Sodium Butyrate Inhibits the Malignant Proliferation of Colon Cancer Cells via the miR-183/DNAJB4 Axis.

Colorectal carcinoma (CRC) is one of the most common malignant tumors in the digestive tract. It was found that butyric acid could inhibit the expression of miR-183 to slow down malignant progression of CRC in the early stage. However, its regulatory mechanism remains unclear. This study screened the IC50 value of butyrate on inhibition of CRC cells malignant progression. Its inhibitory effects were detected by MTT assay, colony formation experiment, Transwell migration experiment, and apoptosis evaluation by flow cytometry. Next, the expressions of miR-183 and DNAJB4 were, respectively, determined in butyrate treated and miR-183 analog or si-DNAJB4-transfected CRC cells to further detect the role of upregulated miR-183 or silencing DNAJB4 in CRC cells malignant progression. Subsequently, the targeted regulatory relationship between miR-183 and si-DNAJB4 was confirmed by bioinformatic prediction tools and double luciferase report genes analysis method. The regulatory mechanism of butyrate on miR-183/DNAJB4 axis signal pathway was evaluated in molecular level, and verified in nude mouse xerograft tumor model and immunohistochemical analysis tests of Ki67 positive rates. The results displayed that butyrate with increased concentration can hinder the proliferation and improve apoptosis of CRC cells by decreasing the expression of miR-183. Thus, butyrate reduces miR-183 expression and increases DNAJB4 expression via the miR-183/DNAJB4 axis, ultimately inhibiting the malignant progression and increasing apoptosis of CRC. While over expression of miR-183 downregulate the expression of DNAJB4, which can reverse the inhibitory effect of butyrate.

Single-cell sequencing reveals the immune microenvironment landscape related to anti-PD-1 resistance in metastatic colorectal cancer with high microsatellite instability.

BACKGROUND: The objective response rate of microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) patients with first-line anti-programmed cell death protein-1 (PD-1) monotherapy is only 40-45%. Single-cell RNA sequencing (scRNA-seq) enables unbiased analysis of the full variety of cells comprising the tumor microenvironment. Thus, we used scRNA-seq to assess differences among microenvironment components between therapy-resistant and therapy-sensitive groups in MSI-H/mismatch repair-deficient (dMMR) mCRC. Resistance-related cell types and genes identified by this analysis were subsequently verified in clinical samples and mouse models to further reveal the molecular mechanism of anti-PD-1 resistance in MSI-H or dMMR mCRC. METHODS: The response of primary and metastatic lesions to first-line anti-PD-1 monotherapy was evaluated by radiology. Cells from primary lesions of patients with MSI-H/dMMR mCRC were analyzed using scRNA-seq. To identify the marker genes in each cluster, distinct cell clusters were identified and subjected to subcluster analysis. Then, a protein‒protein interaction network was constructed to identify key genes. Immunohistochemistry and immunofluorescence were applied to verify key genes and cell marker molecules in clinical samples. Immunohistochemistry, quantitative real-time PCR, and western blotting were performed to examine the expression of IL-1ß and MMP9. Moreover, quantitative analysis and sorting of myeloid-derived suppressor cells (MDSCs) and CD8+ T cells were performed using flow cytometry. RESULTS: Tumor responses in 23 patients with MSI-H/dMMR mCRC were evaluated by radiology. The objective response rate was 43.48%, and the disease control rate was 69.57%. ScRNA-seq analysis showed that, compared with the treatment-resistant group, the treatment-sensitive group accumulated more CD8+ T cells. Experiments with both clinical samples and mice indicated that infiltration of IL-1ß-driven MDSCs and inactivation of CD8+ T cells contribute to anti-PD-1 resistance in MSI-H/dMMR CRC. CONCLUSIONS: CD8+ T cells and IL-1ß were identified as the cell type and gene, respectively, with the highest correlation with anti-PD-1 resistance. Infiltration of IL-1ß-driven MDSCs was a significant factor in anti-PD-1 resistance in CRC. IL-1ß antagonists are expected to be developed as a new treatment for anti-PD-1 inhibitor resistance.

Bioactive ß-Carbolines Harman and Norharman in Sesame Seed Oils in China.

The ß-carbolines in our diet, mainly including harman and norharman, are a group of biologically active, naturally occurring plant-derived alkaloids. Fragrant sesame seed oil is one of the most popular flavor edible oils in China. Considering that sesame seeds are roasted at 200-240 °C during the processing of flavor sesame seed oils, it is meaningful to investigate the levels of ß-carboline compounds in various sesame seed oils. In this work, the levels of ß-carbolines (harman and norharman) in different types of sesame seed oils in China (e.g., pressed fragrant sesame oil, ground fragrant sesame oil) have been determined systematically. The results showed that the levels of total ß-carbolines in pressed fragrant sesame oils (700.5~2423.2 µg/kg) were higher than that in ground fragrant sesame oils (660.4~1171.7 µg/kg). Roasting sesame seeds at high temperatures (200-240 °C) led to higher levels of ß-carbolines (660~2400 µg/kg) in fragrant sesame seed oils. In addition, the loss of tryptophan might be attributed to the formation of ß-carbolines in sesame seeds during the roasting process. In general, fragrant sesame seed oils (pressed fragrant sesame oils, ground fragrant sesame oils) contain higher levels of ß-carbolines due to the formation of harman and norharman during the roasting sesame seed process.

[Clinical experience in the treatment of incomplete Kawasaki disease with no response to intravenous immunoglobulin: a case report]. / é™è„‰æ³¨å°„å ç–«çƒè›‹ç™½æ— åº”ç­”ä¸å®Œå ¨æ€§å·å´Žç— 1例临床经验交流.

This article reports a case of incomplete Kawasaki disease with no response to intravenous immunoglobulin (IVIG). A girl, aged 1 year, had the symptoms of fever, rash, finger desquamation, and coronary artery ectasia. She still had fever at 36 hours after the first dose of IVIG treatment, and her temperature returned to normal after the second dose of IVIG treatment. The follow-up after 1 month showed that the coronary artery diameter returned to normal. This article summarizes the experience in the treatment of incomplete Kawasaki disease with no response to IVIG in order to reduce the incidence of coronary artery damage.

Herbal medicine derived carbon dots: synthesis and applications in therapeutics, bioimaging and sensing.

Since the number of raw material selections for the synthesis of carbon dots (CDs) has grown extensively, herbal medicine as a precursor receives an increasing amount of attention. Compared with other biomass precursors, CDs derived from herbal medicine (HM-CDs) have become the most recent incomer in the family of CDs. In recent ten years, a great many studies have revealed that HM-CDs tend to be good at theranostics without drug loading. However, the relevant development and research results are not systematically reviewed. Herein, the origin and history of HM-CDs are outlined, especially their functional performances in medical diagnosis and treatment. Besides, we sort out the herbal medicine precursors, and analyze the primary synthetic methods and the key characteristics. In terms of the applications of HM-CDs, medical therapeutics, ion and molecular detection, bioimaging, as well as pH sensing are summarized. Finally, we discuss the crucial challenges and future prospects.

Degradation of ß-Carbolines Harman and Norharman in Edible Oils during Heating.

The ß-carbolines, mainly including harman and norharman, are a group of naturally occurring, plant-derived alkaloids, and are also considered as nonpolar heterocyclic aromatic amines. Sesame seed oils contain a high level of ß-carbolines (harman and norharman). In China, sesame seed oil blends are one of the most popular types of vegetable oils blends, which can be used as cooking oils or frying oils. Thus, it is meaningful to investigate the degradation of ß-carbolines (harman and norharman) in sesame seed oil blends as frying oils during heating. In this work, the loss of harman and norharman in different types of sesame seed oil blends have been investigated. The results showed that the degradation of harman and norharman were dependent both on the type of oil blends, heating temperature and time. Harman and norharman were more degraded during heating (150 °C, 180 °C) in oleic acid-rich oil blends compared to polyunsaturated acid-rich oil blends. Mechanistic investigation suggested that the reduction in harman and norharman in oil blends during heating was mainly due to the oxidative degradation reaction between ß-carbolines and lipid oxidation products. Therefore, the contents of ß-carbolines (harman and norharman) in sesame seed oil blends when used as frying oils and heated can be decreased with prolonged cooking time.

Nobiletin Ameliorates Aging of Chicken Ovarian Prehierarchical Follicles by Suppressing Oxidative Stress and Promoting Autophagy.

With the increase in the age of laying chickens, the aging of follicles is accelerated, and the reproductive ability is decreased. Increased oxidative stress and mitochondrial malfunction are indispensable causes of ovarian aging. In this study, the physiological condition of prehierarchical small white follicles (SWFs) was compared between D280 high-producing chickens and D580 aging chickens, and the effect of a plant-derived flavonoid nobiletin (Nob), a natural antioxidant, on senescence of SWFs granulosa cells (SWF-GCs) was investigated. The results showed that Nob treatment activated cell autophagy by activating the AMP-activated protein kinase (AMPK) and Sirtuin-1 (SIRT1) pathways in D-galactose (D-gal)-generated senescent SWF-GCs, restoring the expression of proliferation-related mRNAs and proteins. In addition, the expression of inflammation-related protein NF-κB was significantly enhanced in aging GCs that were induced by D-gal. Nob supplementation significantly increased the antioxidant capacity and decreased the expression of several genes associated with cell apoptosis. Furthermore, Nob promoted activation of PINK1 and Parkin pathways for mitophagy and alleviated mitochondrial edema. Either the AMPK inhibitor dorsomorphin (Compound C) or SIRT1 inhibitor selisistat (EX-527) attenuated the effect of Nob on mitophagy. The protective effect of Nob on natural aging, GC proliferation, and elimination of the beneficial impact on energy regulation of naturally aging ovaries was diminished by inhibition of Nob-mediated autophagy. These data suggest that Nob treatment increases the expression of mitophagy-related proteins (PINK1 and Parkin) via the AMPK/SIRT1 pathways to prevent ovarian aging in the laying chickens.

Bioactive Lignan Honokiol Alleviates Ovarian Oxidative Stress in Aging Laying Chickens by Regulating SIRT3/AMPK Pathway.

Aging is not only a key internal cause of age-related diseases in humans but also poses a threat to the productivity of farm animals with longer breeding cycles, such as laying chickens. Various measures were taken to prolong the laying period by reducing oxidative stress to improve poultry ovarian functions. Within the mitochondria, SIRT3, a member of the Sirtuin family, plays an important role in post-translational modifications and the regulation of protein activities involved in energy metabolism and oxidative response. This study aimed to investigate the alleviating effect of a bioactive lignan Honokiol (HKL) on oxidative stress in aging chicken ovaries in order to retard decline in egg production. The results showed that HKL treatment restored the abnormal balance between cell proliferation and apoptosis, and it enhanced the antioxidant capacity of the H2O2-induced small white follicles (SWFs) by activating the SIRT3/AMPK pathway. Moreover, HKL significantly increased total egg production, the number of yellow follicles, and the mRNA expression of yolk synthesis and deposition-related genes, serum estrogen, and antioxidant levels. These findings suggest that HKL holds promise in enhancing the egg productivity of aging laying chickens by promoting yolk deposition and reducing ovarian oxidative stress.

Calycosin ameliorates osteoarthritis by regulating the imbalance between chondrocyte synthesis and catabolism.

Osteoarthritis (OA) is a severe chronic inflammatory disease. As the main active component of Astragalus mongholicus Bunge, a classic traditional ethnic herb, calycosin exhibits anti-inflammatory action and its mechanism of exact targets for OA have yet to be determined. In this study, we established an anterior cruciate ligament transection (ACLT) mouse model. Mice were randomized to sham, OA, and calycosin groups. Cartilage synthesis markers type II collagen (Col-2) and SRY-Box Transcription Factor 9 (Sox-9) increased significantly after calycosin gavage. While cartilage matrix degradation index cyclooxygenase-2 (COX-2), phosphor-epidermal growth factor receptor (p-EGFR), and matrix metalloproteinase-9 (MMP9) expression were decreased. With the help of network pharmacology and molecular docking, these results were confirmed in chondrocyte ADTC5 cells. Our results indicated that the calycosin treatment significantly improved cartilage damage, this was probably attributed to reversing the imbalance between chondrocyte synthesis and catabolism.

Distribution of multi-level B cell subsets in thymoma and thymoma-associated myasthenia gravis.

B-cell subsets in peripheral blood (PB) and tumor microenvironment (TME) were evaluated to determine myasthenia gravis (MG) severity in patients with thymoma-associated MG (TMG) and the distribution of B cells in type B TMG. The distribution of mature B cells, including Bm1-Bm5, CD19+ and CD20+ B cells and non-switched (NSMBCs) and switched (SMBCs) memory B cells, were determined in 79 patients with thymoma or TMG. Quantitative relationships between the T and TMG groups and the TMG-low and TMG-high subgroups were determined. NSMBCs and SMBCs were compared in TME and PB. Type B thymoma was more likely to develop into MG, with types B2 and B3 being especially associated with MG worsening. The percentage of CD19+ B cells in PB gradually increased, whereas the percentage of CD20+ B cells and the CD19/CD20 ratio were not altered. The (Bm2 + Bm2')/(eBm5 + Bm5) index was significantly higher in the TMG-high than in thymoma group. The difference between SMBC/CD19+ and NSMBC/CD19+ B cell ratios was significantly lower in the thymoma than TMG group. NSMBCs assembled around tertiary lymphoid tissue in thymomas of patients with TMG. Few NSMBCs were observed in patients with thymoma alone, with these cells being diffusely distributed. MG severity in patients with TMG can be determined by measuring CD19+ B cells and Bm1-Bm5 in PB. The CD19/CD20 ratio is a marker of disease severity in TMG patients. Differences between NSMBCs and SMBCs in PB and TME of thymomas can synergistically determine MG severity in patients with TMG.

Xuefu Zhuyu decoction promotes synaptic plasticity by targeting miR-191a-5p/BDNF-TrkB axis in severe traumatic brain injury.

BACKGROUND: Xuefu Zhuyu decoction (XFZYD) is a traditional Chinese herbal formula known for its ability to eliminate blood stasis and improve blood circulation, providing neuroprotection against severe traumatic brain injury (sTBI). However, the underlying mechanism is still unclear. PURPOSE: We aim to investigate the neuroprotective effects of XFZYD in sTBI from a novel mechanistic perspective of miRNA-mRNA. Additionally, we sought to elucidate a potential specific mechanism by integrating transcriptomics, bioinformatics, and conducting both in vitro and in vivo experiments. METHODS: The sTBI rat model was established, and the rats were treated with XFZYD for 14 days. The neuroprotective effects of XFZYD were evaluated using a modified neurological severity score, hematoxylin and eosin staining, as well as Nissl staining. The anti-inflammatory effects of XFZYD were explored using quantitative real-time PCR (qRT-PCR), Western blot analysis, and immunofluorescence. Next, miRNA sequencing of the hippocampus was performed to determine which miRNAs were differentially expressed. Subsequently, qRT-PCR was used to validate the differentially expressed miRNAs. Target core mRNAs were determined using various methods, including miRNA prediction targets, mRNA sequencing, miRNA-mRNA network, and protein-protein interaction (PPI) analysis. The miRNA/mRNA regulatory axis were verified through qRT-PCR or Western blot analysis. Finally, morphological changes in the neural synapses were observed using transmission electron microscopy and immunofluorescence. RESULTS: XFZYD exhibited significant neuroprotective and anti-inflammatory effects on subacute sTBI rats' hippocampus. The analyses of miRNA/mRNA sequences combined with the PPI network revealed that the therapeutic effects of XFZYD on sTBI were associated with the regulation of the rno-miR-191a-5p/BDNF axis. Subsequently, qRT-PCR and Western blot analysis confirmed XFZYD reversed the decrease of BDNF and TrkB in the hippocampus caused by sTBI. Additionally, XFZYD treatment potentially increased the number of synaptic connections, and the expression of the synapse-related protein PSD95, axon-related protein GAP43 and neuron-specific protein TUBB3. CONCLUSIONS: XFZYD exerts neuroprotective effects by promoting hippocampal synaptic remodeling and improving cognition during the subacute phase of sTBI through downregulating of rno-miR-191a-5p/BDNF axis, further activating BDNF-TrkB signaling.

N6-methyladenosine profiling reveals that Xuefu Zhuyu decoction upregulates METTL14 and BDNF in a rat model of traumatic brain injury.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese herbal formula Xuefu Zhuyu decoction (XFZYD) is a classic formula in the category of invigorating blood circulation and resolving blood stasis. It has been proven to improve the neurological and ethological prognosis of traumatic brain injury. XFZYD promotes synaptic and axonal regeneration after traumatic brain injury, which is functionally modulated by the N6-methyladenosine (m6A) modification of RNA. However, the epigenetic effects of XFZYD on m6A modification remain unknown. AIM OF THE STUDY: To explore how XFZYD protects against traumatic brain injury induced by controlled cortical impact (CCI) injury by altering RNA m6A modification. MATERIALS AND METHODS: The modified neurological severity scoring and Morris water maze were performed to evaluate the neuroprotective effects of XFZYD for 14 days and screen the dose. Then, dot blot, western blotting, and methylated RNA immunoprecipitation sequencing (MeRIP-Seq) were used to explore changes in RNA m6A modification in the perilesional cortex. The Metascape platform was used to analyze the Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway of the differential m6A-tagged genes. Furthermore, MeRIP-qPCR was conducted to quantify differences in the hub differential m6A modification gene brain-derived neurotrophic factor (Bdnf). RESULTS: XFZYD significantly ameliorated the neurological deficits, spatial learning, and memory impairments in rats post-CCI on day 14. XFZYD enhanced the m6A level, and the expression of METTL14 and YTHDC2 in the perilesional cortex of CCI rats. In all three groups, the 3'-untranslated regions and coding sequence were primarily enriched for m6A peaks. XFZYD reversed the increased proportion of 3'-untranslated regions, and the decreased proportion of coding sequence and 5'-untranslated regions post-CCI. Moreover, XFZYD markedly downregulated 41 elevated m6A-tagged transcripts and upregulated 119 decreased m6A-tagged transcripts following CCI. Gene ontology and KEGG pathway analysis revealed that XFZYD-regulated m6A-tagged transcripts were predominantly enriched in synapse assembly, synaptic plasticity, learning or memory, and MAPK signaling pathway. Then, the hub-regulated m6A-tagged gene BDNF was identified. Both the m6A methylation level and the protein level of BDNF were ascended by XFZYD treatment. CONCLUSION: XFZYD improves neurological deficits, spatial learning and memory impairments in rats post-TBI probably through increasing the expression of METTL14 and BDNF in the cortex. Our study highlights a novel post-transcriptional regulation mechanism mediated by herbal medicine for traumatic brain injury treatment.

Valproic Acid Inhibits Glioma and Its Mechanisms.

Glioma is one of the most common intracranial tumors worldwide, and metastasis and chemoresistance remain a challenge in glioma treatment. This study aims to investigate the effect of sodium valproate on the invasion and metastasis of glioma cells and its mechanism. Glioma cell lines were stimulated with VPA at different concentrations and for different durations of action. U87 glioma cells were transfected with Smad4 plasmid and small interfering RNA, and the changes of EMT-related protein indexes in U87 cells after up- or downregulation of Smad4 were detected by Western blotting. Immunohistochemistry was used to detect the differences in the expression of Smad4, TIF1-γ, and TGF-ß proteins in 39 glioma clinical specimens from the Department of Pathology of our hospital. Based on the regulation of EMT-related transcription factors by VPA, our study indicates that VPA inhibits the EMT process of glioma by altering the expression level of Smad4, which is induced by TGF-ß1 to form a Smad3/4 complex, thus inducing the EMT process of the tumor and acting as an antitumor target to inhibit the invasive ability of glioma cells. Sodium valproate inhibits glioma invasion and metastasis through the regulation of Smad4 expression.

Follicle-Stimulating Hormone Alleviates Ovarian Aging by Modulating Mitophagy- and Glycophagy-Based Energy Metabolism in Hens.

As a predominant hormone in the reproductive axis, follicle-stimulating hormone (FSH) is known as the primary surviving factor for follicular growth. In this study, the alleviating effect of FSH on aging chicken granulosa cells (GCs) was investigated. Results showed that FSH activated mitophagy and relieved mitochondrial edema in D-gal-induced senescent GCs, which was evidenced by an increased number of mitophagosomes as well as increased mitochondria-light chain 3 (LC3) colocalization. Mitophagy activation was accompanied by the activation of the AMP-activated protein kinase (AMPK) signaling pathway. Furthermore, upregulated glycophagy was demonstrated by an increased interaction of starch-binding domain protein 1 (STBD1) with GABA type A receptor-associated protein-like 1 (GABARAPL1) in D-gal-induced senescent GCs. FSH treatment further promoted glycophagy, accompanied by PI3K/AKT activation. PI3K inhibitor LY294002 and AKT inhibitor GSK690693 attenuated the effect of FSH on glycophagy and glycolysis. The inhibition of FSH-mediated autophagy attenuated the protective effect of FSH on naturally aging GC proliferation and glycolysis. The simultaneous blockage of PI3K/AKT and AMPK signaling also abolished the positive effect of FSH on naturally senescent ovarian energy regulation. These data reveal that FSH prevents chicken ovarian aging by modulating glycophagy- and mitophagy-based energy metabolism through the PI3K/AKT and AMPK pathways.

Bioinformatics Analysis of miRNAs and mRNAs Network-Xuefu Zhuyu Decoction Exerts Neuroprotection of Traumatic Brain Injury Mice in the Subacute Phase.

Xuefu Zhuyu decoction (XFZYD) is used to treat traumatic brain injury (TBI). XFZYD-based therapies have achieved good clinical outcomes in TBI. However, the underlying mechanisms of XFZYD in TBI remedy remains unclear. The study aimed to identify critical miRNAs and putative mechanisms associated with XFYZD through comprehensive bioinformatics analysis. We established a controlled cortical impact (CCI) mice model and treated the mice with XFZYD. The high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) confirmed the quality of XFZYD. The modified neurological severity score (mNSS) and Morris water maze (MWM) tests indicated that XFZYD improved the neurological deficit (p < 0.05) and cognitive function (p < 0.01). Histological analysis validated the establishment of the CCI model and the treatment effect of XFZYD. HE staining displayed that the pathological degree in the XFZYD-treated group was prominently reduced. The transcriptomic data was generated using microRNA sequencing (miRNA-seq) of the hippocampus. According to cluster analysis, the TBI group clustered together was distinct from the XFZYD group. Sixteen differentially expressed (5 upregulated; 11 downregulated) miRNAs were detected between TBI and XFZYD. The reliability of the sequencing data was confirmed by qRT-PCR. Three miRNAs (mmu-miR-142a-5p, mmu-miR-183-5p, mmu-miR-96-5p) were distinctively expressed in the XFZYD compared with the TBI and consisted of the sequencing results. Bioinformatics analysis suggested that the MAPK signaling pathway contributes to TBI pathophysiology and XFZYD treatment. Subsequently, the functions of miR-96-5p, miR-183-5p, and miR-142a-5p were validated in vitro. TBI significantly induces the down-expression of miR-96-5p, and up-expression of inflammatory cytokines, which were all inhibited by miR-96-5p mimics. The present research provides an adequate fundament for further knowing the pathologic and prognostic process of TBI and supplies deep insights into the therapeutic effects of XFZYD.

Mig-6 could inhibit cell proliferation and induce apoptosis in esophageal squamous cell carcinoma.

BACKGROUND: To investigate the expression and biological functions of mitogen-induced gene 6 (Mig-6) in esophageal squamous cell carcinoma (ESCC). METHODS: The expression of Mig-6 in ESCC tissues and normal esophageal epithelial tissues were measured by immunohistochemistry (IHC) assay. MTT test was applied to detect the proliferative ability of ESCC cells after Mig-6 was upregulated by transfection. A fluid cytology assay was used to detect apoptosis of ESCC cells. Agilent whole human genome oligo microarray was used to screen different expressed genes and the possible signaling pathways which might be involved. RESULTS: The expression of Mig-6 protein was lower in ESCC tissues compared to normal esophageal epithelial tissues. Mig-6 could restrain the ESCC cell growth and induce cell apoptosis. PPAR, CAMs and MAPK signaling pathways might be involved. CONCLUSIONS: Mig-6 might be a new tumor suppressor gene and a possible target for the specific therapy of ESCC.

Dexmedetomidine post-conditioning protects blood-brain barrier integrity by modulating microglia/macrophage polarization via inhibiting NF-κB signaling pathway in intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is one of the most devastating forms of stroke. Dexmedetomidine (DEX) has shown certain neuroprotective roles in ICH. Nevertheless, the details concerning the underlying molecular mechanism of DEX's protective effects still need further elucidation. Herein, a model of ICH was established. The rats were randomly divided into the sham group, the ICH group, and the ICH + DEX group. Neurological outcomes, neuronal injury, and apoptosis were evaluated. Brain water content, Evans blue extravasation, and the expression of tight junction-associated proteins were also detected to assess the blood-brain barrier (BBB) integrity. Subsequently, the microglia/macrophage polarization state and inflammatory cytokine levels were observed. To further explore the underlying mechanism, NF-κB signaling pathway-associated proteins were detected. The results showed that DEX exerted neuroprotective effects against ICH-induced neurological deficits. DEX significantly increased the numbers of the surviving neurons and ameliorated neuronal cell loss and apoptosis in ICH. The rats that received the DEX displayed a lower level of brain water content and EB extravasation, moreover, ZO-1, occludin, and claudin-5 were markedly increased by DEX. Additionally, DEX facilitated M2 microglia/macrophage polarization, the M1-associated markers were reduced by DEX, while the M2-associated identification significantly increased. We found that DEX dramatically diminished pro-inflammatory cytokines expression, simultaneously promoting anti-inflammatory cytokines expression. DEX inhibited nuclear translocation of NF-κB in ICH rats. Our data suggest that DEX post-conditioning protects BBB integrity by modulating microglia/macrophage polarization via inhibiting the NF-κB signaling pathway in ICH.

The Involvement of Long Non-coding RNA and Messenger RNA Based Molecular Networks and Pathways in the Subacute Phase of Traumatic Brain Injury in Adult Mice.

Traumatic brain injury (TBI) is a complex injury with a multi-faceted recovery process. Long non-coding RNAs (lncRNAs) are demonstrated to be involved in central nervous system (CNS) disorders. However, the roles of lncRNAs in long-term neurological deficits post-TBI are poorly understood. The present study depicted the microarray's lncRNA and messenger RNA (mRNA) profiles at 14 days in TBI mice hippocampi. LncRNA and mRNA microarray was used to identify differentially expressed genes. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to validate the microarray results. Bioinformatics analysis [including Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, lncRNA-mRNA co-expression network, and lncRNA-miRNA-mRNA network] were applied to explore the underlying mechanism. A total of 264 differentially expressed lncRNAs and 232 expressed mRNAs were identified (fold change > 1.5 and P-value < 0.05). Altered genes were enriched in inflammation, immune response, blood-brain barrier, glutamatergic neurological effects, and neuroactive ligand-receptor, which may be associated with TBI-induced pathophysiologic changes in the long-term neurological deficits. The lncRNAs-mRNAs co-expression network was generated for 74 lncRNA-mRNA pairs, most of which are positive correlations. The lncRNA-miRNA-mRNA interaction network included 12 lncRNAs, 59 miRNAs, and 25 mRNAs. Numerous significantly altered lncRNAs and mRNAs in mice hippocampi were enriched in inflammation and immune response. Furthermore, these dysregulated lncRNAs and mRNAs may be promising therapeutic targets to overcome obstacles in long-term recovery following TBI.

Metabolomics Analysis of the Prefrontal Cortex in a Rat Chronic Unpredictable Mild Stress Model of Depression.

Background: Depressive disorder is the leading cause of disability and suicidality worldwide. Metabolites are considered indicators and regulators of depression. However, the pathophysiology of the prefrontal cortex (PFC) in depression remains unclear. Methods: A chronic unpredictable mild stress (CUMS) model and a maturation rodent model of depression was used to investigate metabolic changes in the PFC. Eighteen male Sprague-Dawley rats were randomly divided into CUMS and control groups. The sucrose preference test (SPT) and forced swimming test (FST) were employed to evaluate and record depression-associated behaviors and changes in body weight (BW). High-performance liquid chromatography-tandem mass spectrometry was applied to test metabolites in rat PFC. Furthermore, principal component analysis and orthogonal partial least-squares discriminant analysis were employed to identify differentially abundant metabolites. Metabolic pathways were analyzed using MetaboAnalyst. Finally, a metabolite-protein interaction network was established to illustrate the function of differential metabolites. Results: SPT and FST results confirmed successful establishment of the CUMS-induced depression-like behavior model in rats. Five metabolites, including 1-methylnicotinamide, 3-methylhistidine, acetylcholine, glycerophospho-N-palmitoyl ethanolamine, α-D-mannose 1-phosphate, were identified as potential biomarkers of depression. Four pathways changed in the CUMS group. Metabolite-protein interaction analysis revealed that 10 pathways play roles in the metabolism of depression. Conclusion: Five potential biomarkers were identified in the PFC and metabolite-protein interactions associated with metabolic pathophysiological processes were explored using the CUMS model. The results of this study will assist physicians and scientists in discovering potential diagnostic markers and novel therapeutic targets for depression.

Self-assembly hydrogels of therapeutic agents for local drug delivery.

Advanced drug delivery systems are of vital importance to enhance therapeutic efficacy. Among various recently developed formulations, self-assembling hydrogels composed of therapeutic agents have shown promising potential for local drug delivery owing to their excellent biocompatibility, high drug-loading efficiency, low systemic toxicity, and sustained drug release behavior. In particular, therapeutic agents self-assembling hydrogels with well-defined nanostructures are beneficial for direct delivery to the target site via injection, not only improving drug availability, but also extending their retention time and promoting cellular uptake. In brief, the self-assembly approach offers better opportunities to improve the precision of pharmaceutical treatment and achieve superior treatment efficacies. In this review, we intend to cover the recent developments in therapeutic agent self-assembling hydrogels. First, the molecular structures, self-assembly mechanisms, and application of self-assembling hydrogels are systematically outlined. Then, we summarize the various self-assembly strategies, including the single therapeutic agent, metal-coordination, enzyme-instruction, and co-assembly of multiple therapeutic agents. Finally, the potential challenges and future perspectives are discussed. We hope that this review will provide useful insights into the design and preparation of therapeutic agent self-assembling hydrogels.