BACKGROUND: Growing evidence suggests that long non-coding RNAs (lncRNAs) exert pivotal roles in fostering chemoresistance across diverse tumors. Nevertheless, the precise involvement of lncRNAs in modulating chemoresistance within the context of gallbladder cancer (GBC) remains obscure. This study aimed to uncover how lncRNAs regulate chemoresistance in gallbladder cancer, offering potential targets to overcome drug resistance. METHODS: To elucidate the relationship between gemcitabine sensitivity and small nucleolar RNA host gene 1 ( SNHG1 ) expression, we utilized publicly available GBC databases, GBC tissues from Renji Hospital collected between January 2017 and December 2019, as well as GBC cell lines. The assessment of SNHG1, miR-23b-3p, and phosphatase and tensin homolog (PTEN) expression was performed using in situ  hybridization, quantitative real-time polymerase chain reaction, and western blotting. The cell counting kit-8 (CCK-8) assay was used to quantify the cell viability. Furthermore, a GBC xenograft model was employed to evaluate the impact of SNHG1 on the therapeutic efficacy of gemcitabine. Receiver operating characteristic (ROC) curve analyses were executed to assess the specificity and sensitivity of SNHG1. RESULTS: Our analyses revealed an inverse correlation between the lncRNA SNHG1 and gemcitabine resistance across genomics of drug sensitivity in cancer (GDSC) and Gene Expression Omnibus (GEO) datasets, GBC cell lines, and patients. Gain-of-function investigations underscored that SNHG1 heightened the gemcitabine sensitivity of GBC cells in both in vitro and in vivo  settings. Mechanistic explorations illuminated that SNHG1 could activate PTEN -a commonly suppressed tumor suppressor gene in cancers-thereby curbing the development of gemcitabine resistance in GBC cells. Notably, microRNA (miRNA) target prediction algorithms unveiled the presence of miR-23b-3p binding sites within SNHG1 and the 3'-untranslated region (UTR) of PTEN . Moreover, SNHG1 acted as a sponge for miR-23b-3p, competitively binding to the 3'-UTR of PTEN , thereby amplifying PTEN expression and heightening the susceptibility of GBC cells to gemcitabine. CONCLUSION The SNHG1/miR-23b-3p/PTEN axis emerges as a pivotal regulator of gemcitabine sensitivity in GBC cells, holding potential as a promising therapeutic target for managing GBC patients.
Humans ; Deoxycytidine/pharmacology* ; PTEN Phosphohydrolase/genetics* ; Gemcitabine ; RNA, Long Noncoding/metabolism* ; MicroRNAs/genetics* ; Gallbladder Neoplasms/genetics* ; Cell Line, Tumor ; Animals ; Mice ; Drug Resistance, Neoplasm/genetics* ; Mice, Nude ; Antimetabolites, Antineoplastic ; Gene Expression Regulation, Neoplastic

Abuse of amphetamine-based stimulants is a primary public health concern. Recent studies have underscored a troubling escalation in the inappropriate use of prescription amphetamine-based stimulants. However, the neurophysiological mechanisms underlying the impact of acute methamphetamine exposure (AME) on sleep homeostasis remain to be explored. This study employed non-human primates and electroencephalogram (EEG) sleep staging to evaluate the influence of AME on neural oscillations. The primary focus was on alterations in spindles, delta oscillations, and slow oscillations (SOs) and their interactions as conduits through which AME influences sleep stability. AME predominantly diminishes sleep-spindle waves in the non-rapid eye movement 2 (NREM2) stage, and impacts SOs and delta waves differentially. Furthermore, the competitive relationships between SO/delta waves nesting with sleep spindles were selectively strengthened by methamphetamine. Complexity analysis also revealed that the SO-nested spindles had lost their ability to maintain sleep depth and stability. In summary, this finding could be one of the intrinsic electrophysiological mechanisms by which AME disrupted sleep homeostasis.
Animals ; Methamphetamine ; Electroencephalography ; Male ; Sleep/drug effects* ; Central Nervous System Stimulants ; Delta Rhythm/drug effects* ; Sleep Stages/drug effects*

Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca²⁺ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^-/- OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^-/- OPCs in vitro and myelination in Tmem63a^-/- mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca²⁺ influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
Animals ; Cell Differentiation/physiology* ; Oligodendroglia/metabolism* ; Mice, Knockout ; Mice ; Male ; Myelin Sheath/metabolism* ; Humans ; Child ; Cells, Cultured ; Oligodendrocyte Precursor Cells/metabolism*

The prefrontal cortex and hippocampus may support sequential working memory beyond episodic memory and spatial navigation. This stereoelectroencephalography (SEEG) study investigated how the dorsolateral prefrontal cortex (DLPFC) interacts with the hippocampus in the online processing of sequential information. Twenty patients with epilepsy (eight women, age 27.6 ± 8.2 years) completed a line ordering task with SEEG recordings over the DLPFC and the hippocampus. Participants showed longer thinking times and more recall errors when asked to arrange random lines clockwise (random trials) than to maintain ordered lines (ordered trials) before recalling the orientation of a particular line. First, the ordering-related increase in thinking time and recall error was associated with a transient theta power increase in the hippocampus and a sustained theta power increase in the DLPFC (3-10 Hz). In particular, the hippocampal theta power increase correlated with the memory precision of line orientation. Second, theta phase coherences between the DLPFC and hippocampus were enhanced for ordering, especially for more precisely memorized lines. Third, the theta band DLPFC → hippocampus influence was selectively enhanced for ordering, especially for more precisely memorized lines. This study suggests that theta oscillations may support DLPFC-hippocampal interactions in the online processing of sequential information.
Adult ; Female ; Humans ; Young Adult ; Epilepsy ; Hippocampus ; Memory, Short-Term ; Mental Recall ; Prefrontal Cortex ; Theta Rhythm ; Male

Objective: To understand the knowledge, attitude and behavior of adult residents on influenza, pneumococcus, human papillomavirus (HPV), herpes zoster (HZ), COVID-19, hepatitis B and rabies vaccination in Shandong Province. Methods: From August to September 2022, a multi-stage stratified random sampling method was used to investigate community-dwelling residents aged 18 years old and above in 12 counties (cities and districts) of Shandong Province. A questionnaire survey was used to collect the basic information of the respondents, such as knowledge, attitude and vaccination behavior of influenza, pneumococcus, HPV, HZ, COVID-19, hepatitis B and rabies vaccine. Analysis of variance was used to compare the differences in the respondents' knowledge and attitude scores of different vaccines. The Chi-square test was conducted to compare the differences in vaccination reasons among different characteristics, and a logistic regression model was used to analyze the influencing factors of vaccination behavior. Results: The median age (Q₁, Q₃) of the 2 754 respondents was 39 (29, 57) years ranging from 18 to 94 years, with a number of 1 234 (44.81%) males. The average score of the respondents' understanding of various knowledge about adult vaccines was less than 4 points, with the highest score for understanding which diseases can be prevented by adult vaccines. The average score of consent and necessity for adult vaccines to prevent diseases was greater than 3.6 points. In terms of knowledge demand and trust in information channels, there was a high level of trust in the recommendations of vaccination outpatient staff and clinical doctors [with scores of (4.15±0.79) and (4.02±0.80), respectively]. The highest demand for information on vaccination safety knowledge was (4.18±0.84) points. In recent two years, 52.11% of the population had been vaccinated with other vaccines in addition to the COVID-19 vaccine and rabies vaccine, and 45.44% of the population felt it was necessary to be vaccinated through media publicity. Women, age growth, high education level, and high-income level were the promoting factors for adopting vaccination behavior. Conclusion: Adult residents in Shandong Province have a basic understanding and supportive attitude towards vaccination, but the vaccination behavior rate is still relatively low, with significant differences in sex, age, education level, and income level. It is necessary to further increase efforts in the breadth and depth of adult vaccination promotion and education, as well as promotion strategies targeting different populations.
Adult ; Male ; Female ; Humans ; Adolescent ; COVID-19 Vaccines ; Health Knowledge, Attitudes, Practice ; Influenza, Human ; Papillomavirus Infections ; Rabies Vaccines ; Influenza Vaccines ; COVID-19/prevention & control* ; Hepatitis B ; Herpes Zoster

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood-brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).

ObjectiveTo explore the effect of Weiwei Tongtiao decoction （WTD） on chronic atrophic gastritis （CAG） rats and the underlying mechanism. MethodA total of 90 SD rats were randomized into normal control group， model group， high-dose， medium-dose， and low-dose WTD groups （18， 9， 4.5 g·kg^-1·d^-1 WTD， respectively， ig）， and weifuchun control group （0.45 g·kg^-1·d^-1 weifuchun aqueous solution， ig）， with 15 rats in each group. The N-methyl-N'-nitro-N-nitrosoguanidine （MNNG） was employed to induced CAG in rats. After the modeling （identified by histopathological examination）， the administration began and lasted 12 weeks. Then， gastric mucosa tissues of the rats were collected and stained with hematoxylin and eosin （HE）， and the pathological changes of gastric mucosa were observed under the optical microscope. Real-time PCR， immunohistochemistry （IHC）， and Western blotting were applied to examine the mRNA and protein expression of indexes in nuclear factor kappa-B （NF-κB） signaling pathway in the gastric mucosa of rats. ResultCAG rats showed irregular arrangement and morphology of the inherent glands in gastric mucosa and the glands decreased or disappeared. In addition， inflammatory cell infiltration was observed in the lamina propria of CAG rats， and about 48.4% presented intestinal metaplasia. WTD significantly alleviated the reduction of the glands and intestinal metaplasia in a dose-dependent manner. Compared with the normal control group， the model group demonstrated increase in the mRNA expression of cyclooxygenase-2 （COX-2）， NF-κB p65， interleukin （IL）-1α， IL-1β， IL-10， IL-8α， and IL-8β， and protein expression of COX-2， NF-κB p65， and IL-10 （P<0.01）. WTD and weifuchun lowered the mRNA expression of COX-2， NF-κB p65， IL-1α， IL-1β， IL-10， IL-8α， and IL-8β， and the protein expression of COX-2， NF-κB p65， and IL-10 in gastric mucosa of CAG rats （P<0.01）. The expression of the above indexes after the intervention with high-dose WTD was close to that of the normal control group. ConclusionWTD can improve or even reverse the diseased gastric mucosa of CAG rats， and the mechanism is the likelihood that WTD down-regulates the mRNA and protein expression of the indexes in NF-κB signaling pathway in gastric mucosa of CAG rats.

OBJECTIVE: To investigate the effects of composite Sophora colon-soluble Capsule (CSCC) on gut microbiota-mediated short-chain fatty acids (SCFAs) production and downstream group 3 innate lymphoid cells (ILC3s) of dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice model. METHODS: The main components of CSCC were analyzed by hybrid ultra-high-performance liquid chromatography ion mobility spectromety quadrupole time-of-flight mass spectrometry (UHPLC-IM-QTOF/MS). Twenty-four male BALB/c mice were randomly divided into 4 groups (n=6) by using a computer algorithm-generated random digital, including control, DSS model, mesalazine, and CSCC groups. A DSS-induced colitis mice model was established to determine the effects of CSCC by recording colonic weight, colonic length, index of colonic weight, and histological colonic score. The variations in ILC3s were assessed by immunofluorescence and flow cytometry. The results of gut microbiota and SCFAs were acquired by 16s rDNA and gas chromatography-mass spectrometry (GC-MS) analysis. The expression levels of NCR⁺ ILC3^-, CCR6⁺ Nkp46^- (Lti) ILC3^-, and ILCreg-specific markers were detected by enzyme-linked immunosorbent assay, and real-time quantitative polymerase chain reaction and Western blot, respectively. RESULTS: The main components of CSCC were matrine, ammothamnine, Sophora flavescens neoalcohol J, and Sophora oxytol U. After 7 days of treatment, CSCC significantly alleviated colitis by promoting the reproduction of intestinal probiotics manifested as upregulation of the abundance of Bacteroidetes species and specifically the Bacteroidales_S24-7 genus (P<0.05). Among the SCFAs, the content of butyric acid increased the most after CSCC treatment. Meanwhile, compared with the model group, Lti ILC3s and its biomarkers were significantly downregulated and NCR⁺ ILC3s were significantly elevated in the CSCC group (P<0.01). Further experiments revealed that ILC3s were differentiated from Lti ILC3s to NCR⁺ ILC3s, resulting in interleukin-22 production which regulates gut epithelial barrier function. CONCLUSION CSCC may exert a therapeutic effect on UC by improving the gut microbiota, promoting metabolite butyric acid production, and managing the ratio between NCR⁺ ILC3s and Lti ILC3s.
Male ; Animals ; Mice ; Colitis, Ulcerative/pathology* ; Immunity, Innate ; Butyric Acid/therapeutic use* ; Sophora ; Gastrointestinal Microbiome ; Lymphocytes ; Colon ; Colitis/pathology* ; Disease Models, Animal ; Mice, Inbred C57BL