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Background Sepsis-associated encephalopathy (SAE) is characterised by cognitive impairment and is a common complication in patients with sepsis. Microglia are involved in various cognitive impairment-related diseases through phagocytic synapses. Cholecystokinin (CCK), an abundant neuropeptide in the brain, is closely related to cognitive function. However, the role of CCK in SAE and the relationship between CCK and microglial phagocytosis of synapses are unknown. Methods Lipopolysaccharide (LPS) was used to construct SAE models in 3-month-old male mice and BV2 microglial cells. To investigate the effects of CCK on cognitive impairment in SAE model mice, we used exogenous CCK injection into the dorsal hippocampal CA1 region or the chemogenetic activation of CCK-positive neurons to promote endogenous CCK release. Morris water maze and fear conditioning test were used to assess cognitive function in mice. RNA sequencing was performed to explore the potential signalling pathways involved in CCK-induced neuroprotection. Western blot and immunofluorescence were used to assess the effects of CCK on microglial phagocytosis of synapses, neurotoxic astrocytes, and excitatory synapses. Whole-cell recording was used to determine excitatory synaptic transmission. Results LPS successfully established in vivo and in vitro models of SAE. Both exogenous CCK injection and activation of CCK-positive neurons in hippocampal CA1 region attenuated cognitive impairment in SAE mice. Mechanistically, CCK significantly alleviated excitatory synaptic plasticity damage via inhibiting complement 1q (C1q)-mediated microglial phagocytosis of synapses and neurotoxic astrocyte polarisation. Moreover, in vitro SAE model of BV2 cells demonstrated that CCK exerts neuroprotective effects through microglial CCK2-type receptor. Conclusions CCK may alleviate cognitive impairment by inhibiting microglia C1q-mediated phagocytosis of excitatory synapses, suggesting that both CCK drugs and specific activation of CCK-positive neurons are potential treatments for SAE.

Background Diabetic foot ulcers (DFU), perpetually trapped in a vicious cycle of inflammation and ischemia, remain a significant clinical challenge. Exosomes (Exo) therapy holds promise for tissue repair, yet its functional potency and delivery efficiency are often limited. Methods We proposed an integrated strategy combining trace elements (TE) programming, Exo engineering, and intelligent delivery to overcome both functional and delivery constraints. Multiple TE (Fe, Mg, Zn, Mn, and Se) were incorporated into a three-dimensional (3D) dynamic culture system to construct high-activity engineered Exo (3D-TE-Exo). The biological mechanisms were explored via transcriptomics, mitochondrial function assays, and oxidative stress analyses. A dual-network hydrogel, incorporating dynamic Schiff base bonds and ultraviolet (UV)-triggered disulfide bond reorganization, was developed for precise and sustained Exo release in vivo. Results 3D-TE-Exo achieved a yield of 1.9 × 10 12 particles/ml, representing a 29-fold increase over conventional culture (6.5 × 10 10 particles/ml). These Exo modulated the complement pathway, restored mitochondrial membrane potential, enhanced adenosine triphosphate (ATP) production, and activated autophagy, thereby alleviating oxidative stress, with complement 1q binding protein (C1QBP) identified as a key mediator. The hydrogel enabled prolonged Exo retention and controlled release at the wound site. In DFU rat models, this system achieved 89.71% wound closure by day 14, significantly higher than the 50.64% observed in controls. Conclusions This study presents a synergistic approach integrating engineered Exo and smart biomaterials to accelerate DFU healing. The platform offers a multi-target intervention strategy with strong translational potential for the clinical management of chronic wounds.

Lupus nephritis (LN) is a kidney disorder that is a critical cause of mortality in patients with systemic lupus erythematosus. The present study aimed to explore the protective role of complement component 1q (C1q) on LN and the underlying mechanism involving the nuclear factor (NF)-κB singling pathway. MRL/lpr mice served as the LN mouse model, and pcDNA-C1q was injected into LN mice to determine the role of C1q. C1q mRNA expression was detected using reverse transcription-quantitative PCR. Urine protein and blood urea nitrogen (BUN) levels were measured, and the histological damage index was determined using H&E staining. ELISA was used to measure the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, anti-C1q and anti-double stranded DNA (dsDNA). CD68- and Ki67-positivity were detected using immunofluorescence, and NF-κB-related protein expression was examined using western blotting. C1q mRNA expression was downregulated in renal tissues of LN mice. Overexpression of C1q decreased urine protein, BUN levels and the histological damage index in LN mice. The levels of TNF-α, IL-1β, IL-6, anti-C1q and anti-dsDNA in renal tissues of LN mice were also reduced after pcDNA-C1q treatment. Additionally, overexpression of C1q decreased the CD68- and Ki67-positivity in glomeruli and attenuated the expression of NF-κB-related proteins. Phorbol 12-myristate 13-acetate, an NF-κB pathway activator, reversed the inhibitory effect of C1q on inflammation, macrophage infiltration and mesangial cell (MC) proliferation in renal tissues of LN mice. Thus, it was demonstrated that C1q ameliorated inflammation and macrophage infiltration and decreased MC proliferation in renal tissues of LN mice by inhibiting the NF-κB pathway.

The complement system is involved in promoting secondary injury after traumatic brain injury (TBI), but the roles of the classical and lectin pathways leading to complement activation need to be clarified. To this end, we aimed to determine the ability of the brain to activate the synthesis of classical and lectin pathway initiators in response to TBI and to examine their expression in primary microglial cell cultures. We have modeled TBI in mice by controlled cortical impact (CCI), a clinically relevant experimental model. Using Real-time quantitative polymerase chain reaction (RT-qPCR) we analyzed the expression of initiators of classical the complement component 1q, 1r and 1s (C1q, C1r, and C1s) and lectin (mannose binding lectin A, mannose binding lectin C, collectin 11, ficolin A, and ficolin B) complement pathways and other cellular markers in four brain areas (cortex, striatum, thalamus and hippocampus) of mice exposed to CCI from 24 h and up to 5 weeks. In all murine ipsilateral brain structures assessed, we detected long-lasting, time- and area-dependent significant increases in the mRNA levels of all classical (C1q, C1s, C1r) and some lectin (collectin 11, ficolin A, ficolin B) initiator molecules after TBI. In parallel, we observed significantly enhanced expression of cellular markers for neutrophils (Cd177), T cells (Cd8), astrocytes (glial fibrillary acidic protein—GFAP), microglia/macrophages (allograft inflammatory factor 1—IBA-1), and microglia (transmembrane protein 119—TMEM119); moreover, we detected astrocytes (GFAP) and microglia/macrophages (IBA-1) protein level strong upregulation in all analyzed brain areas. Further, the results obtained in primary microglial cell cultures suggested that these cells may be largely responsible for the biosynthesis of classical pathway initiators. However, microglia are unlikely to be responsible for the production of the lectin pathway initiators. Immunofluorescence analysis confirmed that at the site of brain injury, the C1q is localized in microglia/macrophages and neurons but not in astroglial cells. In sum, the brain strongly reacts to TBI by activating the local synthesis of classical and lectin complement pathway activators. Thus, the brain responds to TBI with a strong, widespread and persistent upregulation of complement components, the targeting of which may provide protection in TBI.

C1Q (Complement 1Q) is an important recognition molecule in the immunological complement system, which could also be putatively involved in the stress responses induced by endotoxins or exotoxins, potentially through detoxification processes. Marine bivalves are well adapted to highly complex aquatic environments with various stressors. As filter feeders, they have to cope with highly potent microalgae-derived neurotoxins, such as paralytic shellfish toxin (PSTs). Zhikong scallops, Chlamys farreri , are commercially important bivalve with the remarkable ability to accumulate PSTs. Exploring the C1Q s related to PST accumulation in C. farreri could benefit our understanding of the adaptations of bivalve species. In the present study, we systematically analyzed C1Q genes in C. farreri . In total, 97 CfC1Q genes mainly from the expanded C1Q-B subfamily were identified, from which the C1QL , C1QTNF , and C1QDC1 members in C. farreri were revealed to be under positive selection. Spatiotemporal expression analysis revealed that most CfC1QL s and CfC1QDC1 s were highly expressed during the post-umbo stage and in hepatopancreas, while most CfC1QTNF members were highly expressed after the creeping larva stage and in mantle. The hepatopancreas and kidney in C. farreri are two toxin-rich organs with the highest concentrations of PSTs, acting as major “centers” for toxin accumulation and transformation, respectively. Therefore, after feeding the scallops with PST-producing dinoflagellates Alexandrium minutum and Alexandrium catenella , we determined the expression patterns of CfC1Q s in these two organs. In kidney, more than 85% of CfC1QL s and CfC1QDC1 s showed drastic up-regulation with both diets. However, among these members with significant induction, a different response manner was detected after feeding with A. minutum and A. catenella , respectively as acute and chronic response patterns. In comparison, far fewer CfC1Q s showing significant up-regulation in hepatopancreas with both toxic diets and only mild regulation pattern could be found. This organ-, toxin-, and time-dependent genetic regulation of CfC1Q s may contribute to the virulence difference on account of the tissue-specific or dinoflagellate-specific different toxin analogs composition, implying the possible involvement of CfC1Q s in PST transport and homeostasis. Our findings imply the functional diversity of scallop C1Q genes in coping with PST accumulation, which might be developed as potential molecular indicators for monitoring toxin accumulation in edible mollusks or provide insight into the lineage-specific adaptation of scallops for dealing with microalgal toxin challenges.

IntroductionWalking is a popular exercise but does not increase lower limb muscle strength and balance. We hypothesized that muscle strength, physical and cognitive function would be improved by inserting lunges in conventional walking.MethodsEleven regular walkers (54–88 years) who had more than 5000 steps in exercise walking a day at least 5 days a week participated in this study. They walked as usual for the first 4 weeks and included lunges and descending stairs or slope walking (i.e., eccentric walking) for the next 8 weeks. The steps of eccentric walking were gradually increased from 100 to 1000 steps per week over 8 weeks.ResultsThe average steps per day were 10,535 ± 3516 in the first 4 weeks, and 10,118 ± 3199 in the eccentric walking period without a significant difference. No significant changes in maximal voluntary isometric contraction torque of the knee extensors (MVC), 30-s chair stand (CS), 2-min step, balance assessed by center of pressure movement area with eyes close, sit and reach, a digit symbol substitution test (DSST) for cognitive function were observed in the first 4 weeks. However, significant (P < 0.05) improvements were evident in MVC (18.6 ± 15.7%), CS (24.2 ± 17.3%), balance ( – 45.3 ± 34.5%), and DSST (20.8 ± 16.7%) from weeks 4 to 12. Serum complement component 1q concentration decreased (P < 0.05) from weeks 4 to 12, although no changes in serum glucose, triglyceride, and cholesterol concentrations were observed.ConclusionThese results supported the hypothesis, and suggest that eccentric walking provides effects that are not achieved by conventional walking.

Aims/Introduction As a member of the tumor necrosis factor‐α‐related protein family, complement‐1q tumor necrosis factor‐α‐related protein isoform 5 (CTRP5) has been found to be associated with obesity and insulin resistance (IR). Previous studies in humans and animals have reported contradictory results related to the association between CTRP5 and IR. The purpose of the present study was to explore the relationship between CTRP5 and IR through a cross‐sectional study and drug intervention study of type 2 diabetes patients. Materials and Methods A cross‐sectional study was carried out with 118 newly diagnosed patients with type 2 diabetes and 116 healthy adults. In an interventional study, 78 individuals with newly diagnosed type 2 diabetes received sodium–glucose cotransporter 2 inhibitor (dapagliflozin) treatment for 3 months. Circulating CTRP5 concentrations were measured by enzyme‐linked immunosorbent assay. Results Serum CTRP5 concentrations were markedly reduced in patients with type 2 diabetes when compared with those of healthy individuals (P < 0.01). When considering the study population as a whole, individuals with IR (homeostasis model of assessment of IR ≥2.78) had lower CTRP5 concentrations than the individuals without IR (homeostasis model of assessment of IR <2.78; P < 0.01). Serum CTRP5 negatively correlated with age, body mass index, waist‐to‐hip ratio, Systolic blood pressure, triglyceride, total cholesterol, glycated hemoglobin, fasting blood glucose, 2‐h blood glucose, fasting insulin and homeostasis model of assessment of IR. After 12 weeks of sodium–glucose cotransporter 2 inhibitor treatment, serum CTRP5 levels in type 2 diabetes patients were significantly reduced accompanied with ameliorated glycometabolism and IR compared with before treatment (P < 0.01). Conclusions CTRP5 is likely a marker for type 2 diabetes in humans. The present study found that complement‐1q tumor necrosis factor‐α‐related protein isoform 5 (CTRP5) levels were reduced in type 2 diabetes patients and that plasma CTRP5 levels were related to insulin resistance. Furthermore, we found that plasma CTRP5 concentrations further decreased after dapaglifozin treatment, which showed that CTRP5 might play an important role in the development of type 2 diabetes.

Systemic lupus erythematosus (SLE) is characterized by excessive production of various autoantibodies, which play important roles in the pathogenesis of SLE. Apart from classical autoantibodies such as anti-double stranded DNA antibody (anti-dsDNA), anti-Smith antibody (anti-Sm), and anti-phospholipid antibody (APL), recent studies focus on some novel autoantibodies including anti-complement (C) 1q antibody (anti-C1q), which is closely correlated with lupus nephritis; anti-N-methyl- d -asparate receptor antibody (NMDAR), which mediates neuropsychiatric manifestations in SLE to some extent; anti-galectin, which is involved in secondary anti-phospholipid syndrome (APS) in SLE; and anti-Müllerian hormone (AMH), which represents a more specific biomarker for subclinical ovarian damage caused by the disease itself or cytotoxic drugs in SLE patients. Correlation of these autoantibodies with disease activity and organ involvement of SLE may help to evaluate disease severity, efficacy of treatment, and long-term prognosis. Furthermore, combined measurement of a variety of autoantibodies is supposed to be more valuable in estimating disease activity and severity.

A type of aplastic anemia (AA), non-severe aplastic anemia (NSAA) is defined as AA that does not meet the diagnostic criteria of severe aplastic anemia (SAA). Complement component 1q (C1q) has an important role in the pathogenesis of various autoimmune diseases; however, the role of C1q in the immune pathogenesis of NSAA is not clear. The current study aimed to determine whether C1q has an important role in the pathogenesis of NSAA. Isobaric tags for relative and absolute quantitation (iTRAQ) was used to compare the protein expression in bone marrow mononuclear cells from patients with NSAA and healthy volunteers. Pathway enrichment analysis was performed to determine the biological functions involved in NSAA. The differential expression of C1q was marked compared with other proteins. Subsequently, the concentration of C1q in serum samples was determined using ELISA and the correlation of C1q levels and NSAA severity was evaluated. The serum concentrations of C1q were significantly lower in untreated patients with newly diagnosed NSAA compared with NSAA cases in remission and normal controls. Furthermore, there was no significant difference in C1q concentration between newly diagnosed patients with NSAA and patients with autoimmune hemolytic anemia or immune thrombocytopenia. The serum concentration of C1q in newly diagnosed NSAA was significantly lower in patients with SAA (P<0.0001); whereas, there was no significant difference between the patients with SAA, patients with NSAA remission and normal controls (P>0.05). Additionally, the serum C1q concentration was significantly correlated with granulocyte counts, the level of hemoglobin, platelet counts, reticulocyte percentage and remission in patients with NSAA. The serum C1q concentration was also positively correlated with the myeloid/plasmacytoid dendritic cell ratio, and negatively correlated with the CD4(+)/CD8(+) ratio. These findings suggested that C1q may be a reliable serological marker for monitoring and evaluating disease severity in patients with NSAA. C1q may have an important role in the immune pathogenesis of NSAA.

Personalized protein corona significantly influences the biodistribution and therapeutic efficacy of nanomedicines, generating unique profiles that can impact treatment outcomes. Here, we demonstrate that pegylated liposomal doxorubicin (PLD) exhibits increased tumor accumulation and enhanced antitumor immunity in obese mice bearing ovarian tumor, inducing a greater capacity to inhibit tumor growth compared to normal mice. Mechanistically, the protein corona, particularly enriched with complement component 1q (C1q) in the plasma of obese mice, significantly enhances the internalization of PLD by ovarian cancer cells and elicits strong immunogenic cell death (ICD) effects. Concurrently, C1q adsorbed on PLD promotes the engulfment of apoptotic tumor cells by dendritic cells (DCs), activating T cell-mediated antitumor immune responses and amplifying the overall antitumor efficacy of PLD in obese mice. Our findings provide new insights into the role of the personalized protein corona in modulating the therapeutic response to chemotherapy and highlight the potential of targeting C1q for enhancing the efficacy of nanomedicines in cancer treatment. Graphical Abstract