Modified Zhenwu Decoction improved intestinal barrier function of experimental colitis through activation of sGC-mediated cGMP/PKG signaling.

BACKGROUND: The invasion of luminal antigens and an aberrant immune response resulting from a disrupted physical epithelial barrier are the key characteristics of ulcerative colitis (UC). The restoration of damaged epithelial function is crucial for maintaining mucosal homeostasis and disease quiescence. Current therapies for UC primarily focus on suppressing inflammation. However, most patients fail to respond to therapy or develop secondary resistance over time, emphasizing the need to develop novel therapeutic targets for UC. Our study aimed to identify the potential targets of a novel modified herbal formula from the Zhen Wu Decoction, namely CDD-2103, which has demonstrated promising efficacy in treating chronic colitis. METHODS: The effect of CDD-2103 on epithelial barrier function was examined using in vitro and ex vivo models of tissue injury, as well as a chronic colitis C57BL/6 mouse model. Transcriptomic analysis was employed to profile gene expression changes in colonic tissues following treatment with CDD-2103. RESULTS: Our in vivo experiments demonstrated that CDD-2103 dose-dependently reduced disease severity in mice with chronic colitis. The efficacy of CDD-2103 was mediated by a reduction in goblet cell loss and the enhancement of tight junction protein integrity. Mechanistically, CDD-2103 suppressed epithelial cell apoptosis and tight junction protein breakdown by activating the soluble guanynyl cyclase (sGC)-mediated cyclic guanosine monophosphate (cGMP)/PKG signaling cascade. Molecular docking analysis revealed strong sGC ligand recognition by the CDD-2103-derived molecules, warranting further investigation. CONCLUSION: Our study revealed a novel formulation CDD-2103 that restores intestinal barrier function through the activation of sGC-regulated cGMP/PKG signaling. Furthermore, our findings suggest that targeting sGC can be an effective approach for promoting mucosal healing in the management of UC.

Modified Zhenwu Decoction suppresses chronic colitis via targeting macrophage CCR2/Fyn/p38 MAPK signaling axis.

BACKGROUND: Ulcerative colitis (UC) is associated with intestinal macrophage infiltration due to disruption of the mucosal barrier and bacterial invasion. Therefore, it is crucial to identify therapeutic agents capable of attenuating the macrophage-induced inflammatory response to preserve mucosal homeostasis and immune tolerance. The modified Zhenwu decoction (CDD-2103) is a novel herbal formulation developed based on the principles of Traditional Chinese medicine. To date, there are no clinically approved herbal formulations for UC with a well-known mechanism of action on macrophages. PURPOSE: The objective of this study was to systematically investigate the inhibitory effect of the active fraction of CDD-2103 in a mouse model of chronic colitis and delineate the mechanisms underlying its inhibitory action. METHODS: CDD-2103 was extracted into four fractions using organic solvents with increasing polarity. A chronic 49-day dextran sulfate sodium (DSS)-induced colitis mice model, closely resembling human clinical conditions, was used to examine the effect of CDD-2103 on chronic colitis. To confirm the effect of CDD-2103 on macrophages in this chronic colitis model, adoptive macrophage transfer and CCL2 supplementation were conducted. The mechanisms of action of CDD-2103 were further elucidated utilizing bone marrow-derived macrophages (BMDMs). Transcriptome analysis was conducted to gain insights into the underlying mechanism of action of CDD-2103 in BMDMs. RESULTS: Our in vitro and in vivo findings demonstrated that the ethanol-enriched fraction of CDD-2103 exhibited significant anti-inflammatory effects, leading to the suppression of colitis severity. This effect was associated with diminished accumulation of colonic macrophages in the lamina propria of CDD-2103-intervened colitis mice. Specifically, CDD-2103 inhibited CCR2/L2-mediated proinflammatory macrophage infiltration into the colon without affecting macrophage proliferation. Mechanistically, CDD-2103 inhibited Fyn expression-mediated p38 MAPK activation and subsequently suppressed CCR2 expression in BMDMs. CONCLUSIONS: Collectively, our study supports the potential use of CDD-2103 to limit macrophage infiltration, thereby reducing inflammation during UC treatment. CDD-2103 and the components in the ethanolic fraction are promising candidates for the development of novel drugs for UC management. Additionally, our study underscores Fyn-mediated CCR2 expression as a potential therapeutic target for the management of UC.

VNN1 as a potential biomarker for sepsis diagnosis and its implications in immune infiltration and tumor prognosis.

Background: This study explored novel biomarkers for diagnosing sepsis, a severe disease prevalent in clinical settings, particularly threatening to elderly patients. Methods: Using microarray gene expression datasets and fatty acid metabolism signatures, we identified differentially expressed genes between sepsis and healthy control groups. Correlations between candidate genes, immune cells, and immune function were assessed. Logistic regression analysis and single-gene GSEA analysis were performed to identify potential biomarkers. The biomarkers' association with different types of tumors was investigated. Results: Twelve genes related to fatty acid metabolism were excluded. CA4, OLAN, and VNN1 were found relevant to immune cells and function. Among these, only VNN1 showed statistical significance (p < 0.05), with a strong area under the ROC curve (0.995). High VNN1 expression indicated activation of certain metabolic pathways, while low expression suggested potential autoimmune responses. VNN1 was up-regulated in eight tumors and down-regulated in eight others. High VNN1 expression was linked to poor prognosis in six types of tumors, and low expression was linked to poor prognosis in four types of tumors. VNN1 expression showed correlations with stromal scores, immune scores, and cancer purity in different types of tumors. Conclusion: VNN1 holds promise as a potential biomarker for sepsis diagnosis and is significant in identifying immune infiltration in tumor tissue and predicting tumor prognosis.

Recurrent Sepsis Exacerbates CD4+ T Cell Exhaustion and Decreases Antiviral Immune Responses.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection. It is a disease with a high incidence, mortality, and recurrence rate and frequently results in its survivors requiring readmission into hospitals. The readmission is mainly due to recurrent sepsis. Patients with recurrent sepsis are more susceptible to secondary infections partly due to immune dysfunction, leading to a higher mortality in the long term. However, there remains a gap in the understanding of immunological characteristics and underlying mechanisms of recurrent sepsis. In this study, we used mouse models of acute and recurrent sepsis to investigate their different immunological characteristics. And then we subjected the two mouse models to a secondary influenza A virus (H1N1) infection and characterized the different immune responses. Here, we demonstrated that CD4+ T cells present an exacerbated exhaustion phenotype in response to recurrent sepsis as illustrated by the decreased frequency of CD4+ T cells, reduced co-stimulatory CD28 and increased inhibitory PD-1 and Tim-3 expression on CD4+ T cells, increased frequency of regulatory T cells, and reduced MHC-II expression on antigen-presenting cells. Moreover, we showed that antiviral immune responses decrease in the recurrent sepsis mouse model subjected to a secondary infection as illustrated by the reduced pathogen clearance and inflammatory response. This may be a consequence of the exacerbated CD4+ T cell exhaustion. In summary, recurrent sepsis exacerbates CD4+ T cell exhaustion and decreases antiviral immune responses, contributing to significant morbidity, increased late mortality, and increased health care burden in recurrent sepsis patients.

Glycyrrhizic acid exerts inhibitory activity against the spike protein of SARS-CoV-2.

Coronavirus causes a disease with high infectivity and pathogenicity, especially SARS in 2003, MERS in 2012, and COVID-2019 currently. The spike proteins of these coronaviruses are critical for host cell entry by receptors. Thus, searching for broad-spectrum anti-coronavirus candidates, such as spike protein inhibitors, is vital and desirable due to the mutations in the spike protein. In this study, a combination of computer-aided drug design and biological verification was used to discover active monomers from traditional Chinese medicine. Surface plasmon resonance (SPR) assays and NanoBit assays were used to verify the predicated compounds with their binding activities to spike proteins and inhibitory activities on the SARS-CoV-2 RBD/ACE2 interaction, respectively. Furthermore, an MTT assay was used to evaluate the cell toxicities of active compounds. As a result, glycyrrhizic acid (ZZY-44) was found to be the most efficient and nontoxic broad-spectrum anti-coronavirus molecule in vitro, especially, the significant effect on SARS-CoV-2, which provided a theoretical basis for the study of the pharmacodynamic material basis of traditional Chinese medicine against SARS-CoV-2 and offered a lead compound for further structural modification in order to obtain more effective candidate drugs against SARS-CoV-2.

Non-pharmacological interventions for improving sleep quality in patients on dialysis: systematic review and meta-analysis.

We conducted a meta-analysis to summarise and quantify the effects of non-pharmacological interventions on sleep quality improvement in uraemic patients on dialysis. We defined the primary outcome as the change of sleep quality before and after interventions (evaluated by polysomonography or subjective questionnaires such as Pittsburgh sleep quality index, PSQI). The change of fatigue scales, inflammatory cytokines and adverse events were analysed as secondary outcomes. Twelve eligible randomised controlled trials and one prospective cohort study were identified. All three identified non-pharmacological interventions could result in a greater PSQI score reduction compared to controls: 1) cognitive-behavioural therapy (CBT) versus sleep hygiene education (standardised mean difference (SMD) 0.85, 95% CI 0.37-1.34); 2) physical training versus no training (SMD 3.36, 95% CI 2.16-4.57) and 3) Acupressure (including other acupoints massages) versus control (SMD 1.77, 95% CI 0.80-2.73). In terms of subscores, we found that CBT may shorten sleep latency, alleviate sleep disturbance and reduce the use of sleep medications. The finding of the cohort study suggested that intradialytic aerobic exercise training improved sleep quality in haemodialysis patients with restless leg syndrome. In conclusion, in dialysis-dependent patients, CBT could shorten sleep latency, alleviate sleep disturbance and reduce the use of sleep medications. Acupressure (including other acupoints massages) and exercise training are promising interventions but the results in these subgroups should be interpreted cautiously due to the concern of methodological quality and potential confounding factors.