Blocking Gremlin1 inhibits M1 macrophage polarization through Notch1/Hes1 signaling pathway in apical periodontitis.

BACKGROUND: Gremlin1 is a multifunctional protein whose expression is demonstrated to be involved in a series of physiology and pathological processes. The association between Gremlin1 and apcial periodontitis (AP) has been established. M1-polarized macrophages are crucial immune cells that exacerbate the progression of apical periodontal inflammatory response, but the function of Gremlin1 during macrophages activation in periapical lesions is still unclear. This study attempts to explore the regulatory effects of Gremlin1 on macrophage polarization on apical periodontitis microenviroment. METHODS: Clinical specimens were used to determine the expression of Gremlin1 in periapical tissues by immunohistochemical (IHC) staining. Then, the disease models of periapical inflammation in rats were established, and adenovirus- associated virus (AAVs) was used to blockade Gremlin1 expression. Lentivirus carrying sh-Gremlin1 particles were used to transfect THP-1 induced M1-subtype macrophages. To assess the expression of associated molecules, Western-blot, immunofluorescence staining were performed. RESULTS: Gremlin1 was significantly up-regulated in the periapical tissues of subjects with AP as identified by IHC staining, and positively correlated with levels of M1 macrophage-associated genes. Rats AP model with inhibition of Gremlin1 in periapical lesions exhibited limited infiltration of macrophages and decreased expression of M1 macrophage-related genes in periapical lesions. Furthermore, Gremlin1 blockade substantially decreased the Notch1/Hes1 signaling pathway activation level. The in vitro experiments confirmed the above results. CONCLUSION: Taken together, current study illustrated that the Gremlin1 suppression in periapical lesions inhibited M1 macrophage polarization through Notch1/Hes1 axis. Moreover, Gremlin1 may act as a potential candidate in the treatment of AP.

Host-Guest Metal-Organic Frameworks-Based Long-Afterglow Luminescence Materials.

Long-afterglow materials have a broad of applications in optoelectronic devices, sensors, medicine and other fields due to their excellent luminescent properties. The host-guest long-afterglow MOFs material combines the advantages of multi-component characteristics and the stability of MOFs, which improves its luminous performance and expands its other properties. This review introduces the classification, synthesis and application of host-guest MOFs materials with long afterglow. Due to their rigid frames and multi-channel characteristics, MOFs can load common guest materials including rare earth metals, organic dyes, carbon dots, etc. The synthesis methods of loading guest materials into MOFs include solvothermal synthesis, post-encapsulation, post-modification, etc. Those long-afterglow host-guest MOFs have a wide range of applications in the fields of sensors, information security and biological imaging.

Design, docking optimization, and evaluation of biotin-PEG4-1,8-naphthalimide as a potent and safe antitumor agent with dual targeting of ferroptosis and DNA.

A set of biotin-polyethylene glycol (PEG)-naphthalimide derivatives 4a-4h with dual targeting of ferroptosis and DNA were designed and optimized using docking simulation as antitumor agents. Docking simulation optimization results indicated that biotin-PEG4-piperazine-1,8-naphthalimide 4d should be the best candidate among these designed compounds 4a-4h, and therefore, we synthesized and evaluated it as a novel antitumor agent. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and MGC-803 and U251 xenograft models identified 4d as a good candidate antitumor agent with potent efficacy and safety profiles, compared with amonafide and temozolomide. The findings of the docking simulations, fluorescence intercalator displacement (FID), western blot, comet, 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transmission electron microscopy, and BODIPY-581/591-C11, FerroOrange, and dihydroethidium (DHE) fluorescent probe assays revealed that 4d could induce DNA damage, affect DNA synthesis, and cause cell cycle arrest in the S phase in MGC-803 cells. Also, it could induce lipid peroxidation and thus lead to ferroptosis in MGC-803 cells, indicating that it mainly exerted antitumor effects through dual targeting of ferroptosis and DNA. These results suggested that it was feasible to design, optimize using docking simulation, and evaluate the potency and safety of biotin-PEG-1,8-naphthalimide as a antitumor agent with dual targeting of ferroptosis and DNA, based on a multi-target drug strategy.

A randomized controlled clinical trial of concentrated growth factor combined with sodium hyaluronate in the treatment of temporomandibular joint osteoarthritis.

OBJECTIVE: To investigate the effect of concentrated growth factor (CGF) combined with sodium hyaluronate (SH) on temporomandibular joint osteoarthritis (TMJOA). METHODS: Sixty patients with TMJOA who were diagnosed by cone-beam computed tomography (CBCT) between March 2020 and March 2023 at the Stomatological Hospital of Xi'an Jiaotong University were randomly divided into a control group (n = 30) and an experimental group (n = 30). The patients in the experimental group were treated with CGF + SH, and those in the control group were treated with SH only. The visual analogue scale (VAS) score indicating pain in the temporomandibular joint (TMJ) area; the Helkimo Clinical Dysfunction Index (Di); and changes in condylar CBCT at the first visit and 2 weeks, 3 months and 6 months after treatment were recorded. The CBCT data of the patients in the experimental and control groups were collected, and the three-dimensional CBCT image sequences were imported into Mimics Medical 19.0 software in DICOM format for condylar reconstruction. RESULTS: The VAS scores at 2 weeks, 3 months and 6 months after treatment were significantly lower in the experimental group than in the control group (P < 0.05), and the pain in the experimental group was significantly relieved. The Di was significantly lower in the experimental group than in the control group (P < 0.05), and the clinical function of the TMJ improved. After treatment, the CBCT score was significantly lower in the experimental group than in the control group (P < 0.05), and the condylar bone cortex was obviously repaired. Observation of the condylar bone cortex by three-dimensional reconstruction showed the same results as those obtained by CBCT. CONCLUSION: CGF combined with SH is effective in the treatment of TMJOA and can improve muscle pain, TMJ pain, Impaired TMJ function, Impaired range of movement, Pain on movement of the mandible and promote bone repair. THE REGISTRATION NUMBER (TRN): ChiCTR2400082712. THE DATE OF REGISTRATION: April 5, 2024.

Identification of Early Warning Signals of Infectious Diseases in Hospitals by Integrating Clinical Treatment and Disease Prevention.

The global incidence of infectious diseases has increased in recent years, posing a significant threat to human health. Hospitals typically serve as frontline institutions for detecting infectious diseases. However, accurately identifying warning signals of infectious diseases in a timely manner, especially emerging infectious diseases, can be challenging. Consequently, there is a pressing need to integrate treatment and disease prevention data to conduct comprehensive analyses aimed at preventing and controlling infectious diseases within hospitals. This paper examines the role of medical data in the early identification of infectious diseases, explores early warning technologies for infectious disease recognition, and assesses monitoring and early warning mechanisms for infectious diseases. We propose that hospitals adopt novel multidimensional early warning technologies to mine and analyze medical data from various systems, in compliance with national strategies to integrate clinical treatment and disease prevention. Furthermore, hospitals should establish institution-specific, clinical-based early warning models for infectious diseases to actively monitor early signals and enhance preparedness for infectious disease prevention and control.

Identification of immune-associated biomarker for predicting lung adenocarcinoma: bioinformatics analysis and experiment verification of PTK6.

BACKGROUND: Abnormal expression of protein tyrosine kinase 6 (PTK6) has been proven to be involved in the development of gynecological tumors. However, its immune-related carcinogenic mechanism in other tumors remains unclear. OBJECTIVE: The aim of this study was to identify PTK6 as a novel prognostic biomarker in pan-cancer, especially in lung adenocarcinoma (LUAD), which is correlated with immune infiltration, and to clarify its clinicopathological and prognostic significance. METHODS: The prognostic value and immune relevance of PTK6 were investigated by using bio-informatics in this study. PTK6 expression was validated in vitro experiments (lung cancer cell lines PC9, NCI-H1975, and HCC827; human normal lung epithelial cells BEAS-2B). Western blot (WB) revealed the PTK6 protein expression in lung cancer cell lines. PTK6 expression was inhibited by Tilfrinib. Colony formation and the Cell Counting Kit-8 (CCK-8) assay were used to detect cell proliferation. The wound healing and trans-well were performed to analyze the cell migration capacity. Then flow cytometry was conducted to evaluate the cell apoptosis. Eventually, the relationship between PTK6 and immune checkpoints was examined. WB was used to estimate the PD-L1 expression at different Tilfrinib doses. RESULTS: PTK6 was an independent predictive factor for LUAD and was substantially expressed in LUAD. Pathological stage was significantly correlated with increased PTK6 expression. In accordance with survival analysis, poor survival rate in LUAD was associated with a high expression level of PTK6. Functional enrichment of the cell cycle and TGF-ß signaling pathway was demonstrated by KEGG and GSEA analysis. Moreover, PTK6 expression considerably associated with immune infiltration in LUAD, as determined by immune analysis. Thus, the result of vitro experiments indicated that cell proliferation and migration were inhibited by the elimination of PTK6. Additionally, PTK6 suppression induced cell apoptosis. Obviously, PD-L1 protein expression level up-regulated while PTK6 was suppressed. CONCLUSION: PTK6 has predictive value for LUAD prognosis, and could up regulated PD-L1.

Antibiotic heteroresistance in Klebsiella pneumoniae: Definition, detection methods, mechanisms, and combination therapy.

Klebsiella pneumoniae is a common opportunistic pathogen that presents significant challenges in the treatment of infections due to its resistance to multiple antibiotics. In recent years, K. pneumoniae has been reported for the development of heteroresistance, a phenomenon where subpopulations of the susceptible bacteria exhibit resistance. This heteroresistance has been associated with increased morbidity and mortality rates. Complicating matters further, its definition and detection pose challenges, often leading to its oversight or misdiagnosis. Various mechanisms contribute to the development of heteroresistance in K. pneumoniae, and these mechanisms differ among different antibiotics. Even for the same antibiotic, multiple mechanisms may be involved. However, our current understanding of these mechanisms remains incomplete, and further research is needed to gain a more comprehensive understanding of heteroresistance. While the clinical recommendation is to use combination antibiotic therapy to mitigate heteroresistance, this approach also comes with several drawbacks and potential adverse effects. In this review, we discuss the definition, detection methods, molecular mechanisms, and treatment of heterogenic resistance, aiming to pave the way for more effective treatment and management in the future. However, addressing the problem of heteroresistance in K. pneumoniae represents a long and complex journey that necessitates comprehensive research efforts.

NK-92MI Cells Engineered with Anti-claudin-6 Chimeric Antigen Receptors in Immunotherapy for Ovarian Cancer.

Background: The application of chimeric antigen receptor (CAR) NK cells in solid tumors is hindered by lack of tumor-specific targets and inefficient CAR-NK cell efficacy. Claudin-6 (CLDN6) has been reported to be overexpressed in ovarian cancer and may be an attractive target for CAR-NK cells immunotherapy. However, the feasibility of using anti-CLDN6 CAR-NK cells to treat ovarian cancer remains to be explored. Methods: CLDN6 expression in primary human ovarian cancer, normal tissues and cell lines were detected by immunohistochemistry and western blot. Two types of third-generation CAR NK-92MI cells targeting CLDN6, CLDN6-CAR1 NK-92MI cells with domains containing self-activated elements (NKG2D, 2B4) and CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB) were constructed by lentivirus transfection, sorted by flow cytometry and verified by western blot and qPCR. OVCAR-3, SK-OV-3, A2780, Hey and PC-3 cells expressing the GFP and luciferase genes were transduced. Subcutaneous and intraperitoneal tumor models were established via NSG mice. The ability of CLDN6-CAR NK cells to kill CLDN6-positive ovarian cancer cells were evaluated in vitro and in vivo by live cell imaging and bioluminescence imaging. Results: Both CLDN6-CAR1 and CLDN6-CAR2 NK-92MI cells could specifically killed CLDN6-positive ovarian cancer cells (OVCAR-3, SK-OV-3, A2780 and Hey), rather than CLDN6 negative cell (PC-3), in vitro. CLDN6-CAR1 NK-92MI cells with domains containing self-activated elements (NKG2D, 2B4) exhibited stronger cytotoxicity than CLDN6-CAR2 NK-92MI cells with classical domains (CD28, 4-1BB). Furthermore, CLDN6-CAR1 NK cells could effectively eliminate ovarian cancer cells in subcutaneous and intraperitoneal tumor models. More importantly, CAR-NK cells combined with immune checkpoint inhibitors, anti-PD-L1, could synergistically enhance the antitumor efficacy of CLDN6-targeted CAR-NK cells. Conclusions: These results indicate that CLDN6-CAR NK cells possess strong antitumor activity and represent a promising immunotherapeutic modality for ovarian cancer.

The novel HLA-B*58:144N allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-B*58:144N differs from HLA-B*58:01:01:01 by one nucleotide in exon 2.

Role of microglia in retinal neurovascular unit of diabetic retinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

Diabetic retinopathy(DR)represents the primary cause of blindness among the global working-age population, and the disruption of the blood-retinal barrier is a crucial factor. Research in recent years has elucidated that DR transcends the scope of a mere microvascular disorder into a complex interplay of retinal glial cells and neurodegeneration microvascular pathology. Neuronal damage may precede vascular endothelial changes in the retinal neurovascular unit(RNVU)in the early stage of DR, and glial cell activation further exacerbates vascular barrier dysfunction. Retinal microglia are immune cells that reside in the retina and are involved in chronic inflammatory responses induced by long-term exposure to high glucose levels. Microglia secrete various inflammatory factors in response to high glucose levels, which can lead to the destruction of the blood-retinal barrier structure, increased neuronal apoptosis, and altered gliosis of Muller cells, thus affecting the retina's homeostatic balance. The RNVU has received increasing attention in recent years as a unitary structural study, and the mechanism of microglia in the RNVU and the progress of the study are reviewed.

Intermittent Theta Burst Stimulation Attenuates Cognitive Deficits and Alzheimer's Disease-Type Pathologies via ISCA1-Mediated Mitochondrial Modulation in APP/PS1 Mice / 神经科学通报·英文版

Intermittent theta burst stimulation (iTBS), a time-saving and cost-effective repetitive transcranial magnetic stimulation regime, has been shown to improve cognition in patients with Alzheimer's disease (AD). However, the specific mechanism underlying iTBS-induced cognitive enhancement remains unknown. Previous studies suggested that mitochondrial functions are modulated by magnetic stimulation. Here, we showed that iTBS upregulates the expression of iron-sulfur cluster assembly 1 (ISCA1, an essential regulatory factor for mitochondrial respiration) in the brain of APP/PS1 mice. In vivo and in vitro studies revealed that iTBS modulates mitochondrial iron-sulfur cluster assembly to facilitate mitochondrial respiration and function, which is required for ISCA1. Moreover, iTBS rescues cognitive decline and attenuates AD-type pathologies in APP/PS1 mice. The present study uncovers a novel mechanism by which iTBS modulates mitochondrial respiration and function via ISCA1-mediated iron-sulfur cluster assembly to alleviate cognitive impairments and pathologies in AD. We provide the mechanistic target of iTBS that warrants its therapeutic potential for AD patients.

Effects of Rosa roxburghii Radix on ulcerative colitis in rats based on pyroptosis and neutrophil extracellular traps / 中成药

AIM To explore the effects of Rosa roxburghii Radix on ulcerative colitis(UC)in rats based on pyroptosis and neutrophil extracellular traps(NETs).METHODS Rats were randomly divided into the normal group and the model group.The successfully established UC rat models by trinitrobenzene sulfonic acid(TNBS)/ethanol enema were then randomly divided into the model group,the sulfasalazine group(0.3 g/kg)and the low,medium and high dose R.roxburghii Radix groups(2,4,8 g/kg),followed by dosing of corresponding drugs by gavage.21 days later,the rats had their disease activity index(DAI)score calculated;their pathological changes of colon tissue observed by HE staining;their levels of serum interleukin(IL)-18,IL-1β and myeloperoxidase(MPO)detected by ELISA;and their protein expressions of NE,MPO,NLRP3,caspase-1 and GSDMD in colon tissue detected by Western blot and immunohistochemistry.RESULTS Compared with the normal group,the model group displayed increased DAI score(P＜0.01),increased serum levels of IL-1β,IL-18 and MPO(P＜0.01),and increased protein expressions of NE,MPO,caspase-1,NLRP3 and GSDMD in colon tissue(P＜0.01).Compared with the model group,the groups intervened with sulfasalazine,or medium,or high dose R.roxburghii Radix demonstrated with decreased DAI scores(P＜0.05,P＜0.01),decreased serum levels of IL-1β,IL-18 and MPO(P＜0.01),and decreased protein expressions of NE,MPO,caspase-1,NLRP3 and GSDMD in colon tissue(P＜0.05,P＜0.01).CONCLUSION R.roxburghii Radix may alleviate the inflammatory reaction in a rat model of UC and improve its pathological injury of colon via regulating pyroptosis and NETs.

Clinical efficacy of Amplatzer duct occluder-Ⅱ device for the treatment of ventricular septal defect with aortic sinus prolapse in child patients / 介入放射学杂志

Objective To investigate the efficacy of Amplatzer duct occluder-Ⅱ device(ADO-Ⅱ)in treating ventricular septal detect(VSD)with aortic sinus prolapse(ASP)in child patients.Methods The clinical data of 94 child patients with VSD complicated by ASP,who were admitted to the Hunan Provincial Children's Hospital of China between January 2018 and September 2022,were retrospectively collected.The child patients included 60 males and 34 females with a mean age of(4.7±3.1)years.Mild-moderate ASP was seen in 83 child patients,with a mean(4.12±0.97)mm-sized VSD.Severe ASP was seen in 11 child patients,with a mean(4.95±0.51)mm-sized VSD.Perimembrane VSD was observed in 54 child patients and intracristal VSD in 40 child patients.The relationship of VSD size and degree of ASP to the selection of ADO-Ⅱ,postoperative middle period aortic valve regurgitation and residual leakage was analyzed,so as to clarify the applicability of ADO-Ⅱ to such child patients.Results In the postoperative middle period,6 child patients had mild aortic valve regurgitation,most seen in the child patients who received 4-4 mm or 5-4 mm ADO-occluder;and 10 child patients had residual leakage,mainly seen in the child patients who received 5-4 mm or 6-4 mm occluder.Conclusion In the condition when the ADO-Ⅱ occluder shows satisfactory placement pattern,this treatment is suitable for the child patient having＜6 mm VSD with ASP.Although there are some residual leakage and aortic valve regurgitation after surgery,this interventional therapy still meets the clinical requirements.(J Intervent Radiol,2024,32:17-21)

Mechanism of Helicobacter pylori metabolites antagonizing host innate immunity / 中国免疫学杂志

Objective:To investigate potential mechanism of Helicobacter pylori metabolites antagonizing host innate immunity.Methods:RNA sequencing and pathway enrichment analysis were used to analyze only LPS-stimulated gastric mucosal cells GES-1,GES-1 cells co-treated with LPS and Helicobacter pylori culture supernatant,and untreated GES-1 cells.The culture supernatant of He-licobacter pylori was filtered by a 3KD ultrafiltration tube,and the filtered filtrate(metabolite part)and the retained solution(protein part)were treated with LPS-stimulated GES-1 cells to detect activity of NF-κB pathway,phosphorylation level of NF-κB,secretion levels of NF-κB pathway effectors TNF-α,IL-6 and IL-8.Identification of key metabolites by untargeted metabolic mass spectrometry.Results:Compared with GES-1 cells stimulated only by LPS,after co-treated with LPS and Helicobacter pylori culture supernatant,expression levels of various genes were regulated and tended to the level of GES-1 in untreated gastric mucosal cells,mainly in the NF-κB pathway.After co-treatment with LPS and culture supernatant of Helicobacter pylori,activity of NF-κB pathway was inhibited(P<0.05).Helicobacter pylori metabolites could inhibit the activity of NF-κB pathway,inhibit phosphorylation of NF-κB,and inhibit the secretion of NF-κB pathway effectors TNF-α,IL-6 and IL-8(P<0.05).1,5 and 25 μmol/L of Helicobacter pylori metabolite 2-D-Glu-copyranose(2DG)treatment inhibited activity of NF-κB pathway and phosphorylation of NF-κB in GES-1 cells,and secretion of NF-κB pathway effectors TNF-α,IL-6 and IL-8 were inhibited(P<0.05).After 2DG treatment,activity of NF-κB in GES-1 cells with TLR3,TLR4,TLR5,TLR6,TLR7,TLR8,TLR9 and TLR10 knockout were significantly decreased(P<0.05);while there was no significant changes in activity of NF-κB in TLR1 and TLR2 knockout GES-1 cells.Both TLR1 and TLR2 interactions were attenuated in GES-1 cells after 2DG treatment.Molecular docking showed that 2DG could bind to TLR2 amino acid disabled R321,K347 and F349,the binding energy was-12 kcal/mol.TLR2 wild-type and mutant plasmids(R321K,K347R,F349A)were constructed,and TLR2-knockout GES-1 cells were respectively transfected.It was found that 2DG treatment did not reduce NF-κB activity in GES-1 cells transfected with TLR2 mutant.Conclusion:Helicobacter pylori metabolite 2DG can interact with TLR2,reduce the formation of het-erodimers between TLR2 and TLR1,and inhibit the activity of innate immune NF-κB pathway.

Porphyromonas gingivalis promotes the progression of oral squamous cell carcinoma by stimulating the release of neutrophil extracellular traps in the tumor immune microenvironment.

BACKGROUND: The aim of this study was to investigate the impact of Porphyromonas gingivalis (P. gingivalis) on the progression of oral squamous cell carcinoma (OSCC) through neutrophil extracellular traps (NETs) in the tumor immune microenvironment. METHODS: The expression of NETs-related markers was identified through immunohistochemistry, immunofluorescence, and Western blotting in different clinical stages of OSCC samples. The relationship between NETs-related markers and clinicopathological characteristics in 180 samples was analyzed using immunohistochemistry data. Furthermore, the ability to predict the prognosis of OSCC patients was determined by ROC curve analysis and survival analysis. The effect of P. gingivalis on the release of NETs was identified through immunofluorescence and immunohistochemistry, both in vitro and in vivo. CAL27 and SCC25 cell lines were subjected to NETs stimulation to elucidate the influence of NETs on various cellular processes, including cell proliferation, migration, invasion, and metastasis in vitro. Furthermore, the impact of NETs on the growth and metastatic potential of OSCC was assessed using in vivo models involving tumor-bearing mice and tumor metastasis mouse models. RESULTS: Immunochemistry analysis revealed a significant correlation between the NETs-related markers and clinical stage, living status as well as TN stage. P. gingivalis has demonstrated its ability to effectively induce the release of NETs both in vivo and in vitro. NETs have the potential to facilitate cell migration, invasion, and colony formation. Moreover, in vivo experiments have demonstrated that NETs play a pivotal role in promoting tumor metastasis. CONCLUSION: High expression of NETs-related markers demonstrates a strong correlation with the progression of OSCC. Inhibition of the NETs release process stimulated by P. gingivalis and targeted NETs could potentially open up a novel avenue in the field of immunotherapy for patients afflicted with OSCC.

Investigation of anti-diabetic effect of a novel coenzyme Q10 derivative.

Introduction: The rising incidence of type 2 diabetes has seriously affected international public health. The search for more drugs that can effectively treat diabetes has become a cutting-edge trend in research. Coenzyme Q10 (CoQ10) has attracted much attention in the last decade due to its wide range of biological activities. Many researchers have explored the clinical effects of CoQ10 in patients with type 2 diabetes. However, CoQ10 has low bio-availability due to its high lipophilicity. Therefore, we have structurally optimized CoQ10 in an attempt to exploit the potential of its pharmacological activity. Methods: A novel coenzyme Q10 derivative (L-50) was designed and synthesized by introducing a group containing bromine atom and hydroxyl at the terminal of coenzyme Q10 (CoQ10), and the antidiabetic effect of L-50 was investigated by cellular assays and animal experiments. Results: Cytotoxicity results showed that L-50 was comparatively low toxicity to HepG2 cells. Hypoglycemic assays indicated that L-50 could increase glucose uptake in IR-HepG2 cells, with significantly enhanced hypoglycemic capacity compared to the CoQ10. In addition, L-50 improved cellular utilization of glucose through reduction of reactive oxygen species (ROS) accumulated in insulin-resistant HepG2 cells (IR-HepG2) and regulation of JNK/AKT/GSK3ß signaling pathway, resulting in hypoglycemic effects. Furthermore, the animal experiments demonstrated that L-50 could restore the body weight of HFD/STZ mice. Notably, the findings suggested that L-50 could improve glycemic and lipid metabolism in HFD/STZ mice. Moreover, L-50 could increase fasting insulin levels (FINS) in HFD/STZ mice, leading to a decrease in fasting blood glucose (FBG) and hepatic glycogen. Furthermore, L-50 could recover triglycerides (TG), total cholesterol (T-CHO), lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) levels in HFD/STZ mice. Discussion: The addition of a bromine atom and a hydroxyl group to CoQ10 could enhance its anti-diabetic activity. It is anticipated that L-50 could be a promising new agent for T2DM.

[Quality evaluation of Lysimachiae Herba from different habitats based on simultaneous determination of multiple bioactive constituents combined with multivariate statistical analysis].

A method based on ultra-high performance liquid chromatography coupled with triple quadrupole linear ion trap-tandem mass spectrometry(UHPLC-QTRAP-MS/MS) was developed for the simultaneous determination of 41 bioactive constituents of flavonoids, organic acids, nucleosides, and amino acids in Lysimachiae Herba. The content of multiple bioactive constituents was compared among the samples from different habitats. The chromatographic separation was performed in a Waters XBridge®C_(18) column(4.6 mm×100 mm, 3.5 µm) at 30 ℃. The gradient elution was performed with 0.4% methanol(A)-formic acid water(B) as the mobile phase at a flow rate of 0.8 mL·min~(-1), and the multiple-reaction monitoring(MRM) mode was adopted. According to the content of 41 constituents, hierarchical cluster analysis(HCA), orthogonal partial least squares discriminant analysis(OPLS-DA), and gray relational analysis(GRA) were perfomed to comprehensively evaluate the samples from different habitats. The results showed that the 41 constituents exhibited good linear relationship within the tested concentration ranges, with the correlation coefficients(r) greater than 0.999 4. The method featured good precision, repeatability, and stability with the relative standard deviations(RSDs) less than 5.0%. The average recoveries of the 41 constituents ranged from 98.06% to 101.9%, with the RSDs of 0.62%-4.6%. HCA and OPLS-DA separated 48 batches of Lysimachiae Herba samples from different habitats into three categories: the producing areas in Sichuan and Chongqing, the producing areas in Jiangsu, Zhejiang, and Jiangxi, and the producing areas in Guizhou. The content of 41 constituents varied among the Lysimachiae Herba samples from different habitats. The GRA results revealed that the Lysimachiae Herba sample from Nanchong City, Sichuan Province had the best comprehensive quality. The method developed in this study was accurate and reliable and thus can be used for comprehensive evaluation of Lysimachiae Herba quality and provide basic information for the selection of habitats.

Programmable DNA hydrogel provides suitable microenvironment for enhancing autophagy-based therapies in intervertebral disc degeneration treatment.

The pathogenesis of intervertebral disc degeneration (IVDD) is attributed to metabolic dysregulation within the extracellular matrix and heightened apoptosis of nucleus pulposus cells (NPC). Therefore, a potential therapeutic strategy for managing IVDD involves the reestablishment of metabolic equilibrium within the extracellular matrix and the suppression of excessive myeloid cell apoptosis. The microRNA, miR-5590, displays marked differential expression in degenerative nucleus pulposus (NP) tissues and exerts a direct influence on the regulation of DDX5 expression. This, in turn, modulates mammalian target of rapamycin (mTOR) phosphorylation, thereby impacting autophagy and apoptosis. However, ensuring the smooth delivery of miRNA to a specific injury site poses a significant challenge. To address this issue, a multifunctional DNA hydrogel was developed and subsequently loaded with miR-5590 via spherical nucleic acids (SNAs) for the treatment of IVDD. The hydrogel, which exhibits versatility, has the potential to be administered through injection at the site of injury, resulting in a consistent and prolonged release of miR-5590. This leads to the creation of a genetic microenvironment within the NP, which triggers the onset of autophagy in NPCs and subsequently suppresses apoptosis. As a result, this process regulates the metabolic equilibrium within the extracellular matrix, thereby impeding the in vitro and in vivo progression of IVDD. The amalgamation of miRNAs and biomaterials offers a promising therapeutic strategy for the management of IVDD in clinical settings.

Tetrachlorovancomycin: Total Synthesis of a Designed Glycopeptide Antibiotic of Reduced Synthetic Complexity.

A technically straightforward total synthesis of a new class of vancomycin analogues of reduced synthetic complexity was developed that provided tetrachlorovancomycin (1, LLS = 15 steps, 15% overall yield) and its precursor aglycon 29 (nearly 20% overall yield). The class retains all the intricate vancomycin structural features that contribute to its target binding affinity and selectivity, maintains the antimicrobial activity of vancomycin, and achieves the simplification by an unusual addition, not removal, of benign substituents to the core structure. The modification, accomplished by addition of two aryl chloride substituents to provide 1, permitted a streamlined total synthesis of the new glycopeptide antibiotic class by removing the challenges associated with CD and DE ring system atropisomer stereochemical control. This also enabled their simultaneous and further-activated SNAr macrocyclizations that establish the tricyclic skeleton of 1. Key elements of the approach include catalyst-controlled diastereoselective formation of the AB biaryl axis of chirality (>30:1 dr), an essentially instantaneous macrolactamization of the AB ring system free of competitive epimerization (>30:1 dr), racemization free coupling of the E ring tetrapeptide, room temperature simultaneous CD and DE ring system cyclizations, a highly refined 4-step conversion of the cyclization product to the aglycon, and a protecting-group-free one-pot enzymatic glycosylation for disaccharide introduction. In addition to the antimicrobial evaluation of tetrachlorovancomycin (1), the preparation of key peripherally modified derivatives, which introduce independent and synergistic mechanisms of action, revealed their exceptional antimicrobial potency and provide the foundation for future use of this new class of synthetic glycopeptide analogues.