Jingjun Lv

Sepsis is a life-threatening condition characterized by a dysregulated immune response to infection, often leading to organ dysfunction and even death. During the recovery phase of sepsis, patients frequently exhibit impaired antimicrobial function of immune cells, which exacerbates the state of immunosuppression and increases the risk of secondary infections. However, therapeutic strategies targeting sepsis-induced immunosuppression have yet to achieve breakthrough progress, with the core challenge lying in the significant gaps in understanding the molecular mechanisms underlying immunosuppression. In this study, we integrated clinical samples, mouse models, and molecular mechanisms to reveal that the reduction in macrophage function and epigenetic dysregulation, particularly histone ubiquitination, are central drivers of sepsis-induced immunosuppression. Further investigation demonstrated that MYSM1, a deubiquitinase, plays a pivotal role in regulating this ubiquitination process. Targeted deletion of the N-terminal domain of MYSM1 markedly enhances the inflammatory response during the early phase of secondary infection in sepsis, facilitating bacterial clearance and significantly mitigating tissue damage in the late phase of secondary infection, thereby improving the survival outcomes in mice. Overall, our study elucidates the role of MYSM1-mediated dysregulation of epigenetic modifications in the immune response during the late phase of sepsis, providing a novel therapeutic approach for addressing sepsis-related immune dysfunction.

Objective To examine the independent risk factors of type-2 myocardial infarction (T2MI) elicited by acute upper gastrointestinal bleeding (AUGIB), and to establish a nomogram model for the prediction of AUGIB-induced T2MI. Methods A nomogram model was established on the basis of a retrospective study that involved 533 patients who suffered from AUGIB in the Department of Critical Care Medicine (CCM) or Emergency Intensive Care Unit (EICU) of Renmin Hospital of Wuhan University, Wuhan, China, from January 2017 to December 2020. The predictive accuracy and discriminative power of the nomogram were initially evaluated by internal validation, which involved drawing the receiver operating characteristic (ROC) curve, calculating the area under the curve (AUC), plotting the calibration curve derived from 1000 resampled bootstrap data sets, and computing the root mean square error (RMSE). The predictive ability of the nomogram was further validated through the prospective and multicenter study conducted by the investigators, which enrolled 240 AUGIB patients [including 88 cases from Renmin Hospital of Wuhan University, 73 cases from Qilu Hospital of Shandong University (Qingdao), and 79 cases from Northern Jiangsu People’s Hospital)], who were admitted to the Department of CCM or EICU, from February 2021 to July 2021. Results Among the 533 patients in the training cohort, 78 (14.6%) patients were assigned to the T2MI group and 455 (85.4%) patients were assigned to the non-T2MI group. The multivariate analysis revealed that age >65, hemorrhagic shock, cerebral stroke, heart failure, chronic kidney disease, increased blood urea nitrogen, decreased hematocrit, and elevated D-Dimer were independent risk factors for AUGIB-induced T2MI. All these factors were incorporated into the nomogram model. The AUC for the nomogram for predicting T2MI was 0.829 (95% CI, 0.783–0.875) in the internal validation cohort and 0.848 (95% CI, 0.794–0.902) in the external validation cohort. The calibration curve for the risk of T2MI exhibited good consistency between the prediction by the nomogram and the actual clinical observation in both the internal validation (RMSE=0.016) and external validation (RMSE=0.020). Conclusion The nomogram was proven to be a useful tool for the risk stratification of T2MI in AUGIB patients, and is helpful for the early identification of AUGIB patients who are prone to T2MI for early intervention, especially in emergency departments and intensive care units.

To explore the effects of antiepileptic drug sodium valproate on magnetic resonance imaging (MRI) images, neurological cognition, and JAK1/STAT3 pathway in hippocampus of rats with depression, 30 Sprague Dawley (SD) rats were included. The depression model (DM) was prepared through the chronic stress restraint test. Some model rats were injected with 10 mg/kg sodium valproate into abdominal cavity before modeling (RT group)), and healthy rats were selected as controls (healthy control (HC) group). Depth of split brain was greatly increased in DM group, and nitrogen-acetyl aspartic acid (NAA)/creatine (Cr), glutamic acid (Glu)/Cr, and choline (Cho)/Cr ratios were greatly reduced (P < 0.05). Behavioral test results showed that sugar water preference rate, escape latency, and divergence index in DM group were greatly reduced (P < 0.05), and cumulative immobility time, target quadrant stay time, and number of crossings in forced swimming and tail suspension were prolonged dramatically (P < 0.05), with no difference between the two groups (P > 0.05). Expression levels of interleukin 1β (IL-1β) and interleukin 6 (IL-6) in hippocampus of DM group were obviously increased (P < 0.05), and expression levels of JAK1 and STAT3 were decreased visibly (P < 0.05), with no difference between the two (P > 0.05). In summary, anti-epileptic drug sodium valproate effectively improves hippocampal volume characteristics and memory and neurocognitive dysfunction of depression models.

One of the key factors in repairing spinal cord injury is reducing inflammation and oxidative stress. So, it was tried to increase the growth of neurons more rapidly by enhancing the macrophage M2 and reducing the M1 to M2 ratio by using the possible role of tacrolimus (TAC) loaded on polyethylene glycol-modified maghemite nanospheres (PEG-MNs). In this regard, after designing PEG-MNs-TAC in a three-step process and examining their properties through TEM, DLS and XRD analyses. A toxicity assay was then performed by using MTT test. To investigate the healing role of TAC on damaged tissue, a rat model was used to induce injury in vertebral T6 through physical injury. Then, rats were allocated into five groups: negative control, MNs, PEG-MNs , TAC (and PEG-MNs-TAC. Next, motor scale index, behavioral test, macrophage markers expression, concentration of IL-6, IL-2 and TNF-α, and oxidative stress on rats were analyzed. The results revealed that TAC and PEG-MNs-TAC significantly improved mobility and neuropathic tests. Furthermore, the decrease in TNF-α, IL-6, and IL-2 along with the decrease in ROS levels in the injured spinal cord were considerable in both TAC- and PEG-MNs-TAC-treated groups. Nonetheless, the PEG-MNs-TAC exposed more favorable outcomes compared to TAC. Overall, PEG-MNs-TAC could provide a new treatment for damaged spinal cord care by reducing oxidative stress and decreasing M1 to M2 ratio.

Background: There is no convincing pharmacological treatment for patients withacute respiratory distress syndrome (ARDS). The efficacy of corticosteroids in ARDS patients remains controversial. Neutrophil-to-Lymphocyte Ratio (NLR) has displayed as a good biomarker for inflammation and immune status, and thus a prognostic marker in some critical patients of ARDS. In this study, we hypothesized that NLR could also serve as an indicator for the efficacy of corticosteroid therapy in ARDS patients. Methods: Subjects included in this retrospective cohort study with ARDS patients who were admitted to an academic hospital in Wuhan, China, from May 1st, 2020 to April 20th, 2021. Multivariable logisitic regression model was used to evaluate risk factors of 30-day in-hospital mortality and ventilator-free days. Multi-Cox regression model was used to assess the efficacy of corticosteroid treatment in terms of NLR cutoff value. Results: Among the 357 patients in our study, 89 (24.9%) had NLR=14.35 and 268 (75.1%) had NLR<14.35. Among them, 53 patients with NLR=14.35 (58.9%) received corticosteroids and 99 patients with NLR<14.35 (37.1%) received corticosteroids. Post-adjustment analysis (by APACHE II score and age) revealed that corticosteroid treatment was associated with a decreased risk of 30-day mortality in the NLR=14.35 group but with an increased risk of death in the NLR<14.35 group. Use of corticosteroid in NLR=14.35 group significantly increased ventilator-free days (7.0 vs. 13.0, P<0.001). Conclusion: NLR may be used to help identify ARDS patients who may benefit from corticosteroid treatment. Large-sized randomized controlled trials are warranted to determine the optimal cutoff value of NLR.

Background:Understanding of the incidence and effects of acute kidney injury (AKI) in patients diagnosed with COVID-19 is limited. The purpose of this study was to examine risk factors and related outcomes associated with AKI among patients diagnosed with COVID-19. Method: This is a retrospective cohort study of patients diagnosed with COVID-19 associated-pneumonia admitted to a tertiary hospital in Wuhan between January to February 2020. AKI was defined and staged according to the Kidney Disease: Improving Global Outcome (KDIGO) classification criteria. Cox’s multivariate regression and logistic regression modelling were used to assess the effects of AKI on hospital mortality and risk factors associated with occurrence of AKI. Primary outcomes were risk-adjusted in-hospital mortality.Results:342 patients were finally enrolled in this study. AKI occurred in 13.4% (n = 46), among them 7.0% (n = 24) developed stage 1AKI, and 6.4% (n = 22) developed stage 2 - 3 AKI. Overall 26.9% (n = 92) died during hospitalization. Among them 19.3% (57/296) of the non-AKI patients died, 62.5%(15/24) of stage 1 AKI patients, and 90.9% (20/22) of stage 2 - 3 AKI patients died. AKI was strongly associated with mortality (HR 2.52; 95% CI, 1.59-3.96; p＜0.001). Further analysis shows that progression to AKI stage 2 - 3 doubles the hazard ratio for death. Age, leukocytes number, fibrinogen concentration, C-reative protein level, and severity of pneumonia at admission were independent risk factors associated with the development of AKI. Conclusion:Acute kidney injury is common among hospitalized COVID-19 patients and strongly associated with increased mortality, early detection and prevention of the progression of AKI may be critical to reduce mortality of these patients.

Summary: Background: The novel coronavirus (CoV) severe acute respiratory syndrome (SARS)-CoV-2 outbreak started at the end of 2019 in Wuhan, China, and spread over 100 countries. SARS-CoV-2 uses the membrane protein Angiotensin I converting enzyme 2(ACE2) as a cell entry receptor. Indeed, it was reported that the balance of Renin-Angiotensin System (RAS), regulated by both ACE and ACE2, was altered in COVID-19 patients. It is controversial, however, whether commonly used anti-hypertensive drugs Angiotensin I converting enzyme inhibitor (ACEI) and Angiotensin II receptor blocker (ARB) shall be continued in the confirmed COVID-19 patients. This study was designed to investigate any difference in disease severity between COVID-19 patients with hypertension comorbidity. The included COVID-19 patients used ACEI, ARB, calcium channel blockers (CCB), beta blockers (BB), or thiazide to treat preexisting hypertension prior to the hospital were compared to patients who did not take any of those drugs. Methods: In this multicentre retrospective study, clinical data of 511 COVID-19 patients were analyzed. Patients were categorized into six sub-groups of hypertension comorbidity based on treatment using one of anti-hypertension drugs (ACEI, ARB, CCB, BB, thiazide), or none. A meta-analysis was performed to evaluate the use of ACEI and ARB associated with pneumonia using published studies. Findings: Among the elderly (age>65) COVID-19 patients with hypertension comorbidity, the risk of COVID-19-S (severe disease) was significantly decreased in patients who took ARB drugs prior to hospitalization compared to patients who took no drugs (OR=0·343, 95% CI 0·128-0·916, p=0·025). The meta-analysis showed that ARB use has positive effects associated with morbidity and mortality of pneumonia. Interpretation: Elderly (age>65) COVID-19 patients with hypertension comorbidity who are taking ARB anti-hypertension drugs may be less likely to develop severe lung disease compared to patients who take no anti-hypertension drugs. Funding: National Natural Science Foundation of China, Chinese Academy of Medical Sciences Research in context: Evidence before this study: We searched PubMed for articles published up to March 15, 2020 using keywords “2019-nCoV”, “SARS-CoV-2”, “novel coronavirus”, and COVID-19 AND “ARB”, and “angiotensin II receptor blocker” for papers published in both English and Chinese. We found three papers: one from our group, published in Science China Life Science that demonstrated an elevated Angiotensin II level in blood samples from COVID-19 patients; another a perspective article in Chinese recommending ACEI and ARBs as potential remedies for SARS-CoV-2 infections; the third a retrospective study in Chinese identifying no significant difference between ACEI/ARB associated with outcomes in 112 COVID-19 patients with CVD comorbidity. The International society of Hypertension stated on March 16 ^th , 2020: “there are no clinical data in human to show that ACE-inhibitors or ARBs either improve or worsen susceptibility to COVID-19 infection nor do they affect the outcomes of those infected”. Added value of this study: We retrospectively reviewed different types of anti-hypertensive drugs taken by COVID-19 patients with hypertension comorbidity prior to entering the hospital. We discovered that ARB hypertensive drugs were associated with a decreased risk of severe disease in elderly (age>65) COVID-19 patients (OR=0·343, 95% CI 0·128-0·916, p=0·025), the first evidence of ARBs association to COVID-19 infections in human. We conducted a meta-analysis in the literature and found that ARB has positive effects associated with morbidity and mortality of pneumonia. Implications of all the available evidence: ARB drugs are widely used in the population with hypertension. Treatments with ACEI and ARBs should be continuous according to medical guidelines. RCT trials of ARB associated with morbidity and mortality of SARS-CoV-2 infection are recommended in the future.