Early diagnostic value of carotid artery ultrasound parameters combined with epicardial adipose layer thickness in coronary heart disease.

BACKGROUND: Coronary heart disease is associated with coronary atherosclerosis indicated by carotid intima-media thickness (CIMT) thickening and altered vascular elasticity. The epicardial adipose layer can secrete proinflammatory factors that promote the formation of coronary atherosclerosis. Thus, the epicardial fat layer thickness (EAT) may also predict coronary heart disease. AIM: To determine the role of common carotid artery ultrasound parameters and EAT in the early diagnosis of coronary artery disease. METHODS: Based on coronary angiography, patients with newly suspected coronary heart disease were divided into case (n = 107) and control (n = 41) groups. The carotid ultrasound parameters, including vascular stiffness (ß), elastic coefficient (EP), pulse wave conduction velocity (PWV-ß), CIMT, and EAT were compared between the case and control groups and among patients with different lesion numbers in the case group. Pearson correlation was used to evaluate the early diagnostic value of EAT, common carotid artery elasticity, and CIMT for coronary heart disease. RESULTS: EP, ß, PWV-ß, CIMT, and EAT were significantly higher in the case group compared with the levels in the control group (all P < 0.001). In the case group, lesions were detected in one vessel in 34 patients, two vessels in 38 patients, and three vessels in 35 patients. Within the case group, ß, EP, PWV-ß, CIMT, and EAT levels significantly increased with an increased number of lesions (all P < 0.001). EAT positively correlated with ß, EP, PWV-ß, and CIMT (all P < 0.01). The area under the curve for diagnosing coronary heart disease using EAT combined with CIMT and carotid elasticity was 0.893, and the sensitivity and specificity were 0.890 and 0.837. CONCLUSION: EAT correlated well with changes in carotid artery elasticity and CIMT in patients with coronary heart disease. The combination of EAT, carotid artery elasticity, and CIMT facilitates the early diagnosis of coronary heart disease.

RRP8, associated with immune infiltration, is a prospective therapeutic target in hepatocellular carcinoma.

BACKGROUND: Ribosomal RNA Processing 8 (RRP8) is a nucleolar Rossman fold-like methyltransferase that exhibits increased expression in many malignant tumours. However, the role of RRP8 in hepatocellular carcinoma (HCC) is still uncertain. We explored the relationships between RRP8 and prognosis and immune infiltration, as well as the putative pathological function and mechanism of RRP8 in HCC. METHODS: Analysis of RRP8 expression across cancers was performed by using multiple databases. Associations between RRP8 expression and clinicopathological factors were further examined. Gene enrichment analysis was used to identify various putative biological activities and regulatory networks of RRP8 in HCC. The relationship between RRP8 expression and immune infiltration was confirmed by single-sample gene set enrichment analysis (ssGSEA). Univariate and multivariate Cox regression analyses were conducted to assess the impact of clinical variables on patient outcomes. Furthermore, a nomogram was constructed to estimate survival probability based on multivariate Cox regression analysis. Functional validation of RRP8 in HCC was performed with two different systems: doxycycline-inducible shRNA knockdown and CRISPR-Cas9 knockout. RESULTS: RRP8 was markedly overexpressed in HCC clinical specimens compared to adjacent normal tissues. Further analysis demonstrated that RRP8 was directly connected to multiple clinical characteristics and strongly associated with various immune markers in HCC. Moreover, elevated RRP8 expression indicated an unfavourable prognosis. Our functional studies revealed that both knockdown and knockout of RRP8 dramatically attenuated liver cancer cells to proliferate and migrate. Knockout of RRP8 decreased the phosphorylation of MEK1/2 and ß-catenin-(Y654) signalling pathway components; downregulated downstream signalling effectors, including Cyclin D1 and N-cadherin; and upregulated E-cadherin. CONCLUSIONS: RRP8 is strongly implicated in immune infiltration and could be a potential therapeutic target in HCC.

Liver Transplantation Reverses Hepatic Myelopathy in the Decompensated Phase of Cirrhosis: Case Report and Literature Review.

Hepatic myelopathy (HM) is a rare neurological complication in the end stage of many liver diseases and is characterized by bilateral spastic paraparesis without sensory and sphincter dysfunction. It occurs owing to metabolic disorders and central nervous system dysfunction associated with cirrhosis. Without timely and effective clinical intervention, the prognosis of these patients is devastating. Although liver transplantation (LT) is an effective treatment for HM, the prognosis of these patients remains unsatisfactory. Early recognition and diagnosis of this disease are essential for improving patient prognosis. Here, we report a case of hepatitis B virus-associated decompensated cirrhosis with HM. The patient recovered well after LT. We also summarize the clinical characteristics and post-transplant outcomes of 25 patients with HM treated by LT through 2023, including this case.

Research on waste gas treatment technology and comprehensive environmental performance evaluation for collaborative management of pollution and carbon in China's pharmaceutical industry based on life cycle assessment (LCA).

China is the largest industrial and pharmaceutical country in the world. The pharmaceutical industry, being a highly polluting sector, is the primary target of environmental regulation in the industry. The rapid development of pharmaceutical industry has posed a severe challenge to the environmental protection strategy of "carbon reduction and carbon neutrality" and the goal of "synergizing the reduction of pollution and carbon emissions" in China's "14th Five-Year Plan". Therefore, this paper starts from the whole industry, takes the life cycle of the whole production process of the pharmaceutical industry as the guidance, and selects a pharmaceutical company in Tianjin as the research object. Then using Life Cycle Assessment (LCA) to Characterization, Standardization, and Weighting the environmental impact of the waste gas treatment process before and after improvement based on waste gas emission characteristics from the pharmaceutical factory. LCA results show that GWP and AP are the most important environmental impact types, which account for >85 % of the total characterization value. I and II - Chemical Pharmaceutical Stage is the critical life cycle stage, accounting for over 80 % of the total characteristic values. This research proposes emission reduction countermeasures based on LCA results and simulates Emission reduction scenarios and economic evolution. If effectively implementing emission reduction countermeasures, reducing the environmental characterization value by 80 to 90 %, and generating economic benefit of 2.66 × 108 RMB/year. This research could guide improvement plans and emission reduction countermeasures of waste gas treatment in the pharmaceutical industry, which realizes collaborative management about efficient reduction of pollution and carbon and generates significant environmental, technological, economic, and social benefits.

Land management policy shift influenced seasonal variation of erosion-induced nitrogen and phosphorus outputs from intensive agricultural catchment.

A shift in policy to intensive agricultural production and land management often leads to excessive fertilizer application and accelerated erosion with consequent detrimental effects to water bodies. We investigated the impact of that shift by quantifying the spatial and temporal change in sediment sources and associated total nitrogen (TN) and total phosphorus (TP) pollutants output loads in an intensive agricultural catchment in North China across one year (November 2021-November 2022). We describe the implications of this work for intensive agriculture elsewhere in China and other countries. Seasonal sediment source apportionment was estimated at the catchment outlet using Berillium-7 (7Be) combined with compound-specific stable isotope (CSSI) signatures from sources and sediments. Diagnostic 'fingerprints' in MixSIAR were used to discriminate sediment sources between forest and crop farmland converted from forest (F + C(F)), crop farmland (C), and vegetable farmland (V). Our study identified F + C(F) as the dominant sediment source (mean 55.24 ± 2.91 %), intermediate on V (mean 30.06 ± 2.20 %), and least on C (mean 14.70 ± 2.13 %). Sedimentation ranged from 37.98 ± 3.02 to 89.60 ± 12.68 t·ha-1·event-1 and coincided with shifted land use policy and rainfall distribution. The TN and TP in sediment were both mainly derived from F + C(F) (averaged 22.27 ± 4.26 t·event-1 and 11.62 ± 2.28 t·event-1) and least from V (averaged 1.63 ± 0.29 and 2.09 ± 0.33 t·event-1). Despite being a significant sediment source, V contributed little sediment TN and TP input for eutrophication. Our findings imply that F + C(F) are diffuse sources of catchment pollution over the short term. These results describe the successful use of CSSI and 7Be to cost-effectively quantify the seasonal variation of sediment TN and TP loads from land-use-specific sources in the catchment under shifting land management policy in China with potential for use elsewhere. These findings enable soil conservation strategies and land management practices optimized for implementing targeted pollutant abatement initiatives in intensive agriculture in China and elsewhere.

Characteristics of mucin hypersecretion in different inflammatory patterns based on endotypes of chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is usually accompanied by mucin hypersecretion that can lead to mucus accumulation and impair nasal mucociliary clearance, thus exacerbating airway inflammation. Abnormal mucin hypersecretion is regulated by different T helper (Th) cytokines, which are associated with different endotype-driven inflammatory responses. Therefore, it is of great significance to understand how these factors regulate mucin hypersecretion to provide precise treatment strategies for different endotypes of CRS. BODY: Thus far, the most common endotypes of CRS are classified as type 1, type 2, or type 3 immune responses based on innate and adaptive cell-mediated effector immunity, and the representative Th cytokines in these immune responses, such as IFN-γ, TNF-α, IL-4, IL-5, IL-13, IL-10, IL-17, and IL-22, play an important regulatory role in mucin secretion. We reviewed all the related literature in the PubMed database to determine the expression of these Th cytokines in CRS and the role they play in the regulation of mucin secretion. CONCLUSION: We believe that the main Th cytokines involved in specific endotypes of CRS play a key role in regulating abnormal mucin secretion, which contributes to better understanding of the pathogenesis of CRS and provides therapeutic targets for airway inflammatory diseases associated with mucin hypersecretion.

Splenectomy ameliorates liver cirrhosis by restoring the gut microbiota balance.

BACKGROUND: Dysbiosis of gut microbiota is frequent in liver cirrhosis (LC) patients, and splenectomy (SP) has been reported to improve LC. Herein, we report the effects of SP on gut microbiota, especially on Veillonella parvula, a Gram-negative coccus of the gastrointestinal tract, in LC mice, and the underlying mechanism. METHODS: LC mice models were induced by tail vein injection of concanavalin A (ConA), followed by SP. 16 s rRNA sequencing was conducted to analyze the effects of ConA induction and SP on mouse gut microbiota and the gene expression affected by gut microbiota. LC mice receiving SP were gavaged with Veillonella parvula. Likewise, hepatic stellate cells (HSC) and hepatocytes (HC) were induced with conditioned medium (CM) of Veillonella parvula. RESULTS: SP alleviated LC in mice by restoring gut barrier function and maintaining gut microbiota balance, with Veillonella as the key genus. The Veillonella parvula gavage on LC mice reversed the ameliorative effect of SP. The CM of Veillonella parvula promoted the activation of HSC and the release of IL-6, IL-1ß, and TNF-α. Also, the CM of Veillonella parvula induced HC pyroptosis and the release of ALT and AST. Veillonella parvula represented an imbalance in the gut microbiota, thus enhancing gut-derived endotoxins in the liver with the main target being Tlr4/Nlrp3. Inhibition of Tlr4 blocked Veillonella parvula-induced HC damage, HSC activation, and subsequent LC progression. CONCLUSION: SP-mediated gut microbiota regulation ameliorates ConA-related LC progression by inhibiting Tlr4/Nlrp3 in the liver.

Dapagliflozin Suppresses Isoprenaline-Induced Cardiac Hypertrophy Through Inhibition of Mitochondrial Fission.

ABSTRACT: Dapagliflozin (DAPA) is a novel oral hypoglycemic agent, and there is increasing evidence that DAPA has a protective effect against cardiovascular disease. The study aimed to investigate how DAPA inhibits cardiac hypertrophy and explore its potential mechanisms. By continuously infusing isoprenaline (ISO) for 2 weeks using a subcutaneous osmotic pump, a cardiac hypertrophic model was established in male C57BL/6 mice. On day 14 after surgery, echocardiography showed that left ventricle mass (LV mass), interventricular septum, left ventricle posterior wall diastole, and left ventricular posterior wall systole were significantly increased, and ejection fraction was decreased compared with control mice. Masson and Wheat Germ Agglutinin staining indicated enhanced myocardial fibrosis and cell morphology compared with control mice. Importantly, these effects were inhibited by DAPA treatment in ISO-induced mice. In H9c2 cells and neonatal rat cardiomyocytes, we found that mitochondrial fragmentation and mitochondrial oxidative stress were significantly augmented in the ISO-induced group. However, DAPA rescued the cardiac hypertrophy in ISO-induced H9c2 cells and neonatal rat cardiomyocytes. Mechanistically, we found that DAPA restored the PIM1 activity in ISO-induced H9c2 cells and subsequent increase in dynamin-associated protein 1 (Drp1) phosphorylation at S616 and decrease in Drp1 phosphorylation at S637 in ISO-induced cells. We found that DAPA mitigated ISO-induced cardiac hypertrophy by suppressing Drp1-mediated mitochondrial fission in a PIM1-dependent fashion.

Gut microbial dysbiosis is associated with metabolism and immune factors in liver fibrosis mice.

Gut microbial dysbiosis has always served as a potential factor in the occurrence and development of liver fibrosis. Liver and gut microflora can regulate each other through the gut-liver axis. In this study, the 16S rRNA and RNA-seq were chosen to sequence gut microbiota alteration and liver differentially expressed genes (DEGs) in carbon tetrachloride (CCl4) included-liver fibrosis mice, and analyze the correlations between gut microbiota constituents and DEGs. Results indicated that, CCl4 significantly increased the abundance of Desulfobactera in the phylum level, destroyed gut microbiota balance in the genus levels, especially Enterorhabdus and Desulfovibrio. Through analysis, 1416 genes were found differentially expressed in mice liver tissue in the CCl4 Group, compared with the Control Group; and the DEGs were mainly involved in the lipid metabolic process and immune system process. The correlation analysis revealed that the relative abundance of microbiota phylum (Desulfobactera) and genus (Enterorhabdus and Desulfovibrio) was negatively correlated with the metabolism related genes, while positively correlated with immune-related genes and the genes enriched in PI3K-Akt signaling pathway. To sum up, CCl4 can partially regulate gene expression in metabolism, immune response and the PI3K/Akt pathway, and further maintain the stability of the gut environment in liver fibrosis mice.

Discovery of novel tetrahydrobenzothiophene derivatives as MSBA inhibitors for antimicrobial agents.

The incidence of infections caused by drug-resistant bacteria has been one of the most serious health threats in the past and is substantially increasing in an alarming rate. Therefore, the development of new antimicrobial agents to combat bacterial resistance effectively is urgent. This study focused on the design and synthesis of 40 novel tetrahydrobenzothiophene amide/sulfonamide derivatives and their antibacterial activities were evaluated. Compounds 2p, 6p, and 6 s exhibited significant inhibitory effects on the growth of bacteria. To assess their safety, the cytotoxicity of the compounds was assessed using human normal liver cells, revealing that compound 6p has lower cytotoxicity. A mouse wound healing experiment demonstrated that compound 6p effectively improved wound infection induced by trauma and accelerated the healing process. Compound 6p holds promise as a potential therapeutic agent for combating bacterial infections.

Single-cell dissection of the multicellular ecosystem and molecular features underlying microvascular invasion in HCC.

BACKGROUND AND AIMS: Microvascular invasion (MVI) is a crucial pathological hallmark of HCC that is closely associated with poor outcomes, early recurrence, and intrahepatic metastasis following surgical resection and transplantation. However, the intricate tumor microenvironment and transcriptional programs underlying MVI in HCC remain poorly understood. APPROACH AND RESULTS: We performed single-cell RNA sequencing of 46,789 individual cells from 10 samples of MVI+ (MVI present) and MVI- (MVI absent) patients with HCC. We conducted comprehensive and comparative analyses to characterize cellular and molecular features associated with MVI and validated key findings using external bulk, single-cell, and spatial transcriptomic datasets coupled with multiplex immunofluorescence assays. The comparison identified specific subtypes of immune and stromal cells critical to the formation of the immunosuppressive and pro-metastatic microenvironment in MVI+ tumors, including cycling T cells, lysosomal associated membrane protein 3+ dendritic cells, triggering receptor expressed on myeloid cells 2+ macrophages, myofibroblasts, and arterial i endothelial cells. MVI+ malignant cells are characterized by high proliferation rates, whereas MVI- malignant cells exhibit an inflammatory milieu. Additionally, we identified the midkine-dominated interaction between triggering receptor expressed on myeloid cells 2+ macrophages and malignant cells as a contributor to MVI formation and tumor progression. Notably, we unveiled a spatially co-located multicellular community exerting a dominant role in shaping the immunosuppressive microenvironment of MVI and correlating with unfavorable prognosis. CONCLUSIONS: This study provides a comprehensive single-cell atlas of MVI in HCC, shedding light on the complex multicellular ecosystem and molecular features associated with MVI. These findings deepen our understanding of the underlying mechanisms driving MVI and provide valuable insights for improving clinical diagnosis and developing more effective treatment strategies.

Dapagliflozin attenuates myocardial hypertrophy via activating the SIRT1/HIF-1α signaling pathway.

As a sodium-glucose transporter 2 inhibitor (SGLT2i), the cardioprotective benefits of Dapagliflozin (DAPA) are now widely appreciated. However, the underlying mechanism of DAPA on angiotensin II (Ang II)-induced myocardial hypertrophy has never been evaluated. In this study, we not only investigated the effects of DAPA on Ang II-induced myocardial hypertrophy, but explored its underlying mechanisms. Mice were injected with Ang II (500 ng /kg/min) or saline solution as control, followed by intragastric administration DAPA (1.5 mg/kg/day) or saline for four weeks. DAPA treatment alleviated the condition of decrease in left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) caused by Ang II. In addition, DAPA treatment significantly alleviated Ang II-induced elevation of the ratio of heart weight to tibia length, as well as cardiac injury and hypertrophy. In mice stimulated with Ang II, the degree of myocardial fibrosis and upregulation of the markers of cardiac hypertrophy (atrial natriuretic peptide, ANP and B-type natriuretic peptide, BNP) were attenuated by DAPA. What's more, DAPA partially reversed the Ang II-induced upregulation of HIF-1α and the decrease in levels of SIRT1. Taken together, activating the SIRT1/HIF-1α signaling pathway was found to confer a protective effect against experimental myocardial hypertrophy in mice induced by Ang II, demonstrating its potential as an effective therapeutic target for pathological cardiac hypertrophy.

Early postsurgical lethal outcome due to splenic littoral cell angioma: A case report.

BACKGROUND: Littoral cell angioma (LCA) is a rare benign vascular tumor of the spleen. Given its rarity, standard diagnostic and therapeutic recommendations have yet to be developed for reported cases. Splenectomy is the only method of obtaining a pathological diagnosis and providing treatment to obtain a favorable prognosis. CASE SUMMARY: A 33-year-old female presented with abdominal pain for one month. Computed tomography and ultrasound revealed splenomegaly with multiple lesions and two accessory spleens. The patient underwent laparoscopic total splenectomy and accessory splenectomy, and splenic LCA was confirmed by pathology. Four months after surgery, the patient presented with acute liver failure, was readmitted, rapidly progressed to multiple organ dysfunction syndrome and died. CONCLUSION: Preoperative diagnosis of LCA is challenging. We systematically reviewed online databases to identify the relevant literature and found a close relationship between malignancy and immunodysregulation. When a patient suffers from both splenic tumors and malignancy or immune-related disease, LCA is possible. Due to potential malignancy, total splenectomy (including accessory spleen) and regular follow-up after surgery are recommended. If LCA is diagnosed after surgery, a comprehensive postoperative examination is needed.

Characterization of prognostic value and immunological roles of RAB22A in hepatocellular carcinoma.

Background: The protein-coding gene RAB22A, a member of the RAS oncogene family, is amplified or overexpressed in certain cancers. However, its action mechanism in hepatocellular carcinoma (HCC) remains unclear. Here, we aimed to examine the connection between RAB22A and survival prognosis in HCC and explore the biological significance of RAB22A. Methods: A database-based pan-cancer expression analysis of RAB22A was performed. Kaplan-Meier analysis and Cox regression were performed to evaluate the association between RAB22A expression and survival prognosis in HCC. Using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), various potential biological functions and regulatory pathways of RAB22A in HCC were discovered. Tumor immune infiltration was studied using the single sample gene set enrichment analysis (ssGSEA) method. N6-methyladenosine modifications and the regulatory network of competitive endogenous RNA (ceRNA) were verified in the TCGA cohort. Results: RAB22A was upregulated in HCC samples and cell lines. A high RAB22A expression in HCC was strongly correlated with sex, race, age, weight, TNM stage, pathological stage, tumor status, histologic grade, TP53 mutation status, and alpha fetal protein (AFP) levels. Overexpression of RAB22A indicated a poor prognosis was related to overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). GO and KEGG analyses revealed that the differentially expressed genes related to RAB22A might be involved in the proteasomal protein catabolic process, ncRNA processing, ribosome ribosomal subunit, protein serine/threonine kinase activity, protein serine kinase activity, Endocytosis, and non-alcoholic fatty liver disease. GSEA analyses revealed that the differentially expressed genes related to RAB22A might be involved in the T cell receptor, a co-translational protein, that binds to the membrane, axon guidance, ribosome, phagocytosis, and Eukaryotic translation initiation. RAB22A was correlated with N6-methyladenosine expression in HCC and established RAB22A-related ceRNA regulatory networks. Finally,RAB22A expression was positively connected the levels of infiltrating with T helper cells, Tcm cells, and Th2 cells,In contrast, we observed negatively correlations with cytotoxic cells, DCs, and pDCs cells.Moreover,RAB22A expression showed a strong correlation with various immunomarkergroups in HCC. Conclusions: RAB22A is a potential therapeutic target for improving HCC prognosis and is closely related to immune cell infiltration.

Mesh erosion into the colon following repair of parastomal hernia: A case report.

BACKGROUND: In recent years, mesh has become a standard repair method for parastomal hernia surgery due to its low recurrence rate and low postoperative pain. However, using mesh to repair parastomal hernias also carries potential dangers. One of these dangers is mesh erosion, a rare but serious complication following hernia surgery, particularly parastomal hernia surgery, and has attracted the attention of surgeons in recent years. CASE SUMMARY: Herein, we report the case of a 67-year-old woman with mesh erosion after parastomal hernia surgery. The patient, who underwent parastomal hernia repair surgery 3 years prior, presented to the surgery clinic with a complaint of chronic abdominal pain upon resuming defecation through the anus. Three months later, a portion of the mesh was excreted from the patient's anus and was removed by a doctor. Imaging revealed that the patient's colon had formed a t-branch tube structure, which was formed by the mesh erosion. The surgery reconstructed the structure of the colon and eliminated potential bowel perforation. CONCLUSION: Surgeons should consider mesh erosion since it has an insidious development and is difficult to diagnose at the early stage.

Angiotensin-(1-9) prevents angiotensin II-induced endothelial apoptosis through CNPY2/PERK pathway.

Endothelial apoptosis caused by activation of renin-angiotensin system (RAS) plays a vital part in the occurrence and progress of hypertension. Angiotensin-(1-9) (Ang-(1-9)) is a peptide of the counter-regulatory non-classical RAS with anti-hypertensive effects in vascular endothelial cells (ECs). However, the mechanism of action remains unclear. Considering that the endothelial apoptosis was closely related to endoplasmic reticulum stress (ERS) and mitochondrial function. Herein, we aimed to elucidate the effects of Ang-(1-9) on endothelial apoptosis and the underlying molecular mechanism in angiotensin II (Ang II) induced hypertension. In human umbilical vascular endothelial cells (HUVECs), we observed Ang-(1-9) inhibited Ang II-induced ERS associated endothelial apoptosis. Mechanically, Ang-(1-9) inhibited endothelial apoptosis by blocking CNPY2/PERK mediated CaMKII/Drp1-dependent mitochondrial fission and eIF2α/CHOP signal. Consistent with above effects in HUVECs, in Ang II-induced hypertensive mice, we found administration of exogenous Ang-(1-9) attenuated endothelial apoptosis and arterial blood pressure, which were mediated by CNPY2/PERK signaling pathway. Our study indicated Ang-(1-9) inhibited Ang II-induced hypertension through CNPY2/PERK pathway. These findings may provide new insights for prevention and treatment of hypertension in future.

Optimisation of anti-interleukin-6 therapy: Precision medicine through mathematical modelling.

Background: Dysregulated interleukin (IL)-6 production can be characterised by the levels present, the kinetics of its rise and its inappropriate location. Rapid, excessive IL-6 production can exacerbate tissue damage in vital organs. In this situation, therapy with an anti-IL-6 or anti-IL-6 receptor (IL-6R) monoclonal antibody, if inappropriately dosed, may be insufficient to fully block IL-6 signalling and normalise the immune response. Methods: We analysed inhibition of C-reactive protein (CRP) - a biomarker for IL-6 activity - in patients with COVID-19 or idiopathic multicentric Castleman disease (iMCD) treated with tocilizumab (anti-IL-6R) or siltuximab (anti-IL-6), respectively. We used mathematical modelling to analyse how to optimise anti-IL-6 or anti-IL-6R blockade for the high levels of IL-6 observed in these diseases. Results: IL-6 signalling was insufficiently inhibited in patients with COVID-19 or iMCD treated with standard doses of anti-IL-6 therapy. Patients whose disease worsened throughout therapy had only partial inhibition of CRP production. Our model demonstrated that, in a scenario representative of iMCD with persistent high IL-6 production not controlled by a single dose of anti-IL-6 therapy, repeated administration more effectively inhibited IL-6 activity. In a situation with rapid, high, dysregulated IL-6 production, such as severe COVID-19 or a cytokine storm, repeated daily administration of an anti-IL-6/anti-IL-6R agent, or alternating daily doses of anti-IL-6 and anti-IL-6R therapies, could neutralise IL-6 activity. Conclusion: In clinical practice, IL-6 inhibition should be individualised based on pathophysiology to achieve full blockade of CRP production. Funding: EUSA Pharma funded medical writing assistance and provided access to the phase II clinical data of siltuximab for analysis.

Erratum: Comparative study of nanostructured carriers of calcium phosphate and magnesium phosphate loaded with SRT1720 for the protection of H2O2-induced senescent endothelium.

[This corrects the article on p. 2068 in vol. 10, PMID: 30093944.].

Hydrogen Sulfide Diminishes Activation of Adventitial Fibroblasts Through the Inhibition of Mitochondrial Fission.

ABSTRACT: Activation of adventitial fibroblasts (AFs) on vascular injury contributes to vascular remodeling. Hydrogen sulfide (H2S), a gaseous signal molecule, modulates various cardiovascular functions. The aim of this study was to explore whether exogenous H2S ameliorates transforming growth factor-ß1 (TGF-ß1)-induced activation of AFs and, if so, to determine the underlying molecular mechanisms. Immunofluorescent staining and western blot were used to determine the expression of collagen I and α-smooth muscle actin. The proliferation and migration of AFs were performed by using cell counting Kit-8 and transwell assay, respectively. The mitochondrial morphology was assessed by using MitoTracker Red staining. The activation of signaling pathway was evaluated by western blot. The mitochondrial reactive oxygen species and mitochondrial membrane potential were determined by MitoSOX and JC-1 (5,5',6,6'-tetrachloro-1,1,3,3'-tetraethylbenzimidazolyl carbocyanine iodide) staining. Our study demonstrated exogenous H2S treatment dramatically suppressed TGF-ß1-induced AF proliferation, migration, and phenotypic transition by blockage of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and regulated mitochondrial reactive oxygen species generation. Moreover, exogenous H2S reversed TGF-ß1-induced mitochondrial fission and AF activation by modulating Rho-associated protein kinase 1-dependent phosphorylation of Drp1. In conclusion, our results suggested that exogenous H2S attenuates TGF-ß1-induced AF activation through suppression of Drp1-mediated mitochondrial fission in a Rho-associated protein kinase 1-dependent fashion.