A monoallelic variant in CCN2 causes an autosomal dominant spondyloepimetaphyseal dysplasia with low bone mass.

Cellular communication network factor 2 (CCN2) is a secreted extracellular matrix-associated protein, and its aberrantly increased expression has been implicated in a diversity of diseases involving pathological processes of fibrosis, chronic inflammation, or tissue injury, which has promoted the evaluation of CCN2 as therapeutic targets for multiple disorders. However, human phenotypes associated with CCN2 deficiency have remained enigmatic; variants in CCN2 have not yet been associated with a human phenotype. Here, we collected families diagnosed with spondyloepimetaphyseal dysplasia (SEMD), and screened candidate pathogenic genes for families without known genetic causes using next-generation sequencing. We identified a monoallelic variant in signal peptide of CCN2 (NM_001901.2: c.65 G > C [p.Arg22Pro]) as the cause of SEMD in 14 subjects presenting with different degree of short stature, premature osteoarthritis, and osteoporosis. Affected subjects showed decreased serum CCN2 levels. Cell lines harboring the variant displayed decreased amount of CCN2 proteins in culture medium and an increased intracellular retention, indicating impaired protein secretion. And the variant weakened the stimulation effect of CCN2 on osteogenesis of bone marrow mesenchymal stem cells. Zebrafish ccn2a knockout model and osteoblast lineage-specific Ccn2-deficient mice (Ccn2fl/fl;Prx1Cre) partially recapitulated the phenotypes including low bone mass observed in affected subjects. Pathological mechanism implicated in the skeletal abnormality in Ccn2fl/fl;Prx1Cre mice involved decreased bone formation, increased bone resorption, and abnormal growth plate formation. Collectively, our study indicate that monoallelic variants in CCN2 lead to a human inherited skeletal dysplasia, and highlight the critical role of CCN2 in osteogenesis in human.

Design of MEMS Pressure Sensor Anti-Interference System Based on Filtering and PID Compensation.

Due to the inherent temperature drift and lack of static stability in traditional pressure sensors, which make it difficult for them to meet the increasing demands of various industries, this paper designs a new system. The proposed system integrates temperature measurement and regulation circuits, signal processing, and communication circuits to accurately acquire and transmit pressure sensor data. The system designs a filtering algorithm to filter the original data and develops a data-fitting operation to achieve error compensation of the static characteristics. In order to eliminate the temperature drift problem of the sensor system, the system also adopts an improved PID thermostatic control algorithm to compensate for the temperature drift. Finally, it can also transmit the processed pressure data remotely. The experimental results show that the nonlinear error at 50 °C is reduced from the initial 1.82% to 0.24%; the hysteresis error is significantly reduced from 1.23% to 0.046%; and the repeatability error control is reduced from 3.79% to 0.89%. By compensating for thermal drift, the system's thermal sensitivity drift coefficient is reduced by 74.67%, the thermal zero drift coefficient is reduced by 66.24%, and the wireless communication range is up to 1km. The above significant optimization results fully validate the high accuracy and stability of the system, which is perfectly suited for demanding pressure measurement applications.

In situ tuning of platinum 5d valence states for four-electron oxygen reduction.

The oxygen reduction reaction (ORR) catalyzed by efficient and economical catalysts is critical for sustainable energy devices. Although the newly-emerging atomically dispersed platinum catalysts are highly attractive for maximizing atomic utilization, their catalytic selectivity and durability are severely limited by the inflexible valence transformation between Pt and supports. Here, we present a structure by anchoring Pt atoms onto valence-adjustable CuOx/Cu hybrid nanoparticle supports (Pt1-CuOx/Cu), in which the high-valence Cu (+2) in CuOx combined with zero-valent Cu (0) serves as a wide-range valence electron reservoir (0‒2e) to dynamically adjust the Pt 5d valence states during the ORR. In situ spectroscopic characterizations demonstrate that the dynamic evolution of the Pt 5d valence electron configurations could optimize the adsorption strength of *OOH intermediate and further accelerate the dissociation of O = O bonds for the four-electron ORR. As a result, the Pt1-CuOx/Cu catalysts deliver superior ORR performance with a significantly enhanced four-electron selectivity of over 97% and long-term durability.

Correlation between serum uric acid to high-density lipoprotein cholesterol ratio and atrial fibrillation in patients with NAFLD.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is independently associated with atrial fibrillation (AF) risk. The uric acid (UA) to high-density lipoprotein cholesterol (HDL-C) ratio (UHR) has been shown to be closely associated with cardiovascular disease (CVD) and NAFLD. The aim of this study is to clarify whether elevated UHR is associated with the occurrence of AF in patients with NAFLD and to determine whether UHR predicted AF. METHODS: Patients diagnosed with NAFLD in the Department of Cardiovascular Medicine of the Second Hospital of Shanxi Medical University from January 1, 2020, to December 31, 2021, were retrospectively enrolled in this study. The study subjects were categorized into AF group and non-AF group based on the presence or absence of combined AF. Logistic regression was performed to evaluate the correlation between UHR and AF. Sensitivity analysis and subgroup interaction analysis were performed to verify the robustness of the study results. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff value for UHR to predict the development of AF in patients with NAFLD. RESULTS: A total of 421 patients with NAFLD were included, including 171 in the AF group and 250 in the non-AF group. In the univariate regression analysis, NAFLD patients with higher UHR were more likely to experience AF, and the risk of AF persisted after confounding factors were adjusted for (OR: 1.010, 95%CI: 1.007-1.013, P<0.001). AF risk increased with increasing UHR quartile (P for trend < 0.001). Despite normal serum UA and HDL-C, UHR was still connected with AF in patients with NAFLD. All subgroup variables did not interact significantly with UHR in the subgroup analysis. The ROC curve analysis showed that the areas under the curve for UA, HDL-C, and UHR were 0.702, 0.606, and 0.720, respectively, suggesting that UHR has a higher predictive value for AF occurrence in NAFLD patients compared to HDL-C or UA alone. CONCLUSION: Increased UHR level was independently correlated with a high risk of AF in NAFLD patients.

Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration.

Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies, resulting in severe disability. Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation. However, different clusters of macrophages have various functions and receive multiple regulation, which are both still unknown. In our current study, multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury. The transcriptomes of over 74 000 human single cells were profiled. As results, we found that SPP1+ macrophages, RGCC+ endothelial cells, ACKR1+ endothelial cells and ADAM12+ fibroblasts participated in tendon adhesion formation. Interestingly, despite specific fibrotic clusters in tendon adhesion, FOLR2+ macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells. Furthermore, ACKR1 was verified to regulate FOLR2+ macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26RtdTomato mice to lethally irradiated Ackr1-/- mice (Ackr1-/- chimeras; deficient in ACKR1) and control mice (WT chimeras). Compared with WT chimeras, the decline of FOLR2+ macrophages was also observed, indicating that ACKR1 was specifically involved in FOLR2+ macrophages migration. Taken together, our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis, but also uncovered a novel antifibrotic cluster of macrophages and their origin. These results provide potential therapeutic targets against human tendon adhesion.

BMP signaling maintains auricular chondrocyte identity and prevents microtia development by inhibiting protein kinase A.

Elastic cartilage constitutes a major component of the external ear, which functions to guide sound to the middle and inner ears. Defects in auricle development cause congenital microtia, which affects hearing and appearance in patients. Mutations in several genes have been implicated in microtia development, yet, the pathogenesis of this disorder remains incompletely understood. Here, we show that Prrx1 genetically marks auricular chondrocytes in adult mice. Interestingly, BMP-Smad1/5/9 signaling in chondrocytes is increasingly activated from the proximal to distal segments of the ear, which is associated with a decrease in chondrocyte regenerative activity. Ablation of Bmpr1a in auricular chondrocytes led to chondrocyte atrophy and microtia development at the distal part. Transcriptome analysis revealed that Bmpr1a deficiency caused a switch from the chondrogenic program to the osteogenic program, accompanied by enhanced protein kinase A activation, likely through increased expression of Adcy5/8. Inhibition of PKA blocked chondrocyte-to-osteoblast transformation and microtia development. Moreover, analysis of single-cell RNA-seq of human microtia samples uncovered enriched gene expression in the PKA pathway and chondrocyte-to-osteoblast transformation process. These findings suggest that auricle cartilage is actively maintained by BMP signaling, which maintains chondrocyte identity by suppressing osteogenic differentiation.

Comparison studies identify mesenchymal stromal cells with potent regenerative activity in osteoarthritis treatment.

Osteoarthritis affects 15% of people over 65 years of age. It is characterized by articular cartilage degradation and inflammation, leading to joint pain and disability. Osteoarthritis is incurable and the patients may eventually need joint replacement. An emerging treatment is mesenchymal stromal cells (MSCs), with over two hundred clinical trials being registered. However, the outcomes of these trials have fallen short of the expectation, due to heterogeneity of MSCs and uncertain mechanisms of action. It is generally believed that MSCs exert their function mainly by secreting immunomodulatory and trophic factors. Here we used knee osteoarthritis mouse model to assess the therapeutic effects of MSCs isolated from the white adipose or dermal adipose tissue of Prrx1-Cre; R26tdTomato mice and Dermo1-Cre; R26tdTomato mice. We found that the Prrx1-lineage MSCs from the white adipose tissues showed the greatest in vitro differentiation potentials among the four MSC groups and single cell profiling showed that the Prrx1-lineage MSCs contained more stem cells than the Dermo1 counterpart. Only the Prrx1-lineage cells isolated from white adipose tissues showed long-term therapeutic effectiveness on early-stage osteoarthritis models. Mechanistically, Prrx1-lineage MSCs differentiated into Col2+ chondrocytes and replaced the damage cartilage, activated Col1 expressing in resident chondrocytes, and inhibited synovial inflammation. Transcriptome analysis showed that the articular chondrocytes derived from injected MSCs expressed immunomodulatory cytokines, trophic factors, and chondrocyte-specific genes. Our study identified a MSC population genetically marked by Prrx1 that has great multipotentiality and can differentiate into chondrocytes to replace the damaged cartilage.

The c-Abl-RACK1-FAK signaling axis promotes renal fibrosis in mice through regulating fibroblast-myofibroblast transition.

BACKGROUND: Renal fibrosis is a prevalent manifestation of chronic kidney disease (CKD), and effective treatments for this disease are currently lacking. Myofibroblasts, which originate from interstitial fibroblasts, aggregate in the renal interstitium, leading to significant accumulation of extracellular matrix and impairment of renal function. The nonreceptor tyrosine kinase c-Abl (encoded by the Abl1 gene) has been implicated in the development of renal fibrosis. However, the precise role of c-Abl in this process and its involvement in fibroblast-myofibroblast transition (FMT) remain poorly understood. METHODS: To investigate the effect of c-Abl in FMT during renal fibrosis, we investigated the expression of c-Abl in fibrotic renal tissues of patients with CKD and mouse models. We studied the phenotypic changes in fibroblast or myofibroblast-specific c-Abl conditional knockout mice. We explored the potential targets of c-Abl in NRK-49F fibroblasts. RESULTS: In this study, fibrotic mouse and cell models demonstrated that c-Abl deficiency in fibroblasts mitigated fibrosis by suppressing fibroblast activation, fibroblast-myofibroblast transition, and extracellular matrix deposition. Mechanistically, c-Abl maintains the stability of the RACK1 protein, which serves as a scaffold for proteins such as c-Abl and focal adhesion kinase at focal adhesions, driving fibroblast activation and differentiation during renal fibrosis. Moreover, specifically targeting c-Abl deletion in renal myofibroblasts could prove beneficial in established kidney fibrosis by reducing RACK1 expression and diminishing the extent of fibrosis. CONCLUSIONS: Our findings suggest that c-Abl plays a pathogenic role in interstitial fibrosis through the regulation of RACK1 protein stabilization and myofibroblast differentiation, suggesting a promising strategy for the treatment of CKD.

A Natural Peptide from A Traditional Chinese Medicine Has the Potential to Treat Chronic Atrophic Gastritis by Activating Gastric Stem Cells.

Chronic atrophic gastritis (AG) is initiated mainly by Helicobacter pylori infection, which may progress to stomach cancer following the Correa's cascade. The current treatment regimen is H. pylori eradication, yet evidence is lacking that this treatment is effective on later stages of AG especially gastric gland atrophy. Here, using AG mouse model, patient samples, gastric organoids, and lineage tracing, this study unraveled gastric stem cell (GSC) defect as a crucial pathogenic factor in AG in mouse and human. Moreover, a natural peptide is isolated from a traditional Chinese medicine that activated GSCs to regenerate gastric epithelia in experimental AG models and revitalized the atrophic gastric organoids derived from patients. It is further shown that the peptide exerts its functions by stabilizing the EGF-EGFR complex and specifically activating the downstream ERK and Stat1 signaling. Overall, these findings advance the understanding of AG pathogenesis and open a new avenue for AG treatment.

The processes and transport fluxes of land-based macroplastics and microplastics entering the ocean via rivers.

Approximately 80% of marine plastic waste originates from land-based sources and enters oceans through rivers. Hence, to create effective regulations, it is crucial to thoroughly examine the processes by which land-based plastic waste flows into marine environments. To this end, this review covers the complete journey of macro- and microplastics from their initial input into rivers to their ultimate release into oceans. Here, we also discuss the primary influencing factors and current popular research topics. Additionally, the principles, applicability, accuracy, uncertainty, and potential improvement of the standard methods used for flux estimation at each stage are outlined. Emission estimates of land-based macro- and microplastics are typically assessed using the emission factor approach, coefficient accounting approach, or material flow analysis. Accurately estimating mismanaged plastic waste is crucial for reducing uncertainty in the macroplastic emission inventory. In our review of the processes by which land-originating plastics enter rivers, we categorized them into two major types: point-source and diffuse-source pollution. Land surface hydrological models simulate transport from diffuse sources to rivers, necessitating further research. Riverine (micro)plastic flux to the ocean is often estimated using monitoring statistics and watershed hydrological models at the watershed scale; however, standardized monitoring methods have not yet been established. At the global scale, algorithms based on river datasets are often used, which require further improvements in river data selection and microplastic number-mass conversion factors. Furthermore, the article summarizes the accuracy and sources of uncertainty of various methods. Future research efforts should focus on quantifying and mitigating uncertainties in resultant projections. Overall, this review deepens our understanding of the processes by which land-based plastic waste enters the ocean and helps scholars efficiently select or improve relevant methods when studying land-ocean transport fluxes.

Atmospheric HONO emissions in China: Unraveling the spatiotemporal patterns and their key influencing factors.

Nitrous acid (HONO) can be photolyzed to produce hydroxyl radicals (OH) in the atmosphere. OH plays a critical role in the formation of secondary pollutants like ozone (O3) and secondary organic aerosols (SOA) via various oxidation reactions. Despite the abundance of recent HONO studies, research on national HONO emissions in China remains relatively limited. Therefore, this study employed a "wetting-drying" model and bottom-up approach to develop a high-resolution gridded inventory of HONO emissions for mainland China using multiple data. We used the Monte Carlo method to estimate the uncertainty in HONO emissions. In addition, the primary sources of HONO emissions were identified and their spatiotemporal distribution and main influencing factors were studied. The results indicated that the total HONO emissions in mainland China in 2016 were 0.77 Tg N (R50: 0.28-1.42 Tg N), with soil (0.42 Tg N) and fertilization (0.26 Tg N) as the primary sources, jointly contributing to over 87% of the total. Notably, the North China Plain (NCP) had the highest HONO emission density (3.51 kg N/ha/yr). Seasonal HONO emissions followed the order: summer (0.38 kg N/ha) > spring (0.19 kg N/ha) > autumn (0.17 kg N/ha) > winter (0.06 kg N/ha). Moreover, HONO emissions were strongly correlated with fertilization, cropland, temperature, and precipitation. This study provides vital scientific groundwork for the atmospheric nitrogen cycle and the formation of secondary pollutants.

A decadal atmospheric ammonia reanalysis product in China.

Atmospheric ammonia has great environmental implications due to its important role in ecosystem and nitrogen cycle, as well as contribution to formation of secondary particles. China is recognized as a hotspot of NH3 pollution owing to agricultural and livestock intensification. In the quest to achieve a comprehensive understanding of atmospheric ammonia load and to quantify its environmental impacts in China, relying solely either on existing measurements or on model simulations falls short. Their limitations, either in spatial coverage and integrity or in data quality, fails to meet the needs. Available reanalysis products exhibit a marked deficiency in ammonia data. We therefore aim to propose an integrated ammonia reanalysis product in China, adeptly melding satellite observations from the Infrared Atmospheric Sounding Interferometer (IASI) NH3 retrievals with chemical transport model simulation, capitalizing on the robust Ensemble Kalman Filter (EnKF) data assimilation methodology. The product is validated in high quality via the comparison against independent measurements from ground monitoring stations. Spanning a decade from 2013 to 2022, our reanalysis uncovers not just the spatial intricacies of NH3 concentrations but also their temporal dynamics. Our findings pinpointed the spatial disparities in atmospheric ammonia intensities, highlighting regional hotspots in the NCP, SCB, and Northeast China, and identified annual and seasonal patterns. Our research provides crucial insights for shaping future NH3 pollution prevention and control strategies in China.

Stromal BMP signaling regulates mucin production in the large intestine via interleukin-1/17.

Bone morphogenic protein (BMP) signaling is critical for intestinal development, homeostasis, and function performance. Although the function of BMP signaling in the intestinal epithelium is well appreciated, the direct effect of BMP on intestinal stromal cells is poorly understood. Here, we show that disruption of BMP signaling by genetic ablation of Alk3 or Smad4 expands the stromal cell pool, the mucosa tumefaction, and colonic polyposis in the large intestine. Interleukin (IL) secretion by stromal cells is notably increased, including IL-1, IL-11, and IL-17. Specifically, IL-1 and IL-17a hyperactivate the mucin production by goblet cells through nuclear factor κB signaling, and abnormal mucin accumulation results in the morphological changes, epithelial barrier destruction, and polyposis development. Together, our results provide an insight into the role of BMP signaling in intestinal stromal cells to regulate epithelium function. This study further highlights the role of mucin-producing goblet cells in intestinal homeostasis and colitis development.

The cyclooxygenase-expressing mesenchyme resists intestinal epithelial injury by paracrine signaling.

Paracrine signals play pivotal roles in organ homeostasis. Mesenchymal stromal cells (MSCs) play a key role in regulating epithelium homeostasis in the intestine while their paracrine effects are poorly characterized. Here, we identified prostaglandin E2 (PGE2) secreted by cyclooxygenase (COX)-expressing MSCs as a vital factor to maintain the intestinal mucosal barrier. We found that MSCs-induced organoid swelling through paracrine effect in vitro, a process due to enhanced water adsorption and is mediated by the COX-PGE2-EP4 axis. To further explore the regulatory effect of this axis on the intestinal epithelial barrier in vivo, we established the conditional knockout mouse model to specifically delete COX in MSCs and found that PGE2 reduction downregulated the gene Muc2 and induced a gastric metaplasia-like phenotype. Moreover, PGE2 defects increased the susceptibility of intestinal epithelium to colitis. Our study uncovers the paracrine signaling of COX-expressing MSCs in intestinal mucosal barrier maintenance, providing a basis for understanding the role of mesenchymal cells in the pathophysiological function of the intestine.

A stromal lineage maintains crypt structure and villus homeostasis in the intestinal stem cell niche.

BACKGROUND: The nutrient-absorbing villi of small intestines are renewed and repaired by intestinal stem cells (ISCs), which reside in a well-organized crypt structure. Genetic studies have shown that Wnt molecules secreted by telocytes, Gli1+ stromal cells, and epithelial cells are required for ISC proliferation and villus homeostasis. Intestinal stromal cells are heterogeneous and single-cell profiling has divided them into telocytes/subepithelial myofibroblasts, myocytes, pericytes, trophocytes, and Pdgfralow stromal cells. Yet, the niche function of these stromal populations remains incompletely understood. RESULTS: We show here that a Twist2 stromal lineage, which constitutes the Pdgfralow stromal cell and trophocyte subpopulations, maintains the crypt structure to provide an inflammation-restricting niche for regenerating ISCs. Ablating Twist2 lineage cells or deletion of one Wntless allele in these cells disturbs the crypt structure and impairs villus homeostasis. Upon radiation, Wntless haplo-deficiency caused decreased production of anti-microbial peptides and increased inflammation, leading to defective ISC proliferation and crypt regeneration, which were partially rescued by eradication of commensal bacteria. In addition, we show that Wnts secreted by Acta2+ subpopulations also play a role in crypt regeneration but not homeostasis. CONCLUSIONS: These findings suggest that ISCs may require different niches for villus homeostasis and regeneration and that the Twist2 lineage cells may help to maintain a microbe-restricted environment to allow ISC-mediated crypt regeneration.

Correlation investigation between a single nucleotide polymorphism in ADAMTS14 (rs4747096) and osteoarthritis: a meta-analysis.

BACKGROUND: Current evidence of the association between a single nucleotide polymorphism (SNP) in ADAMTS14 (rs4747096) and osteoarthritis (OA) is controversial. This study aimed to determine whether the ADAMTS14 SNP is closely related to OA risk. METHODS: An electronic search of for the association between the rs4747096 polymorphisms and OA was performed using four online databases (updated on September 10, 2022). The association between susceptibility to OA and rs4747096 polymorphism was evaluated in four genetic models: the allele (mutation [A] vs. wild type [G]), additive (AA vs. GG and AG vs. GG), recessive (AA vs. AG + GG), and dominant (AA + AG vs. GG). This meta-analysis was performed in the R software, and effects were assessed using odds ratios (ORs) and 95% confidence intervals (CI). RESULTS: Four studies (707 cases in the case group and 859 cases in the control group) were included. The results of the meta-analysis showed that, except in the recessive genetic model, there was a significant correlation between OA risk and the rs4747096 polymorphism using the allele (OR [95% CI] = 1.48 [1.26-1.73], P < 0.001), additive (AG vs. GG, OR [95% CI] = 2.56 [1.79-3.65], P < 0.001; AA vs. GG, OR [95% CI] = 2.81 [1.98-3.98], P < 0.001), and dominant (OR [95% CI)] = 1.72 [1.34-2.2], P < 0.001) genetic models. CONCLUSIONS: The ADAMTS14 rs4747096 polymorphism is associated with susceptibility to OA.

Improved ammonia emission inventory of fertilizer application for three major crops in China based on phenological data.

NH3 has an important impact on atmospheric chemistry, and its reduction has become a potential pathway to alleviate haze pollution. The existing NH3 emission inventories still have significant uncertainties in terms of their temporal distributions. In this study, we combined satellite remote-sensing phenological data with ground-station phenological data to develop a method for the temporal allocation of NH3 emissions from fertilizer application. A high-resolution dataset for fertilizer application in China was established. We developed NH3 emission inventories for the fertilization of three major crops in China, with a resolution of 1/12° × 1/12°. The results showed that there was a significant temporal variation in fertilizer application dates across the country, mainly concentrated in June (17.16 %), July (19.08 %), and August (18.77 %). The majority of fertilizer application for the three major crops occurred during the spring and summer months, with a particular emphasis on April (5.72 Tg), May (7.05 Tg), and June (4.29 Tg). The total NH3 emission from the three major crops in China in 2019 was 2.73 Tg. The North China Plain (762.23 Gg) and Middle and Lower Yangtze River Plain (606.85 Gg) were identified as the primary regions for high NH3 emissions from fertilizer application. The results also showed that NH3 emissions from the three major crops were predominantly observed during summer, with a peak value in July (606.99 Gg), mainly because of the high proportion of topdressing fertilizers. Areas with high fertilizer application generally coincided with areas of high NH3 emissions. This study may be the first to utilize remote-sensing phenological data to establish the NH3 emission inventory, which is of great significance for further improving the accuracy of the NH3 emission inventory.

Mechanisms of Si-Wu Decoction in the treatment of ulcerative colitis revealed by network pharmacology and experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Si-Wu Decoction (SWD) is a traditional Chinese medicine decoction. SWD is commonly used to treat blood deficiency syndrome. It is also used to treat some ulcerative colitis (UC) patients now, but the mechanism of action remains unclear. AIM OF THE STUDY: This study explored the efficacy and mechanism of action of SWD in treating UC based on network pharmacology and related experimental validation. MATERIALS AND METHODS: Several databases were used to screen SWD for major active ingredients, targets of the ingredients, and UC disease genes. Cytoscape 3.8.2 software was used for topological analysis to construct the drug-compound-disease gene-target relationship network. The String database platform was used to construct the target protein interaction network. The DAVID (Database for Annotation, Visualization and Integrated Discovery) database was used to perform the GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis for the key targets. DSS (Dextran Sulfate Sodium)-induced UC mouse model was used to evaluate the in-vivo activity of SWD. Western Blot analysis and quantitative polymerase chain reaction were performed to verify the targets in the related pathways. RESULTS: Network pharmacology revealed that the SWD targeted pathway network involved 12 core targets and 15 major pathways. SWD may play a part by targeting key targets such as nuclear factor-kappaB (NF-κB), Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) pathway, and several mitogenic pathways. We showed that SWD largely restored the colorectal structure in UC model mice. Compared to the model group, the SWD group showed reduced infiltration of inflammatory cells. SWD significantly decreased the mRNA levels of IL-6 (Interleukin-6), TNF-α (Tumor necrosis factor-alpha), IL-1b (Interleukin-1beta) and other pro-inflammatory factors. Western Blot results showed that SWD concentration-dependently inhibited STAT3 and NF-κB activation in DSS-treated colon tissue. CONCLUSION: Our findings suggest that SWD treats UC by inhibiting STAT3 and NF-κB signaling pathways, reducing the expression of inflammatory cytokines, and improving epithelial repair in experimental colitis, thus shedding light on the mechanisms by which SWD exerts its effects on UC.

ELMO1 Deficiency Reduces Neutrophil Chemotaxis in Murine Peritonitis.

Peritoneal inflammation remains a major cause of treatment failure in patients with kidney failure who receive peritoneal dialysis. Peritoneal inflammation is characterized by an increase in neutrophil infiltration. However, the molecular mechanisms that control neutrophil recruitment in peritonitis are not fully understood. ELMO and DOCK proteins form complexes which function as guanine nucleotide exchange factors to activate the small GTPase Rac to regulate F-actin dynamics during chemotaxis. In the current study, we found that deletion of the Elmo1 gene causes defects in chemotaxis and the adhesion of neutrophils. ELMO1 plays a role in the fMLP-induced activation of Rac1 in parallel with the PI3K and mTORC2 signaling pathways. Importantly, we also reveal that peritoneal inflammation is alleviated in Elmo1 knockout mice in the mouse model of thioglycollate-induced peritonitis. Our results suggest that ELMO1 functions as an evolutionarily conserved regulator for the activation of Rac to control the chemotaxis of neutrophils both in vitro and in vivo. Our results suggest that the targeted inhibition of ELMO1 may pave the way for the design of novel anti-inflammatory therapies for peritonitis.