group, and 1.79±0.14 in the 1 ng/ml rIL-1α group, 2.14±0.17 in the 10 ng/ml rIL-1α group, and 2.21±0.23 in the 100 ng/ml rIL-1α group, showing a positive correlation with the increasing concentration of rIL-1α(P<0.01 for all). IL-1ra significantly inhibited the proliferation and migration of vascular endothelial cells (P<0.01). The levels of VEGF protein were (1.697±0.072) ng/ml, (3.507±0.064)ng/ml and (4.139±0.039)ng/ml in the control, HUVECs+ IL-1α and HUVECs+ HT-29 co-culture system groups, respectively, showing a significant difference between the control and HUVECs+ 10 pg/ml rIL-1α groups and between the control and HUVECs+ HT-29 groups (P<0.01 for both). CONCLUSIONS: Our findings indicate that colon cancer cell-derived IL-1α plays an important role in the liver metastasis of colon cancer through increased VEGF level of the colon cancer cells and enhanced vascular endothelial cells proliferation, migration and angiogenesis, while IL-1ra can suppress the effect of IL-1α and inhibit the angiogenesis in colon cancer.

Comprehensive analysis of the effects of the cuprotosis-associated gene SLC31A1 on patient prognosis and tumor microenvironment in human cancer.

Background: Solute carrier family 31 (copper transporter), member 1 (SLC31A1) is a key factor in maintaining intracellular copper concentration and an important factor affecting cancer energy metabolism. Therefore, exploring the potential biological function and value of SLC31A1 could provide a new direction for the targeted therapy of tumors. Methods: This study assessed gene expression levels, survival, clinicopathology, gene mutations, methylation levels, the tumor mutational burden (TMB), microsatellite instability (MSI), and the immune cell infiltration of SLC31A1 in pan-cancer using the Tumor Immune Estimation Resource 2.0 (TIMER2.0), Gene Expression Profiling Interactive Analysis (GEPIA), University of Alabama at Birmingham CANcer (UALCAN) data analysis portal, and cBioPortal databases. To further understand the potential biological mechanisms of SLC31A1 in different cancers, single-cell level sequencing and a Gene Ontology/Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) enrichment analysis of SLC31A1 were also performed. Finally, real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) were used to validate the expression of SLC31A1 in cancers, such as gastric cancer. Results: SLC31A1 was expressed in most cancer tissues. In kidney renal clear cell carcinoma (KIRC), the high expression of SLC31A1 was associated with good overall survival (OS), while in adrenocortical carcinoma (ACC), breast invasive carcinoma (BRCA), lower grade glioma (LGG), mesothelioma (MESO), and skin cutaneous melanoma (SKCM), the low expression of SLC31A1 was associated with good OS. The highest frequency of SLC31A1 amplification was observed in ACC. In addition, missense mutations accounted for a major portion of the mutation types. The truncation mutation S105Y may be a putative cancer driver. SLC31A1 affected methylation levels in cancer and was associated with the TMB, MSI, and the level of infiltration of various immune cells. Additionally, the single-cell sequencing results showed that SLC31A1 was associated with multiple biological functions in cancer. Finally, the SLC31A1 enrichment analysis revealed that the SLC31A1-related genes were mainly enriched in the mitochondrial matrix and envelope vesicles. The RT-qPCR and WB results were consistent with the predicted results. Conclusions: SLC31A1 may be a potential target related to cancer energy metabolism and may have prognostic value.

Experience sharing on perioperative clinical management of gastric cancer patients based on the "China Robotic Gastric Cancer Surgery Guidelines".

BACKGROUND: With the popularization of robotic surgical systems in the field of surgery, robotic gastric cancer surgery has also been fully applied and promoted in China. The Chinese Guidelines for Robotic Gastric Cancer Surgery was published in the Chinese Journal of General Surgery in August 2021. METHODS: We have made a detailed interpretation of the process of robotic gastric cancer surgery regarding the indications, contraindications, perioperative preparation, surgical steps, complication, and postoperative management based on the recommendations of China's Guidelines for Robotic Gastric Cancer Surgery and supplemented by other surgical guidelines, consensus, and single-center experience. RESULTS: Twenty experiences of perioperative clinical management of robotic gastric cancer surgery were described in detail. CONCLUSION: We hope to bring some clinical reference values to the front-line clinicians in treating robotic gastric cancer surgery. TRIAL REGISTRATION: The guidelines were registered on the International Practice Guideline Registration Platform ( http://www.guidelines-registry.cn ) (registration number: IPGRP-2020CN199).

Systemic inflammatory response index is a predictor of prognosis in gastric cancer patients: Retrospective cohort and meta-analysis.

BACKGROUND: The systemic inflammatory response index (SIRI) has been demonstrated to make a significant difference in assessing the prognosis of patients with different solid neoplasms. However, research is needed to ascertain the accuracy and reliability of applying the SIRI to patients who undergo robotic radical gastric cancer surgery. AIM: To validate the applicability of the SIRI in assessing the survival of gastric cancer patients and evaluate the clinical contribution of preoperative SIRI levels to predicting long-term tumor outcomes in patients, who received robotic radical gastric cancer surgery. METHODS: Initially, an exhaustive retrieval was performed in the PubMed, the Cochrane Library, EMBASE, Web of Science, and Scopus databases to identify relevant studies. Subsequently, a meta-analysis was executed on 6 cohort studies identifying the value of the SIRI in assessing the survival of gastric cancer patients. Additionally, the clinical data of 161 patients undergoing robotic radical gastric cancer surgery were retrospectively analyzed to evaluate their clinicopathological characteristics and relevant laboratory indicators. The association between preoperative SIRI levels and 5-year overall survival (OS) and disease-free survival (DFS) was assessed. RESULTS: The findings demonstrated an extensive connection between SIRI values and the outcome of patients with gastric cancer. Preoperative SIRI levels were identified as an independent hazard feature for both OS and DFS among those who received robotic surgery for gastric cancer. SIRI levels in gastric cancer patients were observed to be associated with the presence of comorbidities, T-stage, carcinoembryonic antigen levels, the development of early serious postoperative complications, and the rate of lymph node metastasis. CONCLUSION: SIRI values are correlated with adverse in the gastric cancer population and have the potential to be utilized in predicting long-term oncological survival in patients who undergo robotic radical gastric cancer surgery.

DJ-1 protects cell death from a mitochondrial oxidative stress due to GBA1 deficiency.

BACKGROUND: GBA1 mutations are the most common genetic risk factor for development of Parkinson's disease (PD). The loss of catalytic activity in GBA1, as well as the reduction of the GBA1 protein in certain cellular compartment, may increase disease progression. However, the mechanisms underlying cellular dysfunction caused by GBA1 deficiency are still mostly unknown. OBJECTIVE: In this study, we focus on the genetic interaction between GBA1 deficiency and PD-causing genes, such as DJ-1, in mitochondrial dysfunction. METHODS: GBA1 knockout (KO) SH-SY5Y cells were used to assess DJ-1 functions against oxidative stress in vitro. The levels of cellular reactive oxygen species were monitored with MitoSOX reagent. The expression of the PARK7 gene was analyzed using the quantitative real-time PCR (qRT-PCR). To understand the mechanism underlying DJ-1 upregulation in GBA1 KO cells, we assess ROS levels, antioxidant protein, and cell viability in GBA1 KO cells with treatment of ROS inhibitor N-acetyl-cysteine or miglustat, which is an inhibitor of glucosylceramide synthase. Dopaminergic degeneration was assessed from Gba1 L444P heterozygous mice mated with Park7 knockout mice. RESULTS: We find that DJ-1 is significantly upregulated in GBA1 KO cells. Elevated levels of DJ-1 are attributed to the transcriptional expression of PARK7 mRNA, but not the inhibition of DJ-1 protein degradation. Because DJ-1 expression is highly linked to oxidative stress, we observe cellular reactive oxygen species (ROS) in GBA1 KO cells. Moreover, several antioxidant gene expressions and protein levels are increased in GBA1 KO cells. To this end, GBA1 KO cells are more susceptible to H2O2-induced cell death. Importantly, there is a significant reduction in dopaminergic neurons in the midbrain from Gba1 L444P heterozygous mice mated with Park7 knockout mice, followed by mild motor dysfunction. CONCLUSION: Taken together, our results suggest that DJ-1 upregulation due to GBA1 deficiency has a protective role against oxidative stress. It may be supposed that mutations or malfunctions in the DJ-1 protein may have disadvantages in the survival of dopaminergic neurons in the brains of patients harboring GBA1 mutations.

The novel psychoactive substance 25E-NBOMe induces reward-related behaviors via dopamine D1 receptor signaling in male rodents.

Novel psychoactive substances (NPSs) are new psychotropic drugs designed to evade substance regulatory policies. 25E-NBOMe (2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine) has recently been identified as an NPS, and its recreational misuse has been reported to be rapidly increasing. However, the psychopharmacological effects and mechanisms of 25E-NBOMe have not been studied. We examined the abuse potential of 25E-NBOMe using the conditioned place preference in male mice and self-administration paradigms in male rats. Additionally, immunoblot assay, enzyme-linked immunosorbent assay, and microdialysis were used to determine the molecular effects of 25E-NBOMe in the nucleus accumbens (NAc). Our data demonstrated that 25E-NBOMe induces conditioned place preference, and the dopaminergic signaling in the NAc mediates these. Following 25E-NBOMe administration, expression of dopamine transporter and dopamine D1 receptor (D1DR) were enhanced in the NAc of male mice, and NAc dopamine levels were reduced in both male mice and rats. Induction of intracellular dopaminergic pathways, DARPP32, and phosphorylation of CREB in the NAc of male mice was also observed. Significantly, pharmacological blockade of D1DR or chemogenetic inhibition of D1DR-expressing medium spiny neurons in the NAc attenuated 25E-NBOMe-induced conditioned place preference in male mice. We also examined the hallucinogenic properties of 25E-NBOMe using the head twitch response test in male mice and found that this behavior was mediated by serotonin 2A receptor activity. Our findings demonstrate that D1DR signaling may govern the addictive potential of 25E-NBOMe. Moreover, our study provides new insights into the potential mechanisms of substance use disorder and the improvement of controlled substance management.