This study investigated the mechanism of Chaishao Kaiyu Decoction in improving hippocampal neuroinflammation in depressed rats based on complement component 3(C3)/C3 receptor(C3aR). A total of 60 SD rats were randomly divided into a blank group, a model group, high, medium, and low dose groups of Chaishao Kaiyu Decoction, and a positive drug group, with 10 rats in each group. Except for the blank group, chronic unpredictable mild stress(CUMS) was used to construct depression models in other groups. Sucrose preference, open-field experiment, forced swimming, and water maze were used to detect the changes in depression-like behavior in each group. Enzyme-linked immunosorbent assay(ELISA) was used to detect the serum inflammatory factor level in rats, and hematoxylin-eosin(HE) staining and Nissl staining were employed to observe the pathological damage of hippocampal neurons. Golgi-Cox staining was used to observe the dendritic spine damage of hippocampal neurons, and immunofluorescence and Western blot were utilized to detect the expression of microglial marker Iba-1 and C3/C3aR protein in the hippocampus of rats. The behavioral results showed that compared with the model group, Chaishao Kaiyu Decoction could significantly strengthen the sugar water preference, increase the distance and number of voluntary activities, shorten the immobility time in forced swimming and the successful incubation period of positioning navigation, and prolong the stay time of space exploration in the target quadrant. ELISA results showed that the content of inflammatory factors in the hippocampus of depressed rats was significantly higher than that of the blank group, and the content of inflammatory factors decreased significantly after the intervention of Chaishao Kaiyu Decoction. In addition, Chaishao Kaiyu Decoction could relieve pathological damage such as cell swelling and loose arrangement of hippocampus tissue. In the Western blot experiment, the expression levels of C3 and C3aR proteins in the model group were higher than those in the blank group, while the expression of C3 and C3aR in Chaishao Kaiyu Decoction could be down-regulated. Immunofluorescence results showed that compared with the model group, the fluorescence intensity of microglia marker Iba-1 decreased significantly after the intervention of Chaishao Kaiyu Decoction and positive drugs. The antidepressant effect of Chaishao Kaiyu Decoction may be related to the down-regulation of C3/C3aR signaling pathway-related proteins, thus alleviating hippocampal inflammation.
Animals ; Hippocampus/metabolism* ; Rats, Sprague-Dawley ; Drugs, Chinese Herbal/administration & dosage* ; Rats ; Male ; Depression/metabolism* ; Complement C3/metabolism* ; Receptors, Complement/metabolism* ; Humans ; Neuroinflammatory Diseases/genetics*

Radiomics handles imaging biomarker from high-throughput feature extraction through complex pattern recognition that is difficult for human to process. Recent medical paradigms are rapidly changing to personalized medicine, including molecular targeted therapy, immunotherapy, and theranostics, and the importance of biomarkers for these is growing day by day. Even though biopsy continues to gold standard for tumor assessment in personalized medicine, imaging is expected to complement biopsy because it allows whole tumor evaluation, whole body evaluation, and non-invasive and repetitive evaluation. Radiomics is known as a useful method to get imaging biomarkers related to intratumor heterogeneity in molecular targeted therapy as well as one-size-fits-all therapy. It is also expected to be useful in new paradigms such as immunotherapy and somatostatin receptor (SSTR) or prostate-specific membrane antigen (PSMA)-targeted theranostics. Radiomics research should move to multimodality (CT, MR, PET, etc.), multicenter, and prospective studies from current single modality, single institution, and retrospective studies. Image-quality harmonization, intertumor heterogeneity, and integrative analysis of information from different scales are thought to be important keywords in future radiomics research. It is clear that radiomics will play an important role in personalized medicine.
Biomarkers ; Biopsy ; Complement System Proteins ; Humans ; Immunotherapy ; Membranes ; Methods ; Molecular Targeted Therapy ; Population Characteristics ; Precision Medicine ; Prospective Studies ; Receptors, Somatostatin ; Retrospective Studies ; Theranostic Nanomedicine ; Weights and Measures

Therapeutic monoclonal antibodies are among the most effective biotherapeutics to date. An important aspect of antibodies is their ability to bind antigen while at the same time recruit immune effector functions. The majority of approved recombinant monoclonal antibody therapies are of the human IgG1 subclass, which can engage both humoral and cellular components of the immune system. The wealth of information generated about antibodies has afforded investigators the ability to molecularly engineer antibodies to modulate effector functions. Here, we review various antibody engineering efforts intended to improve efficacy and safety relative to the human IgG isotype. Further, we will discuss proposed mechanisms by which engineering approaches led to modified interactions with immune components and provide examples of clinical studies using next generation antibodies.
Animals ; Antibodies, Monoclonal ; metabolism ; Antigens ; metabolism ; Complement System Proteins ; metabolism ; Humans ; Immunoglobulin G ; metabolism ; Protein Engineering ; Receptors, Fc ; metabolism

In the intestinal mucosal surface, microfold cells (M cells) are the representative gateway for the uptake of luminal antigens. At the same time, M cells are the primary infection site for pathogens invading mucosal surface for their infection. Although it is well recognized that many mucosal pathogens exploit the M cells for their infection, the mechanism to infect M cells utilized by pathogens is not clearly understood yet. In this study, we found that M cells expressing complement 5a (C5a) receptor (C5aR) also express Toll-like receptor (TLR) 1/2 and TLR4. Infection of Yersinia enterocolitica, an M cell-invading pathogen, synergistically regulated cyclic adenosine monophosphate-dependent protein kinase A (cAMP-PKA) signaling which are involved in signal crosstalk between C5aR and TLRs. In addition, Y. enterocolitica infection into M cells was enhanced by C5a treatment and this enhancement was abrogated by C5a antagonist treatment. Finally, Y. enterocolitica infection into M cells was unsuccessful in C5aR knock-out mice. Collectively, we suggest that exploit the crosstalk between C5aR and TLR signaling is one of infection mechanisms utilized by mucosal pathogens to infect M cells.
Adenosine ; Animals ; Complement C5a* ; Complement System Proteins* ; Cyclic AMP-Dependent Protein Kinases ; Mice ; Mice, Knockout ; Phenobarbital ; Receptor, Anaphylatoxin C5a* ; Toll-Like Receptors* ; Yersinia enterocolitica* ; Yersinia*

We sought to identify common key regulators and build a gene-metabolite network in different nonalcoholic fatty liver disease (NAFLD) phenotypes. We used a high-fat diet (HFD), a methionine-choline-deficient diet (MCDD) and streptozocin (STZ) to establish nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH) and NAFL+type 2 diabetes mellitus (T2DM) in rat models, respectively. Transcriptomics and metabolomics analyses were performed in rat livers and serum. A functional network-based regulation model was constructed using Cytoscape with information derived from transcriptomics and metabolomics. The results revealed that 96 genes, 17 liver metabolites and 4 serum metabolites consistently changed in different NAFLD phenotypes (>2-fold, P<0.05). Gene-metabolite network analysis identified ccl2 and jun as hubs with the largest connections to other genes, which were mainly involved in tumor necrosis factor, P53, nuclear factor-kappa B, chemokine, peroxisome proliferator activated receptor and Toll-like receptor signaling pathways. The specifically regulated genes and metabolites in different NAFLD phenotypes constructed their own networks, which were mainly involved in the lipid and fatty acid metabolism in HFD models, the inflammatory and immune response in MCDD models, and the AMPK signaling pathway and response to insulin in HFD+STZ models. Our study identified networks showing the general and specific characteristics in different NAFLD phenotypes, complementing the genetic and metabolic features in NAFLD with hepatic and extra-hepatic manifestations.
AMP-Activated Protein Kinases ; Animals ; Complement System Proteins ; Diabetes Mellitus ; Diet ; Diet, High-Fat ; Insulin ; Liver ; Metabolism ; Metabolomics ; Models, Animal ; Non-alcoholic Fatty Liver Disease* ; Peroxisomes ; Phenotype ; Rats ; Streptozocin ; Toll-Like Receptors ; Tumor Necrosis Factor-alpha

BACKGROUND: There are a million ragpickers in India who gather and trade recyclable municipal solid wastes materials for a living. The objective of this study was to examine whether their occupation adversely affects their immunity. METHODS: Seventy-four women ragpickers (median age, 30 years) and 65 age-matched control housemaids were enrolled. Flow cytometry was used to measure leukocyte subsets, and leukocyte expressions of Fcγ receptor I (CD64), FcγRIII (CD16), complement receptor 1 (CD35) and CR3 (CD11b/CD18), and CD14. Serum total immunoglobulin-E was estimated with enzyme-linked immunosorbent assay. RESULTS: Compared with the controls, ragpickers had significantly (p < 0.0001) higher levels of CD8+T-cytotoxic, CD16+CD56+natural killer, and CD4+CD45RO+memory T-cells, but depleted levels of CD19+B-cells. The percentage of CD4+T-helper-cells was lower than the control group (p < 0.0001), but their absolute number was relatively unchanged (p = 0.42) due to 11% higher lymphocyte counts in ragpickers. In ragpickers, the percentages of CD14+CD16+intermediate and CD14dim CD16+nonclassical monocyte subsets were elevated with a decline in CD14+CD16-classical monocytes. The expressions of CD64, CD16, CD35, and CD11b/CD18 on both monocytes and neutrophils, and CD14 on monocytes were significantly higher in ragpickers. In addition, ragpickers had 2.7-times more serum immunoglobulin-E than the controls (p < 0.0001). After controlling potential confounders, the profession of ragpicking was positively associated with the changes. CONCLUSION: Ragpicking is associated with alterations in both innate (neutrophils, monocytes, and natural killer cell numbers and expression of complement and Fcγ receptors) and adaptive immunity (numbers of circulating B cells, helper, cytotoxic, and memory T cells).
Adaptive Immunity ; B-Lymphocytes ; Complement System Proteins* ; Enzyme-Linked Immunosorbent Assay ; Female* ; Flow Cytometry ; Humans ; India* ; Killer Cells, Natural ; Leukocytes* ; Lymphocyte Count ; Lymphocytes ; Memory ; Monocytes ; Neutrophils ; Occupations ; Receptors, Complement* ; Solid Waste ; T-Lymphocytes

We investigated the clinical and biological significance of germinal centers (GC) present in the minor salivary glands of patients with Sjogren's syndrome (SS). Minor salivary gland tissue biopsies from 93 patients with SS were used to identify GC-like structures, which were confirmed by CD21-positive follicular dendritic cell networks. Patients were compared based upon sociodemographics, glandular and extraglandular manifestations, and laboratory findings including autoantibody profiles, complement, and immunoglobulin levels; EULAR SS disease activity index (ESSDAI) and SS disease damage index (SSDDI) were also measured. GC-like structures were observed in 28 of 93 SS patients (30.1%). Mean focus scores and CRP levels were significantly higher in GC-positive patients than in GC-negative patients; GC-positive patients also exhibit a higher prevalence of rheumatoid factor and anti-SS-A/Ro antibodies compared to GC-negative patients. No differences in glandular or extra-glandular manifestations were evident between groups. In conclusion, SS patients with GC-like structures in the minor salivary glands exhibited laboratory profiles significantly different from those of their GC-negative counterparts. Long-term follow-up of these patients will be necessary to determine whether these laboratory abnormalities are predictive of clinical outcomes.
Adult ; Autoantibodies/blood ; C-Reactive Protein/analysis ; Demography ; Female ; Germinal Center/*pathology ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Receptors, Complement 3d/metabolism ; Retrospective Studies ; Salivary Glands, Minor/*pathology ; Sjogren's Syndrome/immunology/metabolism/*pathology

We investigated the clinical and biological significance of germinal centers (GC) present in the minor salivary glands of patients with Sjogren's syndrome (SS). Minor salivary gland tissue biopsies from 93 patients with SS were used to identify GC-like structures, which were confirmed by CD21-positive follicular dendritic cell networks. Patients were compared based upon sociodemographics, glandular and extraglandular manifestations, and laboratory findings including autoantibody profiles, complement, and immunoglobulin levels; EULAR SS disease activity index (ESSDAI) and SS disease damage index (SSDDI) were also measured. GC-like structures were observed in 28 of 93 SS patients (30.1%). Mean focus scores and CRP levels were significantly higher in GC-positive patients than in GC-negative patients; GC-positive patients also exhibit a higher prevalence of rheumatoid factor and anti-SS-A/Ro antibodies compared to GC-negative patients. No differences in glandular or extra-glandular manifestations were evident between groups. In conclusion, SS patients with GC-like structures in the minor salivary glands exhibited laboratory profiles significantly different from those of their GC-negative counterparts. Long-term follow-up of these patients will be necessary to determine whether these laboratory abnormalities are predictive of clinical outcomes.
Adult ; Autoantibodies/blood ; C-Reactive Protein/analysis ; Demography ; Female ; Germinal Center/*pathology ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Receptors, Complement 3d/metabolism ; Retrospective Studies ; Salivary Glands, Minor/*pathology ; Sjogren's Syndrome/immunology/metabolism/*pathology

Current influenza virus vaccines are based on strain-specific surface glycoprotein hemagglutinin (HA) antigens and effective only when the predicted vaccine strains and circulating viruses are well-matched. The current strategy of influenza vaccination does not prevent the pandemic outbreaks and protection efficacy is reduced or ineffective if mutant strains emerge. It is of high priority to develop effective vaccines and vaccination strategies conferring a broad range of cross protection. The extracellular domain of M2 (M2e) is highly conserved among human influenza A viruses and has been utilized to develop new vaccines inducing cross protection against different subtypes of influenza A virus. However, immune mechanisms of cross protection by M2e-based vaccines still remain to be fully elucidated. Here, we review immune correlates and mechanisms conferring cross protection by M2e-based vaccines. Molecular and cellular immune components that are known to be involved in M2 immune-mediated protection include antibodies, B cells, T cells, alveolar macrophages, Fc receptors, complements, and natural killer cells. Better understanding of protective mechanisms by immune responses induced by M2e vaccination will help facilitate development of broadly cross protective vaccines against influenza A virus.
Antibodies ; B-Lymphocytes ; Complement System Proteins ; Cross Protection ; Disease Outbreaks ; Hemagglutinins ; Influenza A virus ; Influenza Vaccines ; Influenza, Human* ; Killer Cells, Natural ; Macrophages, Alveolar ; Membrane Glycoproteins ; Orthomyxoviridae* ; Pandemics ; Receptors, Fc ; T-Lymphocytes ; Vaccination ; Vaccines*

OBJECTIVETo study the expression of C3aR and C5aR in trichloroethylene-sensitized mouse liver injury and discuss the pathogenesis of Dermatitis Medicamentosa-like of TCE (DMLT).

METHODS6∼8 w female BALB/c mouse were randomly divided into blank control group, solvent control group and TCE treatment group. TCE was given to the mouse for sensitization at 1th, 4th, 7th, 10th day and challenge at 17th day and 19th day. Before killing mouse, liver weight and body weight were recorded. The livers were separated at 24 h, 48 h, 72 h and 7 d after challenge. And the liver sections were used for immunofluorescence stain and RT-PCR to detect the expression levels of C3aR and C5aR.

RESULTSMicroscopic examination showed no significant change in liver structure or organization in TCE non-sensitized group, while liver cell oedema, cell necrosis and inflammatory cell infiltration were clearly observed in TCE-sensitized groups. The expression levels of C3aR and C5aR in 24 h, 48 h, 72 h and 7 d TCE-sensitized groups were significant higher than blank control group, solvent control group and related TCE non-sensitized groups (P < 0.05).

CONCLUSIONComplement activation was involved in TCE-induced liver injury and C3aR and C5aR might play essential role in the process.

Animals ; Chemical and Drug Induced Liver Injury ; Dermatitis, Occupational ; Edema ; Female ; Liver ; physiopathology ; Mice ; Mice, Inbred BALB C ; Receptor, Anaphylatoxin C5a ; metabolism ; Receptors, Complement ; metabolism ; Solvents ; toxicity ; Trichloroethylene ; toxicity