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Photothermal immunotherapy has become a promising strategy for tumor treatment. However, the intrinsic drawbacks like light instability, poor immunoadjuvant effect, and poor accumulation of conventional inorganic or organic photothermal agents limit their further applications. Based on the superior carrying capacity and active tumor targeting property of living bacteria, an immunoadjuvant-intensified and engineered tumor-targeting bacterium was constructed to achieve effective photothermal immunotherapy. Specifically, immunoadjuvant imiquimod (R837)-loaded thermosensitive liposomes (R837@TSL) were covalently decorated onto Rhodobacter sphaeroides (R.S) to obtain nanoimmunoadjuvant-armed bacteria (R.S-R837@TSL). The intrinsic photothermal property of R.S combined R837@TSL to achieve in situ near-infrared (NIR) laser-controlled release of R837. Meanwhile, tumor immunogenic cell death (ICD) caused by photothermal effect of R.S-R837@TSL, synergizes with released immunoadjuvants to promote maturation of dendritic cells (DCs), which enhance cytotoxic T lymphocytes (CTLs) infiltration for further tumor eradication. The photosynthetic bacteria armed with immunoadjuvant-loaded liposomes provide a strategy for immunoadjuvant-enhanced cancer photothermal immunotherapy.
Subject(s)
Nanoparticles , Neoplasms , Rhodobacter sphaeroides , Humans , Adjuvants, Immunologic , Liposomes , Imiquimod , Neoplasms/pathology , Immunotherapy , Cell Line, Tumor , PhototherapyABSTRACT
The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.
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Covering: 2016 to 2023The synthetic chemistry community is always in pursuit of efficient routes to natural products. Among the many available general strategies, skeletal reorganization, which involves the formation, cleavage, and migration of C-C and C-heteroatom bonds, stands out as a particularly useful approach for the efficient assembly of molecular skeletons. In addition, it allows for late-stage modification of natural products for quick access to other family members or unnatural derivatives. This review summarizes efficient syntheses of steroid, terpenoid, and alkaloid natural products that have been achieved by means of this strategy in the past eight years. Our goal is to illustrate the strategy's potency and reveal the spectacular human ingenuity demonstrated in its use and development.
Subject(s)
Alkaloids , Biological Products , Humans , Biological Products/chemistry , TerpenesABSTRACT
PURPOSE: Despite the revealed role of immunological dysfunctions in the development and progression of Alzheimer's disease (AD) through animal and postmortem investigations, direct evidence regarding the impact of genetic factors on microglia response and amyloid-ß (Aß) deposition in AD individuals is lacking. This study aims to elucidate this mechanism by integrating transcriptomics and TSPO, Aß PET imaging in clinical AD cohort. METHODS: We analyzed 85 patients with PET/MR imaging for microglial activation (TSPO, [18F]DPA-714) and Aß ([18F]AV-45) within the prospective Alzheimer's Disease Immunization and Microbiota Initiative Study Cohort (ADIMIC). Immune-related differentially expressed genes (IREDGs), identified based on AlzData, were screened and verified using blood samples from ADIMIC. Correlation and mediation analyses were applied to investigate the relationships between immune-related genes expression, TSPO and Aß PET imaging. RESULTS: TSPO uptake increased significantly both in aMCI (P < 0.05) and AD participants (P < 0.01) and showed a positive correlation with Aß deposition (r = 0.42, P < 0.001). Decreased expression of TGFBR3, FABP3, CXCR4 and CD200 was observed in AD group. CD200 expression was significantly negatively associated with TSPO PET uptake (r =-0.33, P = 0.013). Mediation analysis indicated that CD200 acted as a significant mediator between TSPO uptake and Aß deposition (total effect B = 1.92, P = 0.004) and MMSE score (total effect B =-54.01, P = 0.003). CONCLUSION: By integrating transcriptomics and TSPO PET imaging in the same clinical AD cohort, this study revealed CD200 played an important role in regulating neuroinflammation, Aß deposition and cognitive dysfunction.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Gene Expression Profiling , Neuroinflammatory Diseases , Positron-Emission Tomography/methods , Prospective Studies , Receptors, GABA/genetics , Receptors, GABA/metabolismABSTRACT
Non-suicidal self-injury (NSSI) is an issue primarily of concern in adolescents and young adults. Recent literature suggests that persistent, repetitive, and uncontrollable NSSI can be conceptualized as a behavioral addiction. The study aimed to examine the prevalence of NSSI with addictive features and the association of this prevalence with demographic and clinical variables using a cross-sectional and case-control design. A total of 548 outpatients (12 to 22 years old) meeting the criteria for NSSI disorder of DSM-5 were enrolled and completed clinical interviews by 4 psychiatrists. NSSI with addictive features were determined by using a single-factor structure of addictive features items in the Ottawa self-injury inventory (OSI). Current suicidality, psychiatric diagnosis, the OSI, the revised Chinese Internet Addiction Scale, the Childhood Trauma Questionnaire, and the 20-item Toronto Alexithymia Scale were collected. Binary logistic regression analyses were used to explore associations between risk factors and NSSI with addictive features. This study was conducted from April 2021 to May 2022. The mean age of participants was 15.93 (SD = 2.56) years with 418 females (76.3%), and the prevalence of addictive NSSI was 57.5% (n = 315). Subjects with addictive NSSI had a higher lifetime prevalence of nicotine and alcohol use, a higher prevalence of current internet addiction, suicidality, and alexithymia, and were more likely to have physical abuse/neglect, emotional abuse, and sexual abuse than NSSI subjects without addictive features. Among participants with NSSI, the strongest predictors of addictive features of NSSI were female (OR = 2.405, 95% CI 1.512-3.824, p < 0.0001), alcohol use (OR = 2.179, 95% CI 1.378-3.446, p = 0.001), current suicidality (OR = 3.790, 95% CI 2.351-6.109, p < 0.0001), and psysical abuse in childhood (OR = 2.470, 95% CI 1.653-3.690, p < 0.0001). Nearly 3 out of 5 patients (12-22 years old) with NSSI met the criteria of NSSI with addictive features in this psychiatric outpatients sample. Our study demonstrated the importance of the necessity to regularly assess suicide risk, and alcohol use, as well as focus more on females and subjects who had physical abuse in childhood to prevent addictive NSSI.
Subject(s)
Behavior, Addictive , Psychological Tests , Self Report , Self-Injurious Behavior , Humans , Female , Adolescent , Young Adult , Child , Adult , Male , Outpatients , Cross-Sectional Studies , Self-Injurious Behavior/epidemiology , Self-Injurious Behavior/psychology , Behavior, Addictive/epidemiology , Risk FactorsABSTRACT
OBJECTIVES: Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) exhibit varying degrees of halitosis. The author speculated that small intestinal bacterial overgrowth (SIBO) might lead to MASLD and subsequent extra-oral halitosis and aimed to test this hypothesis. METHODS: This retrospective cross-sectional study reviewed 885 extra-oral halitosis patients. Halitosis and exhaled dimethyl sulfide (DMS) were measured by organoleptic score (OLS) (0-5) and OralChroma, respectively. SIBO and MASLD were diagnosed by hydrogen breath test and Fibroscan combined with cardiometabolic criteria. RESULTS: In this study, 133/885 (15.05%) of the halitosis patients otherwise healthy had MASLD, while 87/133 (65.41%) of the MASLD patients were SIBO-positive. No significant differences were observed in physical parameters such as age, serum biochemical parameters such as lipids, or Fibroscan parameters between the SIBO-positive and SIBO-negative patients. However, the OLS was 4 (interquartile range: 3-4) and exhaled DMS level was 56 (43-75) parts per billion (ppb) in the SIBO-positive patients, significantly greater than 2 (2-3) and 43 (25-51) ppb in the SIBO-negative patients (both p < 0.001). Exhaled hydrogen levels positively correlated with the OLS and exhaled DMS levels (r = 0.774, r = 0.740, both p < 0.001). CONCLUSION: MASLD can cause halitosis by SIBO.
ABSTRACT
INTRODUCTION: Altered neurometabolism, detectable via proton magnetic resonance spectroscopic imaging (1H-MRSI), is spatially heterogeneous and underpins cognitive impairments in Alzheimer's disease (AD). However, the spatial relationships between neurometabolic topography and cognitive impairment in AD remain unexplored due to technical limitations. METHODS: We used a novel whole-brain high-resolution 1H-MRSI technique, with simultaneously acquired 18F-florbetapir positron emission tomography (PET) imaging, to investigate the relationship between neurometabolic topography and cognitive functions in 117 participants, including 22 prodromal AD, 51 AD dementia, and 44 controls. RESULTS: Prodromal AD and AD dementia patients exhibited spatially distinct reductions in N-acetylaspartate, and increases in myo-inositol. Reduced N-acetylaspartate and increased myo-inositol were associated with worse global cognitive performance, and N-acetylaspartate correlated with five specific cognitive scores. Neurometabolic topography provides biological insights into diverse cognitive dysfunctions. DISCUSSION: Whole-brain high-resolution 1H-MRSI revealed spatially distinct neurometabolic topographies associated with cognitive decline in AD, suggesting potential for noninvasive brain metabolic imaging to track AD progression. HIGHLIGHTS: Whole-brain high-resolution 1H-MRSI unveils neurometabolic topography in AD. Spatially distinct reductions in NAA, and increases in mI, are demonstrated. NAA and mI topography correlates with global cognitive performance. NAA topography correlates with specific cognitive performance.
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We report an endoperoxide compound (E5) which can deliver three therapeutic components by a thermal cycloreversion, namely, singlet oxygen, triplet oxygen and 3-methyl-N-phenyl-2-pyridone (P5), thus targeting multiple mechanisms for treating non-small cell lung cancer and idiopathic pulmonary fibrosis. In aqueous environment, E5 undergoes clean reaction to afford three therapeutic components with a half-life of 8.3â hours without the generation of other by-products, which not only achieves good cytotoxicity toward lung cancer cells and decreases the levels of hypoxia-inducible factor 1α (HIF-1α) protein, but also inhibits the transforming growth factor ß1 (TGF-ß1) induced fibrosis in vitro. In vivo experiments also demonstrated the efficacy of E5 in inhibiting tumor growth and relieving idiopathic pulmonary fibrosis, while exhibiting good biocompatibility. Many lines of evidence reveal the therapeutic efficacy of singlet oxygen and 3-methyl-N-phenyl-2-pyridone for these two lung diseases, and triplet oxygen could downregulate HIF-1α and relieve tumor hypoxia which is a critical issue in photodynamic therapy (PDT). Unlike other combination therapies, in which multiple therapeutic agents are given in independent formulations, our work demonstrates single molecule endoperoxide prodrugs could be developed as new platforms for treatment of cancers and related diseases.
ABSTRACT
Wound healing is a complex and error-prone process. Wound healing in adults often leads to the formation of scars, a type of fibrotic tissue that lacks skin appendages. Hypertrophic scars and keloids can also form when the wound-healing process goes wrong. Leptin (Lep) and leptin receptors (LepRs) have recently been shown to affect multiple stages of wound healing. This effect, however, is paradoxical for scarless wound healing. On the one hand, Lep exerts pro-inflammatory and profibrotic effects; on the other hand, Lep can regulate hair follicle growth. This paper summarises the role of Lep and LepRs on cells in different stages of wound healing, briefly introduces the process of wound healing and Lep and LepRs, and examines the possibility of promoting scarless wound healing through spatiotemporal, systemic, and local regulation of Lep levels and the binding of Lep and LepRs.
Subject(s)
Cicatrix, Hypertrophic , Leptin , Humans , Cicatrix, Hypertrophic/pathology , Leptin/metabolism , Receptors, Leptin/metabolism , Skin/metabolism , Wound Healing , AnimalsABSTRACT
Aberrant smoking-related DNA methylation has been widely investigated as a carcinogenesis mechanism, but whether the cross-cancer epigenetic pathways exist remains unclear. We conducted two-sample Mendelian randomization (MR) analyses respectively on smoking behaviors (age of smoking initiation, smoking initiation, smoking cessation, and lifetime smoking index [LSI]) and smoking-related DNA methylation to investigate their effect on 15 site-specific cancers, based on a genome-wide association study (GWAS) of 1.2 million European individuals and an epigenome-WAS (EWAS) of 5907 blood samples of Europeans for smoking and 15 GWASs of European ancestry for multiple site-specific cancers. Significantly identified CpG sites were further used for colocalization analysis, and those with cross-cancer effect were validated by overlapping with tissue-specific eQTLs. In the genomic MR, smoking measurements of smoking initiation, smoking cessation and LSI were suggested to be casually associated with risk of seven types of site-specific cancers, among which cancers at lung, cervix and colorectum were provided with strong evidence. In the epigenetic MR, methylation at 75 CpG sites were reported to be significantly associated with increased risks of multiple cancers. Eight out of 75 CpG sites were observed with cross-cancer effect, among which cg06639488 (EFNA1), cg12101586 (CYP1A1) and cg14142171 (HLA-L) were validated by eQTLs at specific cancer sites, and cg07932199 (ATXN2) had strong evidence to be associated with cancers of lung (coefficient, 0.65, 95% confidence interval [CI], 0.31-1.00), colorectum (0.90 [0.61, 1.18]), breast (0.31 [0.20, 0.43]) and endometrium (0.98 [0.68, 1.27]). These findings highlight the potential practices targeting DNA methylation-involved cross-cancer pathways.
Subject(s)
DNA Methylation , Neoplasms , Female , Humans , Smoking/adverse effects , Smoking/genetics , Genome-Wide Association Study , Mendelian Randomization Analysis , Neoplasms/epidemiology , Neoplasms/genetics , CpG Islands/geneticsABSTRACT
ThE present work focused on exploring Girdin expression within gastric cancer (GC), examining the effect of Girdin on the cell phenotype of GC, and clarifying the underlying mechanisms. Girdin expression in GC samples was identified by immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR) assays. Girdin-targeting siRNAs were transfected into GC cells; later, we examined GC cell proliferation, migration, invasion, and apoptosis, respectively. Additionally, the protein expression was examined through Western blotting assay. Moreover, the tumor implantation experiment was conducted for examining Girdin knockdown in vivo. The results showed that Girdin expression elevated within GC samples, which was associated with the dismal prognostic outcome. Girdin knockdown suppressed GC cell proliferation, migration, and invasion, and enhanced apoptosis and cell cycle arrest. Girdin promoted the phosphorylation of AKT, GSK3ß, and ß-catenin. Moreover, Girdin inhibited the phosphorylation of ß-catenin. Girdin suppressed cell apoptosis and stimulated cell migration and invasion, while AKT inhibitor (MK2206) treatment reversed the effect of Girdin overexpression, and GSK3ß inhibitor (CHIR99021) treatment enhanced the effect of Girdin overexpression on GC cells. Besides, Girdin delayed tumor growth in vivo. In conclusion, Girdin was abnormally expressed in GC samples, which promoted the development of GC by regulating AKT/GSK3ß/ß-catenin signaling.
Subject(s)
Microfilament Proteins , Proto-Oncogene Proteins c-akt , Stomach Neoplasms , Vesicular Transport Proteins , Humans , beta Catenin/genetics , beta Catenin/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Glycogen Synthase Kinase 3 beta/genetics , Glycogen Synthase Kinase 3 beta/metabolism , Oncogenes , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Stomach Neoplasms/metabolism , Vesicular Transport Proteins/genetics , Vesicular Transport Proteins/metabolism , Microfilament Proteins/genetics , Microfilament Proteins/metabolismABSTRACT
This study aims to identify the efficacy and safety of stent-assisted coiling (SAC) treatment of ruptured intracranial aneurysms (RIAs) combined with intracranial haematoma (ICH) compared to coiling alone or balloon-assisted coiling (non-SAC). A retrospective analysis of 54 consecutive patients receiving endovascular therapy from 2014 to 2020 was performed. The data collected included baseline characteristics, angiographic results, perioperative complications, immediate aneurysm occlusion, clinical outcomes, follow-up at discharge and after 6 months, hospitalisation costs, and inpatient length of stay. Patients were categorised into the SAC group and the non-SAC group. Univariate and multivariate logistic regression analyses were used to identify risk factors related to clinical outcomes. Of the 54 patients harbouring RIAs with ICH, 22 (40.74%) and 32 (59.26%) patients were subject to SAC and non-SAC treatments, respectively. Postoperative rebleeding (1 [4.5%] and 3 [9.3%] in SAC and non-SAC groups, respectively, p > 0.05) and Hunt-Hess grade (IV-V) lesions (13.6% vs. 40.6%, p = 0.067) did not differ between the two groups. In total, 10 (45.5%) patients treated with SAC received a Fisher scale score of 0-3 compared with 6 (18.8%) patients treated with non-SAC methods (p = 0.035). Compared with the non-SAC group (7/21.9%), the rate of wide-necked aneurysms was increased in the SAC group (11/50%) (p = 0.031). No differences in poor outcomes (mRS > 2) were noted between the SAC and non-SAC groups (p > 0.05). Multivariate analysis revealed that ischaemic complication events (p = 0.016) represent the only independent risk factor for adverse outcomes, and a trend towards unfavourable clinical outcomes was noted for patients who smoke (p = 0.087). SAC is a safe and efficient treatment for RIAs combined with ICH when dual antiplatelet therapy (DAPT) is used in the perioperative period. In addition, SAC should be preferentially used in wide-neck RIAs. Ischaemic complications are a risk factor for poor clinical outcomes. Given the small sample size and retrospective bias of this study, these findings should be further verified in a study with a larger sample size or a randomised controlled trial (RCT).
Subject(s)
Aneurysm, Ruptured , Embolization, Therapeutic , Endovascular Procedures , Intracranial Aneurysm , Humans , Aneurysm, Ruptured/complications , Cerebral Angiography , Cerebral Hemorrhage/complications , Embolization, Therapeutic/methods , Endovascular Procedures/methods , Hematoma/surgery , Hematoma/complications , Intracranial Aneurysm/complications , Platelet Aggregation Inhibitors/therapeutic use , Retrospective Studies , Stents , Treatment OutcomeABSTRACT
Genetic hearing loss is a common health problem with no effective therapy currently available. DFNA15, caused by mutations of the transcription factor POU4F3, is one of the most common forms of autosomal dominant non-syndromic deafness. In this study, we established a novel mouse model of the human DFNA15 deafness, with a Pou4f3 gene mutation (Pou4f3Δ) identical to that found in a familial case of DFNA15. The Pou4f3(Δ/+) mice suffered progressive deafness in a similar manner to the DFNA15 patients. Hair cells in the Pou4f3(Δ/+) cochlea displayed significant stereociliary and mitochondrial pathologies, with apparent loss of outer hair cells. Progression of hearing and outer hair cell loss of the Pou4f3(Δ/+) mice was significantly modified by other genetic and environmental factors. Using Pou4f3(-/+) heterozygous knockout mice, we also showed that DFNA15 is likely caused by haploinsufficiency of the Pou4f3 gene. Importantly, inhibition of retinoic acid signaling by the aldehyde dehydrogenase (Aldh) and retinoic acid receptor inhibitors promoted Pou4f3 expression in the cochlear tissue and suppressed the progression of hearing loss in the mutant mice. These data demonstrate Pou4f3 haploinsufficiency as the main underlying cause of human DFNA15 deafness and highlight the therapeutic potential of Aldh inhibitors for treatment of progressive hearing loss.
Subject(s)
Aldehyde Dehydrogenase/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hair Cells, Auditory/pathology , Hearing Loss/drug therapy , Hearing Loss/etiology , Homeodomain Proteins/genetics , Transcription Factor Brn-3C/genetics , Animals , Benzaldehydes/pharmacology , Disease Models, Animal , Haploinsufficiency/genetics , Hearing Loss/genetics , Hearing Loss/pathology , Homeodomain Proteins/metabolism , Humans , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Knockout , Noise/adverse effects , Quinolines/pharmacology , Transcription Factor Brn-3C/metabolism , Tretinoin/pharmacology , para-Aminobenzoates/pharmacologyABSTRACT
Anxiety commonly co-occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL- and not BLA- and vHipp-NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL-NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.
Subject(s)
Anxiety Disorders/drug therapy , Histamine Agonists/administration & dosage , Nucleus Accumbens/physiopathology , Obsessive-Compulsive Disorder/drug therapy , Receptors, Histamine H3/metabolism , Afferent Pathways/drug effects , Afferent Pathways/physiopathology , Animals , Anxiety Disorders/etiology , Anxiety Disorders/physiopathology , Anxiety Disorders/psychology , Disease Models, Animal , Glutamates/metabolism , Histamine/metabolism , Histamine H3 Antagonists/administration & dosage , Humans , Hypothalamic Area, Lateral/drug effects , Hypothalamic Area, Lateral/physiopathology , Male , Neurons/drug effects , Neurons/metabolism , Nucleus Accumbens/cytology , Nucleus Accumbens/drug effects , Obsessive-Compulsive Disorder/etiology , Obsessive-Compulsive Disorder/physiopathology , Obsessive-Compulsive Disorder/psychology , Optogenetics , Patch-Clamp Techniques , Prefrontal Cortex/cytology , Prefrontal Cortex/drug effects , Prefrontal Cortex/physiopathology , Presynaptic Terminals/drug effects , Presynaptic Terminals/metabolism , Rats , Rats, Transgenic , Stereotaxic Techniques , Stress, Psychological/complications , Stress, Psychological/psychology , Synaptic Transmission/drug effects , Synaptic Transmission/physiologyABSTRACT
Fibroblast growth factors (FGFs) have been widely studied by virtue of their ability to regulate many essential cellular activities, including proliferation, survival, migration, differentiation and metabolism. Recently, these molecules have emerged as the key components in forming the intricate connections within the nervous system. FGF and FGF receptor (FGFR) signaling pathways play important roles in axon guidance as axons navigate toward their synaptic targets. This review offers a current account of axonal navigation functions performed by FGFs, which operate as chemoattractants and/or chemorepellents in different circumstances. Meanwhile, detailed mechanisms behind the axon guidance process are elaborated, which are related to intracellular signaling integration and cytoskeleton dynamics.
Subject(s)
Fibroblast Growth Factors , Receptors, Fibroblast Growth Factor , Fibroblast Growth Factors/metabolism , Receptors, Fibroblast Growth Factor/metabolism , Axon Guidance , Signal Transduction/physiology , Axons/metabolismABSTRACT
A phytochemical investigation of the steroidal saponins from the rhizomes of Paris polyohylla var. latifolia led to the discovery and characterization of three new spirostanol saponins, papolatiosides A-C (1-3), and nine known compounds (4-12). Their structures were established via extensive spectroscopic data analysis and chemical methods. Interestingly, compounds 1 and 2 possessed a fructosyl in their oligosaccharide moiety, which is rare in natural product and was firstly reported in family Melanthiaceae. The cytotoxicity of these saponins against several human cancer cell lines was evaluated by a CCK-8 experiment. As a result, compound 1 exhibited a significant cytotoxic effect on LN229, U251, Capan-2, HeLa, and HepG2 cancer cells with IC50 values of 4.18 ± 0.31, 3.85 ± 0.44, 3.26 ± 0.34, 3.30 ± 0.38 and 4.32 ± 0.51 µM, respectively. In addition, the result of flow cytometry analysis indicated that compound 1 could induce apoptosis of glioma cells LN229. The underlying mechanism was explored by network pharmacology and western bolt experiments, which indicated that compound 1 could induce glioma cells LN229 apoptosis by regulating the EGFR/PI3K/Akt/mTOR pathway.
Subject(s)
Antineoplastic Agents , Glioma , Liliaceae , Melanthiaceae , Saponins , Humans , Rhizome/chemistry , Phosphatidylinositol 3-Kinases , Liliaceae/chemistry , Antineoplastic Agents/analysis , Saponins/pharmacology , Saponins/chemistryABSTRACT
This study investigated the mechanism of action of Scutellariae Radix-Coptidis Rhizoma(SR-CR) in intervening in non-alcoholic fatty liver disease(NAFLD) in rats based on lipidomics. Thirty-six SD rats were divided into a control group, a model group, SR-CR groups of different doses, and a simvastatin group, with six rats in each group. Rats in the control group were fed on a normal diet, while those in the remaining groups were fed on a high-lipid diet. After four weeks of feeding, drug treatment was carried out and rats were sacrificed after 12 weeks. Serum liver function and lipid indexes were detected using kits, and the pathomorphology of liver tissues was evaluated by hematoxylin-eosin(HE) staining and oil red O staining. Changes in lipid levels in rats were detected using the LC-MS technique. Differential lipid metabolites were screened by multivariate statistical analysis, and lipid metabolic pathways were plotted. The changes in lipid-related protein levels were further verified by Western blot. The results showed that compared with the control group, the model group showed increased levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c)(P<0.01), and decreased levels of γ-glutamyl transferase(γ-GT) and high-density lipoprotein cholesterol(HDL-c)(P<0.01), which were significantly recovered by the intervention of SR-CR. HE staining and oil red O staining showed that different doses of SR-CR could reverse the steatosis in the rat liver in a dose-dependent manner. After lipidomics analysis, there were significant differences in lipid metabolism between the model group and the control group, with 54 lipids significantly altered, mainly including glycerolipids, phosphatidylcholine, and sphingolipids. After administration, 44 differential lipids tended to normal levels, which indicated that SR-CR groups of different doses significantly improved the lipid metabolism level in NAFLD rats. Western blot showed that SR-CR significantly decreased TG-synthesis enzyme 1(DGAT1), recombinant lipin 1(LPIN1), fatty acid synthase(FASN), acetyl-CoA carboxylase 1(ACC1), and increased the phosphorylation level of ACC1. These changes significantly decreased the synthesis of TG and increased the rate of its decomposition, which enhanced the level of lipid metabolism in the body and finally achieved the lipid-lowering effect. SR-CR can improve NAFLD by inhibiting the synthesis of fatty acids and TG.
Subject(s)
Azo Compounds , Drugs, Chinese Herbal , Non-alcoholic Fatty Liver Disease , Rats , Animals , Non-alcoholic Fatty Liver Disease/drug therapy , Scutellaria baicalensis , Drugs, Chinese Herbal/therapeutic use , Pharmaceutical Preparations , Rats, Sprague-Dawley , Liver , Triglycerides/metabolism , Cholesterol , Diet, High-FatABSTRACT
Crohn's disease (CD), a subtype of inflammatory bowel disease (IBD), has increasing prevalence in the world. Due to the lack of cure strategy, most patients with CD develop progressive disease companying with a series of serious complications. Therefore, exploring molecular mechanism differences between active and inactive CD will help in the screening of predict markers and therapeutic targets. In this study, we analyzed differentially expressed genes (DEGs) and molecular pathways through between active and inactive CD patients. In addition, the abundance of 22 immune cell types were assessed by using the CIBERSORT. The hub DEGs were screened out by the CytoHubba in Cytoscape, followed by the least absolute shrinkage and selection operator (LASSO) regression. Finally, the clinical predictive model was constructed by binary logistic regression model. The diagnostic efficacy was tested by receiver operating characteristic (ROC) curve and verified in independent datasets. The results showed that there were 137 DEGs between the active and inactive CD. Most of them were involved in regulating the immunity process. In addition, the decreased abundance of CD8 T cells and the increased abundance of M0, M1 macrophages, and neutrophils were closely related to CD activation. CXCL9, C3AR1, IL1B, and TLR4 were the hub gene and can be applied to the prediction of CD activation. Our results provided important targets for the prediction of CD activation and the selection of therapeutic targets.
Subject(s)
Crohn Disease , Humans , Crohn Disease/genetics , Crohn Disease/diagnosis , Biomarkers , ROC CurveABSTRACT
INTRODUCTION: Triple-negative breast cancer (TNBC) is known for its aggressive behaviors and lacking of effective treatment. Programmed cell death ligand-1 (PD-L1) inhibitor has just been approved for using in the management of advanced TNBC. To accurately screen TNBC sensitive to anti-PD-L1 treatment and to explore the feasibility of the ataxia-telangiectasia mutation protein (ATM) inhibitor combined with PD-L1 inhibitor, radiotherapy and chemotherapy, we focus on whether ATM participates in the regulation of PD-L1 and affects the prognosis of patients through c-Src, signal transducer and activator of transcription 1&3 (STAT1 and STAT3). MATERIALS AND METHODS: We used immunohistochemical staining to explore the relationship of ATM with c-Src, STAT1, STAT3, PD-1/PD-L1, Tumor-infiltrating lymphocytes (TILs), as well as other clinicopathologic features in 86 pathological stage III TNBCs. Their impact on prognosis was also explored. RESULTS: We found ATM expression was negatively correlated with STAT1, STAT3, PD-L1, TILs and CD8 + cells in TNBC. STAT1 positively correlated the expression of PD-L1. In TNBC with ATM low expression, STAT3 was an independent factor for improved prognosis, while PD-L1 was an independent negative prognostic factor. Furthermore, in low ATM group, the phosphorylation of tyrosine at position 419 of c-Src (p-c-src Y419) was correlated with the overexpression of STAT3. CONCLUSION: Locally advanced TNBC with low ATM expression may be more likely to benefit from anti-PD-L1 inhibitors. The feasibility of ATM functional inhibitor combined with immune checkpoint blockade therapies in the treatment of TNBC is also worthy of further exploration. Our study suggests that STAT3 has different impacts on tumor progression in different tumors.
Subject(s)
Triple Negative Breast Neoplasms , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Biomarkers, Tumor/metabolism , Humans , Immune Checkpoint Inhibitors , Ligands , Lymphocytes, Tumor-Infiltrating , Mutation , Prognosis , Programmed Cell Death 1 Receptor/metabolism , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolism , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/therapy , Tyrosine/metabolismABSTRACT
BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease and its pathogenesis is still unclear. There is dysbiosis of gut microbiota in AD patients. More importantly, dysbiosis of the gut microbiota has been observed not only in AD patients, but also in patients with mild cognitive impairment (MCI). However, the mechanism of gut microbiota dysbiosis in AD is poorly understood. Cholinergic anti-inflammatory pathway is an important pathway for the central nervous system (CNS) regulation of peripheral immune homeostasis, especially in the gut. Therefore, we speculated that dysfunction of cholinergic anti-inflammatory pathway is a potential pathway for dysbiosis of the gut microbiota in AD. METHODS: In this study, we constructed AD model mice by injecting Aß1-42 into the lateral ventricle, and detected the cognitive level of mice by the Morris water maze test. In addition, 16S rDNA high-throughput analysis was used to detect the gut microbiota abundance of each group at baseline, 2 weeks and 4 weeks after surgery. Furthermore, immunofluorescence and western blot were used to detect alteration of intestinal structure of mice, cholinergic anti-inflammatory pathway, and APP process of brain and colon in each group. RESULTS: Aß1-42 i.c.v induced cognitive impairment and neuron damage in the brain of mice. At the same time, Aß1-42 i.c.v induced alteration of gut microbiota at 4 weeks after surgery, while there was no difference at the baseline and 2 weeks after surgery. In addition, changes in colon structure and increased levels of pro-inflammatory factors were detected in Aß1-42 treatment group, accompanied by inhibition of cholinergic anti-inflammatory pathways. Amyloidogenic pathways in both the brain and colon were accelerated in Aß1-42 treatment group. CONCLUSIONS: The present findings suggested that Aß in the CNS can induce gut microbiota dysbiosis, alter intestinal structure and accelerate the amyloidogenic pathways, which were related to inhibiting cholinergic anti-inflammatory pathways.