Model informed precision medicine of Chinese herbal medicines formulas-A multi-scale mechanistic intelligent model.

Recent trends suggest that Chinese herbal medicine formulas (CHM formulas) are promising treatments for complex diseases. To characterize the precise syndromes, precise diseases and precise targets of the precise targets between complex diseases and CHM formulas, we developed an artificial intelligence-based quantitative predictive algorithm (DeepTCM). DeepTCM has gone through multilevel model calibration and validation against a comprehensive set of herb and disease data so that it accurately captures the complex cellular signaling, molecular and theoretical levels of traditional Chinese medicine (TCM). As an example, our model simulated the optimal CHM formulas for the treatment of coronary heart disease (CHD) with depression, and through model sensitivity analysis, we calculated the balanced scoring of the formulas. Furthermore, we constructed a biological knowledge graph representing interactions by associating herb-target and gene-disease interactions. Finally, we experimentally confirmed the therapeutic effect and pharmacological mechanism of a novel model-predicted intervention in humans and mice. This novel multiscale model opened up a new avenue to combine "disease syndrome" and "macro micro" system modeling to facilitate translational research in CHM formulas.

Depression and hepatobiliary diseases: a bidirectional Mendelian randomization study.

Background: More and more evidence suggests a close association between depression and hepatobiliary diseases, but its causal relationship is not yet clear. Method: Using genome-wide association studies (GWAS) to summarize data, independent genetic variations associated with depression were selected as instrumental variables. Firstly, we designed a univariate Mendelian randomization (UVMR) analysis with two samples and simultaneously conducted reverse validation to evaluate the potential bidirectional causal relationship between depression and various hepatobiliary diseases. Secondly, we conducted a multivariate Mendelian randomization (MVMR) analysis on diseases closely related to depression, exploring the mediating effects of waist to hip ratio, hypertension, and daytime nap. The mediating effects were obtained through MVMR. For UVMR and MVMR, inverse variance weighted method (IVW) is considered the most important analytical method. Sensitivity analysis was conducted using Cochran'Q, MR Egger, and Leave-one-out methods. Results: UVMR analysis showed that depression may increase the risk of non-alcoholic fatty liver disease (OR, 1.22; 95% CI, 1.03-1.46; p=0.0248) in liver diseases, while depression does not increase the risk of other liver diseases; In biliary and pancreatic related diseases, depression may increase the risk of cholelithiasis (OR, 1.26; 95% CI, 1.05-1.50; p=0.0120), chronic pancreatitis (OR, 1.61; 95% CI, 1.10-2.35; p=0.0140), and cholecystitis (OR, 1.23; 95% CI, 1.03-1.48; p=0.0250). In addition, through reverse validation, we found that non-alcoholic fatty liver disease, cholelithiasis, chronic pancreatitis, cholecystitis, or the inability to increase the risk of depression (p>0.05). The waist to hip ratio, hypertension, and daytime nap play a certain role in the process of depression leading to non-alcoholic fatty liver disease, with a mediating effect of 35.8%. Conclusion: Depression is a susceptibility factor for non-alcoholic fatty liver disease, and the causal effect of genetic susceptibility to depression on non-alcoholic fatty liver disease is mediated by waist-hip ratio, hypertension, and daytime nap.

Identification and preliminary validation of differently expressed genes as candidate biomarkers associated with atherosclerosis.

OBJECTIVE: Atherosclerosis (AS) is the primary cause of deadly cardio-cerebro vascular diseases globally. This study aims to explore the key differentially expressed genes (DEGs), potentially serving as predictive biomarkers for AS. METHODS: Microarray datasets were retrieved from the GEO database for DEGs and DE-miRNAs identification. Then biological function of DEGs were elucidated based on gene ontology (GO) and KEGG pathway enrichment analysis. The protein-protein interaction (PPI) network and DEGs-DE-miRNAs network were constructed, with emphasis on hub DEGs selection and their interconnections. Additionally, receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic precision of hub DEGs for AS. More importantly, an AS Syrian Golden hamster model was established to validate the expression levels of hub DEGs in AS. RESULTS: A total of 203 DEGs and 10 DE-miRNAs were screened, with six genes were chosen as hub DEGs. These DEGs were significantly enriched in AS-related biological processes and pathways, such as immune and inflammatory response, cellular response to IL-1 and TNF, positive regulation of angiogenesis, Type I diabetes mellitus, Cytokine-cytokine receptor interaction, TLR signaling pathway. Also, these DEGs and DE-miRNAs formed a closely-interacted DE-miRNAs - DEGs - KEGG pathway network. Besides, hub DEGs presented promising diagnostic potential for AS (AUC: 0.781 âˆ¼ 0.887). In addition, the protein expression levels of TNF-α, CXCL8, CCL4, IL-1ß, CCL3 and CCR8 were significantly increased in AS group Syrian Golden hamsters. CONCLUSION: The identified candidate genes TNF, CXCL8, CCL4, IL1B, CCL3 and CCR8 may have the potential to serve as prognostic biomarker in diagnosing AS.

Identification of two hub genes and miRNA­mRNA interactions in chronic obstructive pulmonary disease (COPD) plasma.

BACKGROUND: We aimed to identify hub genes in chronic obstructive pulmonary disease (COPD) plasma through the exploration of a putative miRNA-mRNA regulatory network. METHODS: Three datasets (GSE24709, GSE102915, GSE136390) were utilized to discern differentially expressed miRNAs (DEMs) between COPD and normal plasma. miRNET was employed to predict the potential targets of DEMs. Subsequent GO and KEGG analyses were conducted using DAVID. For the construction of the protein-protein interaction (PPI) network and screening of hub genes, STRING and Cytoscape were employed. The expression validation was assessed through GSE56768. RESULTS: The results revealed 395 genes targeted by up-regulated DEMs and 234 genes targeted by down-regulated DEMs. The target genes exhibited significant enrichment in the PI3K-Akt signaling pathway and the p53 signaling pathway. Through the validation of hub genes' expression, we proposed two potential miRNA-mRNA interactions: miR-126-5p/miR-495-3p/miR-193b-3p - YWHAZ and miR-937-5p/miR-183-5p/miR-34c-5p/miR-98-5p/miR-525-3p/miR-215-5p - ACTB. CONCLUSIONS: In conclusion, our study posits potential miRNA-mRNA interactions in COPD by analyzing datasets from public databases, contributing valuable insights into the understanding of COPD pathogenesis and potential therapeutic avenues.

Clinical application of posterior tibial artery or peroneal artery perforator flap in curing plate exposure after ankle fracture fixation.

The study aims to evaluate the clinical application of posterior tibial artery or peroneal artery perforator flap in the treatment of plate exposure after ankle fracture fixation. A posterior tibial artery or peroneal artery perforator flap was used on 16 patients with plate exposure after ankle fracture fixation in our hospital between July 2018 and July 2021. The time required to harvest the flap, the amount of intraoperative blood loss, the duration of postoperative drainage tube placement, the outcome of the flap and the healing observed at the donor site are reported. The sizes of the flaps were 2.5-7.0 cm × 5.0-18.0 cm and averaged 4.0 cm × 12.0 cm. The time required to harvest the posterior tibial artery or peroneal artery perforator flap ranged from 35 to 55 min and averaged 45 min. The amount of intraoperative blood loss ranged from 20 to 50 mL and averaged 35 mL. The duration of postoperative drainage tube placement ranged from 3 to 5 days and averaged 4 days. A total of 15 flaps survived and one flap had partial necrosis and survived after conservative treatment. All donor area defects were directly sewed and stitched without complications. There are multiple advantages of the posterior tibial artery or peroneal artery perforator flap, including simple preparation technique, reliable repair of the defects and without the need for performing microvascular anastomosis. It can be safely used in curing plate exposure after ankle fracture fixation and worth popularizing in grassroots hospitals.

The association between frailty and osteoarthritis based on the NHANES and Mendelian randomization study.

Introduction: The aim of the study was to examine the association between frailty and osteoarthritis. Methods: We conducted a cross-sectional study in the National Health and Nutrition Examination Survey, while logistic regression was used to explore the association of the two. Mendelian randomization (MR) study was used to explore the causal relationship between the two. Results: In the cross-sectional study, logistic regression analysis showed that odds ratio (OR) (95% CI) value was 1.07 (1.05, 1.08). In the MR study, the inverse-variance weighting (IVW) results showed OR (95% CI) value of 1.69 (1.01-2.83). Conclusions: There is both a correlation and a causal relationship between frailty and osteoarthritis, and frailty may be a potentially better response than age to osteoarthritis.

A Potent and Narrow-Spectrum Antibacterial against Clostridioides difficile Infection.

Clostridioides difficile is an anaerobic Gram-positive bacterium that colonizes the gut of patients treated with broad-spectrum antibiotics. The normal gut microflora prevents C. difficile colonization; however, dysbiosis by treatment with broad-spectrum antibiotics causes recurrent C. difficile infection (CDI) in 25% of patients. There are no fully effective antibiotics for multiple recurrent CDIs. We report herein that oxadiazole antibiotics exhibit bactericidal activity against C. difficile vegetative cells. We screened a library of 75 oxadiazoles against C. difficile ATCC 43255. The findings from this collection served as the basis for the syntheses of an additional 58 analogs, which were tested against the same strain. We report a potent (MIC50 = 0.5 µg/mL and MIC90 = 1 µg/mL values for 101 C. difficile strains) and narrow-spectrum oxadiazole (3-(4-(cyclopentyloxy)phenyl)-5-(4-nitro-1H-imidazol-2-yl)-1,2,4-oxadiazole; compound 57), which is not active against common gut bacteria or other tested organisms. Compound 57 is selectively bactericidal against C. difficile and targets cell-wall synthesis.

Amber-codon suppression for spatial localization and in vivo photoaffinity capture of the interactome of the Pseudomonas aeruginosa rare lipoprotein A lytic transglycosylase.

The 11 lytic transglycosylases of Pseudomonas aeruginosa have overlapping activities in the turnover of the cell-wall peptidoglycan. Rare lipoprotein A (RlpA) is distinct among the 11 by its use of only peptidoglycan lacking peptide stems. The spatial localization of RlpA and its interactome within P. aeruginosa are unknown. We employed suppression of introduced amber codons at sites in the rlpA gene for the introduction of the unnatural-amino-acids Νζ -[(2-azidoethoxy)carbonyl]-l-lysine (compound 1) and Nζ -[[[3-(3-methyl-3H-diazirin-3-yl)propyl]amino]carbonyl]-l-lysine (compound 2). In live P. aeruginosa, full-length RlpA incorporating compound 1 into its sequence was fluorescently tagged using strained-promoted alkyne-azide cycloaddition and examined by fluorescence microscopy. RlpA is present at low levels along the sidewall length of the bacterium, and at higher levels at the nascent septa of replicating bacteria. In intact P. aeruginosa, UV photolysis of full-length RlpA having compound 2 within its sequence generated a transient reactive carbene, which engaged in photoaffinity capture of neighboring proteins. Thirteen proteins were identified. Three of these proteins-PBP1a, PBP5, and MreB-are members of the bacterial divisome. The use of the complementary methodologies of non-canonical amino-acid incorporation, photoaffinity proximity analysis, and fluorescent microscopy confirm a dominant septal location for the RlpA enzyme of P. aeruginosa, as a divisome-associated activity. This accomplishment adds to the emerging recognition of the value of these methodologies for identification of the intracellular localization of bacterial proteins.

A dual-action antibiotic that kills Clostridioides difficile vegetative cells and inhibits spore germination.

Clostridioides difficile infection (CDI) is the most lethal of the five CDC urgent public health treats, resulting in 12,800 annual deaths in the United States alone [Antibiotic Resistance Threats in the United States, 2019 (2019), www.cdc.gov/DrugResistance/Biggest-Threats.html]. The high recurrence rate and the inability of antibiotics to treat such infections mandate discovery of new therapeutics. A major challenge with CDI is the production of spores, leading to multiple recurrences of infection in 25% of patients [C. P. Kelly, J. T. LaMont, N. Engl. J. Med. 359, 1932-1940 (2008)], with potentially lethal consequence. Herein, we describe the discovery of an oxadiazole as a bactericidal anti-C. difficile agent that inhibits both cell-wall peptidoglycan biosynthesis and spore germination. We document that the oxadiazole binds to the lytic transglycosylase SleC and the pseudoprotease CspC for prevention of spore germination. SleC degrades the cortex peptidoglycan, a critical step in the initiation of spore germination. CspC senses germinants and cogerminants. Binding to SleC is with higher affinity than that to CspC. Prevention of spore germination breaks the nefarious cycles of CDI recurrence in the face of the antibiotic challenge, which is a primary cause of therapeutic failure. The oxadiazole exhibits efficacy in a mouse model of recurrent CDI and holds promise in clinical treatment of CDI.

Retrieval of tropospheric ozone profiles using ground-based MAX-DOAS.

In recent years, surface ozone concentrations have increased in many cities in China. Ground-based multi-axis differential optical absorption spectroscopy (MAX-DOAS) is a powerful technique for retrieving the profiles of tropospheric trace gases, such as NO2, SO2, and HCHO. However, since the difficulties in deducting the effects of stratospheric ozone, there are few studies on the retrieval of tropospheric ozone profiles using MAX-DOAS measurements. Here, we developed an accurate inversion method to retrieve tropospheric ozone concentrations during the PRIDE-GBA Campaign, wherein the ozone differential slant column densities (DSCDs) were retrieved in QDOAS software using the "time-interpolated zenith spectrum" as the reference spectrum. The tropospheric DSCDs (DSCDstrop) were then calculated by subtracting the simulated stratospheric DSCDs (DSCDsstr, simulated from the SCIATRAN model) from the DSCDs. Tropospheric ozone profiles were retrieved from the DSCDstrop using the optimal estimation method (OEM). The results showed that high values of tropospheric ozone were mainly distributed below 1 km, which is consistent with lidar measurements. In addition, the observed surface ozone concentrations were highly correlated with the in-situ measurements, with correlation coefficients (R) of 0.75 and 0.81, respectively. Combined with the retrieved NO2 and HCHO profiles using the MAX-DOAS measurements, we found that the planetary boundary layer ozone pollution of HeShan Observatory during the PRIDE-GBA Campaign are controlled by the NOx-limited regime. The results of this study indicate that the MAX-DOAS technique has the potential to retrieve tropospheric ozone profiles with high temporal and spatial resolution.

ARID1A downregulation promotes cell proliferation and migration of colon cancer via VIM activation and CDH1 suppression.

According to our prior findings, ARID1A expression is decreased in colon cancer, which has a poor prognosis. In this study, we investigated the ARID1A-VIM/CDH1 signalling axis's role in colon cancer proliferation and migration. The differentially expressed genes in cells that might be controlled by ARID1A were discovered by a database screening for ARID1A knockout. qPCR was used to analyse ARID1A and EMT markers expression levels in colon cancer. We utilized siRNA RID1A to explore the influence of ARID1A silencing on EMT in CRC cells. The function of ARID1A in the colon was investigated utilizing the wound healing, transwell and CCK-8 WST- assays. The molecular mechanism by which ARID1A regulates VIM and CDH1 was elucidated using chip-qPCR. Numerous genes involved in EMT were dysregulated in the absence of ARID1A. VIM expression increased in cells lacking ARID1A expression and vice versa. Many COAD samples with high ARID1A mRNA expression had low VIM mRNA expression, despite the relevance. CDH1 gene was positively correlated with ARID1A. Moreover, siRNA-ARID1A-transfected cells accelerated cell migration and invasion and increased cell proliferation rate in vitro. Chip-qPCR analysis showed that ARID1A binds to the promoters of both genes and changes their expression in colon cancer. ARID1A inactivation is associated with VIM activation and CDH1 suppression, which might serve as crucial molecules influencing COAD prognosis, accelerate tumour progression, and shorten patients' survival time, and promote metastases of COAD. Thus, depletion of ARID1A can be therapeutically exploited by targeting downstream effects to improve cancer treatment-related outcomes.

Knockdown of Obg-like ATPase 1 enhances sorafenib sensitivity by inhibition of GSK-3ß/ß-catenin signaling in hepatocellular carcinoma cells.

Background: To clarify the molecular mechanism of hepatocellular carcinoma (HCC), conducive to developing an effective HCC therapy. Owing to the severe drug resistance, the clinical use of sorafenib, which is approved for HCC treatment, is limited. The precise molecular mechanisms of sorafenib drug resistance remain unclear. In the current work, we evaluated the role of Obg-like ATPase 1 (OLA1) in sorafenib resistance in HCC. Methods: The survival of HCC patients between OLA1 expression and sorafenib treatment was analyzed by Kaplan-Meier plotter. Cell viability was measured by cell counting kit-8 (CCK-8) and colony formation assays. Cell death was detected by propidium iodide (PI) and trypan blue staining. The mRNA and protein levels were measured by real-time quantitative polymerase chain reaction (RT-qPCR) and western blot (WB), respectively. Results: We found that OLA1 was highly correlated with sorafenib resistance of HCC through a public database. Further study showed that knockdown of OLA1 enhanced cell proliferation inhibition and cell death induced by sorafenib, along with a reduction of proliferation-associated proteins (c-Myc and cyclin D1) and increase of apoptosis-related proteins (cleaved caspase-3 and cleaved PARP) in HCC cells. In addition, knockdown of OLA1 reduced the activation of glycogen synthase kinase 3ß (GSK-3ß)/ß-catenin. Conclusions: Our results proved that OLA1 can be a potential target to enhance sorafenib sensitivity in HCC.

Study of an Arctic blowing snow-induced bromine explosion event in Ny-Ålesund, Svalbard.

Bromine explosion events (BEEs) are important processes that influence the atmospheric oxidation capacity, especially in the polar troposphere during spring. Although sea ice surface is thought to be a significant bromine source, bromine release mechanisms remain unclear. High-resolution ground-based observations of reactive bromine, such as BrO, are important for assessing the potential impacts on tropospheric ozone and evaluating chemical models. However, previous model studies paid little attention to Svalbard, which is surrounded by both open ocean and sea ice. In this paper, we present continuous BrO slant column densities and vertical column densities derived by Multi-Axis Differential Optical Absorption Spectroscopy deployed at Ny-Ålesund (78.92°N, 11.93°E) in March 2017. We focused on one BEE in mid-March, during which the vertical column densities of BrO surged from 4.26 × 1013 molecular cm-2 to the peak at 1.23 × 1014 molecular cm-2 on March 17, surface ozone depleted from a background level of 46.25 parts per billion by volume (ppbv) to 13.9 ppbv. This case study indicates that the BEE was strongly associated with blowing snow induced by the cyclone systems that approached Svalbard from March 14 to 18. By considering meteorological conditions, sea ice coverage, and airmass trajectory history, we demonstrate that sea salt aerosols (SSAs) from blowing snow on sea ice, rather than from open ocean, are attributed to the occurrence of this BEE. Model results from a parallelized-tropospheric offline model of chemistry and transport (p-TOMCAT) indicate that this BEE was mainly triggered by a blowing snow event associated with a low-pressure cyclone system. The concentration of blowing-snow-sourced SSAs surged to peak when the airmass pass across the sea-ice-covered area under high wind speed, which is a critical factor in the process of bromine explosion observed in Ny-Ålesund. Due to the coarse resolution, the possible delayed timing of bromine release from SSA and the model-data discrepancies still exist.

An Atypical ABC Transporter Is Involved in Antifungal Resistance and Host Interactions in the Pathogenic Fungus Cryptococcus neoformans.

ATP-binding cassette (ABC) transporters represent one of the largest protein superfamilies. Functionally diverse, ABC transporters have been implicated in many aspects of microbial physiology. The genome of the human fungal pathogen Cryptococcus neoformans encodes 54 putative ABC transporters and most of them remain uncharacterized. In a previous genetic screen for fungal regulators of phagocytosis, we identified an uncharacterized gene, CNAG_06909, that modulates host interactions. This gene encoded a half-size ABC transporter of the PDR-type, and phenotypic studies of a strain with this gene deleted revealed an altered antifungal susceptibility profile, including hypersensitivity to fluconazole (FLC). This gene, which we named PDR6, localized to the endoplasmic reticulum (ER) and plasma membrane (PM), and when absent, less ergosterol was observed in the PM. Additionally, we observed that the pdr6Δ strain displayed a reduction in secreted polysaccharide capsular material. These changes to the cellular surface may explain the observed increased uptake by macrophages and the reduced intracellular survival. Finally, studies in mice demonstrated that Pdr6 function was required for the normal progression of cryptococcal infection. Taken together, this study demonstrates a novel dual role for PDR transporters in C. neoformans, which could represent a potential target for antifungal therapeutics. Furthermore, the atypical half-size transporter encoded by PDR6 is conserved in many fungal pathogens, but absent in model nonpathogenic fungi. Hence, this study provided a function for this unique group of fungal half-size PDR transporters that, although conserved, remain largely understudied. IMPORTANCE Conserved across all kingdoms of life, ABC transporters comprise one of the largest protein families. They are associated with multidrug resistance, affecting aspects such as resistance to antimicrobials or anti-cancer drugs. Despite their importance, they are understudied in fungal pathogens. In the environmental fungus Cryptococcus neoformans, a leading cause of fungal infections, only a few ABC transporters have been studied. Here, we characterized an atypical, half-size, ABC transporter of the PDR-type, that affected both antifungal resistance and host-pathogen interactions. PDR-type transporters are only present in fungi and plants, and this subgroup of half-size transporters was conserved in fungal pathogens, yet their function was completely unknown. Because the current treatments for cryptococcal infection are suboptimal, understanding the mechanisms of antifungal resistance and the host interactions that drive the infection is critical to improving the management of this disease. Here, we provide insights into these important aspects of cryptococcal pathogenesis.

Downregulated ARID1A by miR-185 Is Associated With Poor Prognosis and Adverse Outcomes in Colon Adenocarcinoma.

AT-rich interaction domain 1A (ARID1A) is a tumor suppressor gene that mutates in several cancer types, including breast cancer, ovarian cancer, and colorectal cancer (CRC). In colon adenocarcinoma (COAD), the low expression of ARID1A was reported but the molecular reason is unclear. We noticed that ARID1A low expression was associated with increased levels of miR-185 in the COAD. Therefore, this study aims to explore ncRNA-dependent mechanism that regulates ARID1A expression in COAD regarding miR-185. The expression of ARID1A was tested in COAD cell line under the effect of miR-185 mimics compared with inhibitor. The molecular features associated with loss of ARID1A and its association with tumor prognosis were analyzed using multi-platform data from The Cancer Genome Atlas (TCGA), and gene set enrichment analysis (GSEA) to identify potential signaling pathways associated with ARID1A alterations in colon cancer. Kaplan-Meier survival curve showed that a low level of ARID1A was closely related to low survival rate in patients with COAD. Results showed that inhibiting miR-185 expression in the COAD cell line significantly restored the expression of ARID1A. Further, the increased expression of ARID1A significantly improved the prolonged overall survival of COAD. We noticed that there is a possible relationship between ARID1A high expression and tumor microenvironment infiltrating immune cells. Furthermore, the increase of ARID1A in tumor cells enhanced the response of inflammatory chemokines. In conclusion, this study demonstrates that ARID1A is a direct target of miR-185 in COAD that regulates the immune modulations in the microenvironment of COAD.

[Roles of ERK/JNK in carbon black induced AP-1 cell signaling pathway changes].

OBJECTIVE: To investigate the role of ERK/JNK in the alteration of activator protein-1(AP-1) signaling pathway in human embryonic lung fibroblasts(HELFs) induced by carbon black. METHODS: HELFs were cultured in RPMI 1640 medium containing 0, 15, 30, 60, 120 or 240 µg/mL carbon black for 24 h, and the appropriate dose of carbon black was determined by MTT assay result. HELFs were divided into three groups: HELFs, HELFs transfected with ERK dominant negative mutant plasmid(DN-ERK) and HELFs transfected with JNK dominant negative mutant plasmid(DN-JNK). 100 µg/mL carbon black was used to treat HELFs(CB), DN-ERK HELFs(CB-DN-ERK), DN-JNK HELFs(CB-DN-JNK), and HELFs without any treatment were considered as control group. At 0, 1, 2, 4, 8, 12, 24 and 36 h of CB and control groups HELFs, the western blot was used to detect ERK, p-ERK, JNK, p-JNK, p38, p-p38, c-Jun, p-c-Jun, c-Fos, p-c-Fos protein expression levels, and AP-1 activity was detected by luciferase method. Whereas CB-DN-ERK and CB-DN-JNK HELFs were detected only at 24 h. RESULTS: Compared with the protein expression levels at 0 h, CB group HELFs ERK and p-ERK protein expression increased at each time point, whereas p38 protein expression decreased. AP-1 activity of CB group HELFs was declined to the lowest at 8 h(0.72±0.12), and upregulated to the peak at 36 h(1.38±0.11). CB group HELFs c-Fos, p-c-Fos and c-Jun protein expression levels at each time point from 1 h to 24 h were greater than those of 0 h, and p-c-Jun protein expression levels at 1 h, 2 h, 4 h, 8 h, 36 h were also greater than those of 0 h. CB group HELFs AP-1 activity, ERK, p-ERK, JNK, p-JNK, p38, p-p38, c-Jun, p-c-Jun, c-Fos, p-c-Fos protein expression levels changes followed biphasic patterns. There were no statistically significant differences in AP-1 activity between CB group HELFs(1.03±0.10) and CB-DN-ERK group(1.02±0.04) or CB-DN-JNK group(1.09±0.10) HELFs(t=0.16, P=0.88; t=0.73, P=0.50). However, compared with CB group HELFs, c-Fos(t=5.31, P=0.01), p-c-Fos(t=4.33, P=0.01), p-c-Jun(t=10.95, P& lt; 0.01)in CB-DN-JNK group, and c-Fos protein expression levels in CB-DN-ERK group(t=42.72, P& lt; 0.01)were significantly decreased. CONCLUSION: While carbon black induces HELFs increased protein expression levels of ERK, p-ERK, c-Jun, p-c-Jun, c-Fos and p-c-Fos, JNK may upregulate c-Fos, p-c-Fos, p-c-Jun protein expression levels, and ERK may upregulate c-Fos protein expression level.

Discovery, Structure-Activity Relationship, and Mechanistic Studies of 1-((3R,4S)-3-((Dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidin-1-yl)-2-(2,4,5-trifluorophenyl)ethan-1-one as a Novel Potent Analgesic.

Management of moderate to severe pain relies heavily on opioid analgesics such as morphine, oxycodone, and fentanyl in clinics. However, their prolonged use was associated with undesirable side effects. Many new strategies to reduce side effects have been proposed, but not without disadvantages. Using a hot plate model as a phenotypic screening method, our studies identified (3R,4S)-9d with a new scaffold as a potent analgesic with ED50 values of 0.54 mg/kg and 0.021 mg/kg in hot plate and antiwrithing models, respectively. Mechanistic studies showed that it elicited its analgesic effect via the active metabolite (3R,4S)-10a. The mechanism of (3R,4S)-10a-induced activation of the µ opioid receptor (MOR) was proposed by means of molecular dynamics (MD) simulation.

Peptidome Analysis of Pancreatic Tissue Derived from T1DM Mice: Insights into the Pathogenesis and Clinical Treatments of T1DM.

Bioactive peptides attract growing concerns for their participation in multiple biological processes. Their roles in the pathogenesis of type 1 diabetes mellitus remain poorly understood. In this study, we used LC-MS/MS technology to compare the peptide profiling between pancreatic tissue of T1DM mice and pancreatic tissue of matched control groups. A total of 106 peptides were differentially expressed in T1DM pancreatic tissue, including 43 upregulated and 63 downregulated peptides. Most of the precursor proteins are insulin. Further bioinformatics analysis (GO and pathway analysis) indicated that the potential functions of these differential peptides were tightly related to regulation of endoplasmic reticulum stress. In conclusion, this study highlights new candidate peptides and provides a new perspective for exploring T1DM pathogenesis and clinical treatments.

Structure-Activity Relationship for the Picolinamide Antibacterials that Selectively Target Clostridioides difficile.

Clostridioides difficile is a leading health threat. This pathogen initiates intestinal infections during gut microbiota dysbiosis caused by oral administration of antibiotics. C. difficile is difficult to eradicate due to its ability to form spores, which are not susceptible to antibiotics. To address the urgent need for treating recurrent C. difficile infection, antibiotics that selectively target C. difficile over common gut microbiota are needed. We herein describe the class of picolinamide antibacterials which show potent and selective activity against C. difficile. The structure-activity relationship of 108 analogues of isonicotinamide 4, a compound that is equally active against methicillin-resistant Staphylococcus aureus and C. difficile, was investigated. Introduction of the picolinamide core as exemplified by analogue 87 resulted in exquisite potency and selectivity against C. difficile. The ability of the picolinamide class to selectively target C. difficile and to prevent gut dysbiosis holds promise for the treatment of recurrent C. difficile infection.