Proteomic and Metabolomic Signatures Associated With the Immune Response in Healthy Individuals Immunized With an Inactivated SARS-CoV-2 Vaccine.

CoronaVac (Sinovac), an inactivated vaccine for SARS-CoV-2, has been widely used for immunization. However, analysis of the underlying molecular mechanisms driving CoronaVac-induced immunity is still limited. Here, we applied a systems biology approach to understand the mechanisms behind the adaptive immune response to CoronaVac in a cohort of 50 volunteers immunized with 2 doses of CoronaVac. Vaccination with CoronaVac led to an integrated immune response that included several effector arms of the adaptive immune system including specific IgM/IgG, humoral response and other immune response, as well as the innate immune system as shown by complement activation. Metabolites associated with immunity were also identified implicating the role of metabolites in the humoral response, complement activation and other immune response. Networks associated with the TCA cycle and amino acids metabolic pathways, such as phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and glycine, serine and threonine metabolism were tightly coupled with immunity. Critically, we constructed a multifactorial response network (MRN) to analyze the underlying interactions and compared the signatures affected by CoronaVac immunization and SARS-CoV-2 infection to further identify immune signatures and related metabolic pathways altered by CoronaVac immunization. These results help us to understand the host response to vaccination of CoronaVac and highlight the utility of a systems biology approach in defining molecular correlates of protection to vaccination.

LIGHT deficiency aggravates cisplatin-induced acute kidney injury by upregulating mitochondrial apoptosis.

Cisplatin is widely used as a chemotherapeutic agent for treating patients with solid tumors. The most common side effect of cisplatin treatment is nephrotoxicity. Recent studies have shown that mitochondrial apoptotic pathways are involved in cisplatin-induced acute kidney injury (Cis-AKI). LIGHT, the 14th member of the tumor necrosis factor superfamily (TNFSF14), was found to induce apoptosis of certain types of tumor cells. So far, a link between LIGHT and Cis-AKI has not been reported. In this study, we observed that expression of LIGHT and its receptors HVEM and LTßR was increased in kidney tissues of mice after cisplatin treatment. LIGHT deficiency aggravated kidney injury, as evidenced by more severe tubular injury; remarkably increased levels of serum creatinine (Scr), blood urea nitrogen (BUN), and both kidney injury molecule-1 (KIM-1) and inflammatory cytokine mRNAs in renal tissues. Moreover, in the renal tissues of LIGHT KO mice, cisplatin-induced mitochondrion injury and the levels of the pro-apoptotic molecules Bax, Cytochrome C (Cyt C), cleaved caspase-3, and cleaved caspase-9 were dramatically increased; in contrast, the expression of anti-apoptotic molecule Bcl-2 was markedly reduced, compared to those in WT mice, suggesting that LIGHT deficiency accelerated cisplatin-induced mitochondrial apoptosis of renal tubular cells in these mice. Accordingly, treatment with recombinant human LIGHT (rLIGHT) was shown to alleviate cisplatin-induced kidney injury in vivo. Similar results were observed after the human renal tubular epithelial cell line HK-2 cells exposure to rLIGHT stimulation, evidenced by the reduction in the mitochondrion dysfunction (as confirmed by the significant reduced oxidative stress and membrane potential changes) and in the percentage of cells apoptosis. While blocking LIGHT with the soluble fusion protein LTßR-Ig or HVEM-Ig accelerated the HK-2 cells apoptosis. In conclusion, LIGHT deficiency aggravates Cis-AKI by promoting mitochondrial apoptosis pathways.

The Metabolic Changes and Immune Profiles in Patients With COVID-19.

To explore the metabolic changes and immune profiles in patients with COVID-19, we analyzed the data of patients with mild and severe COVID-19 as well as young children with COVID-19. Of the leukocytes, 47% (IQR, 33-59) were lymphocytes [2.5 × 109/L (IQR, 2.2-3.3)], and monocytes were 0.51 × 109/L (IQR, 0.45-0.57) in young children with COVID-19. In 32 mild COVID-19 patients, circulating monocytes were 0.45 × 109/L (IQR, 0.36-0.64). Twenty-one severe patients had low PO2 [57 mmHg (IQR, 50-73)] and SO2 [90% (IQR, 86-93)] and high lactate dehydrogenase [580 U/L (IQR, 447-696)], cardiac troponin I [0.07 ng/mL (IQR, 0.02-0.30)], and pro-BNP [498 pg/mL (IQR, 241-1,726)]. Serum D-dimer and FDP were 9.89 mg/L (IQR, 3.62-22.85) and 32.7 mg/L (IQR, 12.8-81.9), and a large number of RBC (46/µL (IQR, 4-242) was presented in urine, a cue of disseminated intravascular coagulation (DIC) in severe patients. Three patients had comorbidity with diabetes, and 18 patients without diabetes also presented high blood glucose [7.4 mmol/L (IQR, 5.9-10.1)]. Fifteen of 21 (71%) severe cases had urine glucose +, and nine of 21 (43%) had urine ketone body +. The increased glucose was partially caused by reduced glucose consumption of cells. Severe cases had extraordinarily low serum uric acid [176 µmol/L (IQR, 131-256)]. In the late stage of COVID-19, severe cases had extremely low CD4+ T cells and CD8+ T cells, but unusually high neutrophils [6.5 × 109/L (IQR, 4.8-9.6)], procalcitonin [0.27 ng/mL (IQR, 0.14-1.94)], C-reactive protein [66 mg/L (IQR, 25-114)] and an extremely high level of interleukin-6. Four of 21 (19%) severe cases had co-infection with fungi, and two of 21 (9%) severe cases had bacterial infection. Our findings suggest that, severe cases had acute respiratory distress syndrome (ARDS) I-III, and metabolic disorders of glucose, lipid, uric acid, etc., even multiple organ dysfunction (MODS) and DIC. Increased neutrophils and severe inflammatory responses were involved in ARDS, MODS, and DIC. With the dramatical decrease of T-lymphocytes, severe cases were susceptible to co-infect with bacteria and fungi in the late stage of COVID-19. In young children, extremely high lymphocytes and monocytes might be associated with the low morbidity of COVID-19. The significantly increased monocytes might play an important role in the recovery of patients with mild COVID-19.

The modulation relationship of genomic pattern of intratumor heterogeneity and immunity microenvironment heterogeneity in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, with the second highest mortality rate among all cancer types. Growing evidence has demonstrated the notable effects of intratumor heterogeneity (ITH) and tumor immune microenvironment heterogeneity (TIMH) on the biological processes involved in HCC. However, the interactive mechanisms between ITH and TIMH is still unclear. The present study systematically screened the mRNA expression, simple nucleotide variation data and clinical data of samples from The Cancer Genome Atlas (TCGA). The mutant-allele tumor heterogeneity (MATH) score was used to represent ITH, and TCGA cohort was divided into two groups according to the MATH score. Next, different immune-related signaling pathways and enriched immune-related genes were identified using Gene Set Enrichment Analysis of these two groups, and the results revealed that interleukin-1α (IL1A) and serine/threonine-protein kinase PAK4 were associated with prognosis. Furthermore, CIBERSORT was utilized to calculate the fractions of 22 types of leukocytes to represent TIMH, and the fractions of M1 and M2 macrophages were confirmed to be associated with prognosis. Therefore, PAK4, interleukin-1α (IL1A), and M1/M2 ratio were selected as the key factors involved in the interaction between ITH and TIMH. Afterwards, microRNAs (miRNAs) that were linearly related to the M1/M2 ratio and the potential target genes of the miRNAs were screened. Finally, the regulatory network between PAK4, IL1A, and the M1/M2 ratio was established, bridged by the above miRNAs and the target genes. In addition, PAK4, heat shock protein 105 kDa and miRNA-1911 were demonstrated to be a key factor involved in immune response via Weighted Correlation Network Analysis in HCC.

Cardiovascular Modulating Effects of Magnolol and Honokiol, Two Polyphenolic Compounds from Traditional Chinese Medicine-Magnolia Officinalis.

Honokiol and its isomer magnolol are poly-phenolic compounds isolated from the Magnolia officinalis that exert cardiovascular modulating effects via a variety of mechanisms. They are used as blood-quickening and stasis-dispelling agents in Traditional Chinese Medicine and confirmed to have therapeutic potential in atherosclerosis, thrombosis, hypertension, and cardiac hypertrophy. This comprehensive review summarizes the current data regarding the cardioprotective mechanisms of those compounds and identifies areas for further research.

Chinese Herbal Formula (CHF03) Attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) Through Inhibiting Lipogenesis and Anti-Oxidation Mechanisms.

Nonalcoholic fatty liver disease (NAFLD) is a hepatic ailment with a rapidly increasing incidence in the human population due largely to dietary hyper nutrition and subsequent obesity. Discovering effective natural compounds and herbs against NAFLD can provide alternative and complementary medical treatments to current chemical pharmaceuticals. In this study, ICR male mice were fed a high-fat diet (HFD) in vivo and the AML12 cells were treated with palmitic acid (PA) in vitro. We explore the protective effect and potential mechanism of Chinese Herbal Formula (CHF03) against NAFLD by HE staining, transmission Electron Microscopy assay, Western blotting, and gene expression. In vivo, oxidative stress markers (GSH, GSH-px, MDA, SOD, and CAT) confirmed that CHF03 alleviated oxidative stress and abundance of NF-κB proteins indicating a reduction in inflammation and oxidative stress. The lower protein abundance of ACACA and FASN indicated a preventive effect on lipogenesis. Histological and ultrastructural observations revealed that CHF03 inhibited NAFLD. Expression of Srebf1, Fasn, and Acaca, which are associated with lipogenesis, were downregulated. In vitro, genes and proteins are expressed in a dose-dependent manner, consistent with those in the liver. CHF03 inhibited lipid accumulation and expression of NF-κB, nuclear transfer, and transcriptional activity in AML12 cells. The CHF03 might have a beneficial role in the prevention of hepatic steatosis by altering the expression of lipogenic genes and attenuating oxidative stress.

Screening and identification of a human domain antibody against Brucella abortus VirB5.

Brucellosis is caused by the genus Brucella. Brucella is widely distributed in cattle, swine, sheep, goat and other mammals including human. Animal brucellosis causes severe economic losses and affects related international transportation and trade. Human brucellosis causes both acute and chronic symptoms of multi-organ dysfunction. Brucella type IV secretion system (T4SS) VirB5 was required for macrophages infection and essential for virulence in mice. VirB5 is located on the cell surface and serves as a specific adhesin targeting host cell receptors. The aim of this study was to isolate and characterize a specific human domain antibody against Brucella abortus (B. abortus) VirB5 from human single domain antibody (sdAb or VHH) phage display library. Following five rounds of screening, an sdAb named as BaV5VH4 showed the highest affinity by enzyme-linked immunosorbent assay (ELISA). Its interaction with B. abortus VirB5 was verified by binding assay, dot blot and molecular docking. These findings in this paper could greatly help elucidate the molecular mechanisms of Brucella infection, and accelerate the development of sdAbs-based vaccines and neutralizing therapeutics of brucellosis.

Intestinal Barrier Function-Non-alcoholic Fatty Liver Disease Interactions and Possible Role of Gut Microbiota.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic stress liver injury that is closely related to obesity, insulin resistance, type 2 diabetes, atherosclerosis, and metabolic syndrome. The pathological features are diffuse hepatic vesicular steatosis, including non-alcoholic steatohepatitis, liver fibrosis, and even liver cancer. A variety of pathological outcomes cause serious harm to human health. At present, an increasing number of researchers are investigating the pathogenesis of NAFLD from the perspective of changes in the function of the intestinal barrier. The physical, chemical, immunological, and microbiological barriers in the intestinal tract constitute the complete intestinal barrier, which plays an important defensive role against the invasion of harmful substances from the intestines. Protecting the function of the intestinal barrier is a new way to treat NAFLD and its related diseases. In this perspective, we summarized the current knowledge of the role of the intestinal barrier in NAFLD.

A canine adenovirus type 2 vaccine vector confers protection against foot-and-mouth disease in guinea pigs.

Vaccination is a key element in the control of foot-and-mouth disease (FMD). The majority of the antigenic sites that induce protective immune responses are localized on the FMD virus (FMDV) capsid that is formed by four virus-encoded structural proteins, VP1 to VP4. In the present study, recombinant canine adenovirus type 2 (CAV2)-based FMD vaccines, Cav-P1/3C R° and Cav-VP1 R°, respectively expressing the structural P1 precursor protein along with the non-structural 3C protein or expressing the structural VP1 protein of the FMDV strain O/FRA/1/2001, were evaluated as novel vaccines against FMD. A strong humoral immune response was elicited in guinea pigs (GP) following immunization with Cav-P1/3C R°, while administration of Cav-VP1 R° did not induce a satisfying antibody response in GP or mice. GP were then used as an experimental model for the determination of the protection afforded by the Cav-P1/3C R° vaccine against challenge with the FMDV strain O1 Manisa/Turkey/1969. The Cav-P1/3C R° vaccine protected GP from generalized FMD to a similar extent as a high potency double-oil emulsion O1 Manisa vaccine. The results of the present study show that CAV2-based vector vaccines can express immunogenic FMDV antigens and offer protection against generalized FMD in GP. This suggest that Cav-P1/3C R° FMDV vaccine may protect natural host species from FMD. In combination with an appropriate diagnostic test, the Cav-P1/3C R° FMDV vaccine may also serve as a marker vaccine to differentiate vaccinated from infected animals.

Early application of citicoline in the treatment of acute stroke: A meta-analysis of randomized controlled trials.

This study was to evaluate the efficacy and safety of early application of citicoline in the treatment of patients with acute stroke by meta-analysis. Randomized controlled trials published until May 2015 were electronically searched in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, WHO International Clinical Trial Registration Platform, Clinical Trial.gov, and China Biology Medicine disc. Two reviewers independently screened the articles and extracted the data based on the inclusion and exclusion criteria. The quality of included articles was evaluated by using Revman5.0, and meta-analysis was performed. The results showed that 1027 articles were obtained in initial retrieval, and finally 7 articles, involving a total of 4039 cases, were included for analysis. The meta-analysis showed that no significant differences were found in the long-term mortality (OR=0.91, 95% CI 0.07 to 1.09, P=0.30), the rate of dependency (OR=1.02, 95% CI 0.87 to 1.24, P=0.85), and the effective rate (OR=0.98, 95% CI 0.84 to 1.14, P=0.82) between citicoline group and control group. The overall rate of adverse events in citicoline group was not significantly different from that in control group (P=0.30). The quality of included articles reached moderate-low level. In conclusion, citicolne cannot reduce long-term mortality and dependence rate in the treatment of acute stroke, and the effective rate of citivoline may be not better than that of controls but with reliable safety.