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Osseointegration seems to be a foreign body reaction equilibrium due to the complicated interactions between the immune and skeletal systems. The heterogeneity of the osteoimmune microenvironment in the osseointegration of implant materials remains elusive. Here, a single-cell study involving 40043 cells is conducted, and a total of 10 distinct cell clusters are identified from five different groups. A preliminary description of the osteoimmune microenvironment revealed the diverse cellular heterogeneity and dynamic changes modulated by implant properties. The increased immature neutrophils, Ly6C  +  CCR2 hi monocytes, and S100a8 hi macrophages induce an aggressive inflammatory response and eventually lead to the formation of fibrous capsule around the stainless steel implant. The enrichment of mature neutrophils, FcgR1 hi and differentiated immunomodulatory macrophages around the titanium implant indicates favorable osseointegration under moderate immune response. Neutrophil-depletion mice are conducted to explore the role of neutrophils in osseointegration. Neutrophils may improve bone formation by enhancing the recruitment of BMSCs via the CXCL12/CXCR3 signal axis. These findings contribute to a better knowledge of osteoimmunology and are valuable for the design and modification of 'osteoimmune-smart' biomaterials in the bone regeneration field., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Objectives: The use of cardiopulmonary bypass in coronary artery bypass grafting (CABG) may contribute to the postoperative inflammatory response. The molecular chaperone heat-shock protein (HSP) 70 may be induced by ischemia, and has been detected both in the myocardium and in the circulation after CABG. In vitro, extracellular HSP70 may activate both innate and adaptive immunity. Hypothesizing that use of cardiopulmonary bypass (CPB) leads to more circulating HSP70, we explored the release of it in 10 patients undergoing CABG with the use of CPB, and in 10 patients undergoing off-pump surgery CABG (OPCAB). Methods: Blood samples were taken preoperatively, twice peroperatively, 2 and 6 h postoperatively and the next day. Serum analyses were performed by means of immunoassays. Results: We detected a significant difference in postoperative circulating HSP70 between on-pump and off-pump patients (median peaks of 2849 and 756 pg/ml, respectively, P<0.01, 2 h postoperatively). Interleukin-6 and -8 increased in all patients, without significant differences between the groups. Serum interleukin-10 increased at the end of the operation in 7 of 10 patients operated with cardiopulmonary bypass (median 51.7 pg/ml), but in none of the off-pump patients. Furthermore, in the first group, interleukin-10 correlated with the HSP70 concentration at the end of the operation, r=0.75, P<0.05. Serum markers of myocardial damage were higher in conventional than off-pump patients on day 1 postoperatively: median cardiac Troponin T was 0.358 and 0.126 μg/l, respectively, P<0.01. Correspondingly, median creatine kinase-MB was 23.6 and 7.8 μg/l in on-pump and off-pump patients, respectively, P<0.01. Peak HSP70 correlated with both Troponin T and creatine kinase-MB measured on day 1. Conclusions: Significantly more HSP70 was released into the circulation following conventional than following off-pump CABG. Circulating HSP70 may indicate cellular stress or damage. Furthermore, HSPs are suggested as immunoregulatory agents, and may be important in the host defence postoperatively. [Copyright &y& Elsevier]

There is increasing evidence that a variety of natural substances derived from the diet may act as potent chemopreventive agents. In this work, we show that DAOY cells, a widely used model of metastatic medulloblastoma (MBL), are highly sensitive to sulforaphane, a naturally occurring isothiocyanate from Brassica vegetables. Sulforaphane induced DAOY cell death by apoptosis, as determined by DNA fragmentation and chromatin condensation. DAOY apoptosis correlates with the induction of caspase-3 and -9 activities, resulting in the cleavage of PARP and vimentin. Both the cytotoxic effect and apoptotic characteristics induced by sulforaphane were reversed by zVAD-fmk, a broad spectrum caspase inhibitor, demonstrating the important role of caspases in its cytotoxic effect. These results identify sulforaphane as a novel inducer of MBL cell apoptosis, supporting the potential clinical usefulness of diet-derived substances as chemopreventive agents. [Copyright &y& Elsevier]

Cerebral ischemia-reperfusion injury induces multi-dimensional damage to neuronal cells through exacerbation of critical protective mechanisms. Targeting more than one mechanism simultaneously namely, inflammatory responses and metabolic energy homeostasis could provide additional benefits to restrict or manage cerebral injury. Being proven neuroprotective agents both, progesterone (PG) and trimetazidine (TMZ) has the potential to add on the individual therapeutic outcomes. We hypothesized the simultaneous administration of PG and TMZ could complement each other to synergize, or at least enhance neuroprotection in reperfusion injury. We investigated the combination of PG and TMZ on middle cerebral artery occlusion (MCAO) induced cerebral reperfusion injury in rats. Molecular docking on targets of energy homeostasis and apoptosis assessed the initial viability of PG and TMZ for neuroprotection. Animal experimentation with MCA induced ischemia-reperfusion (I/R) injury in rats was performed on five randomized groups. Sham operated control group received vehicle (saline) while the other four I-R groups were pre-treated with vehicle (saline), PG (8 ​mg/kg), TMZ treated (25 ​mg/kg), and PG ​+ ​TMZ (8 and 25 ​mg/kg) for 7 days by intraperitoneal route. Neurological deficit, infarct volume, and oxidative stress were evaluated to assess the extent of injury in rats. Inflammatory reactivity and apoptotic activity were determined with alterations in myeloperoxidase (MPO) activity, blood-brain barrier (BBB) permeability, and DNA fragments. Reperfusion injury inflicted cerebral infarct, neurological deficit, and shattered BBB integrity. The combination treatment of PG and TMZ restricted cellular damage indicated by significant ( p  ​< ​0.05) decrease in infarct volume and improvement in free radical scavenging ability (SOD activity and GSH level). MPO activity and LPO decreased which contributed in improved BBB integrity in treated rats. We speculate that inhibition of inflammatory and optimum energy utilization would critically contribute to observed neuroprotection with combined PG and TMZ treatment. Further exploration of this neuroprotective approach for post-recovery cognitive improvement is worth investigating., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier B.V.)

Background: Many of the motor symptoms of Parkinson's disease (PD) impact quality of life and are not fully ameliorated by current pharmacological and surgical treatments. A better understanding of the pathophysiology underlying these symptoms is needed. Previous research has suggested that inflammation may play a significant role in PD pathophysiology and progression, but there is limited research exploring how inflammation directly relates to motor symptoms in PD. Thus, the purpose of this study was to evaluate associations between peripheral immune inflammatory markers and motor symptoms of PD, specifically, tremor, bradykinesia, and postural and gait instability. We hypothesized that peripheral inflammatory cytokines would predict the severity of motor symptoms in persons with PD, and that there will be higher levels of peripheral inflammatory cytokine markers in persons with PD when compared to age-matched healthy older adults., Methods: Twenty-six participants with PD and fourteen healthy older adults completed the study. For participants with PD, the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) was recorded and scored by two Movement Disorders Neurologists masked to the study. A blood sample was collected from both participants with PD and the healthy older adults. Through the MILLIPLEX® map High Sensitivity Human Cytokine Kit, key inflammation-related markers were analyzed (TNF- α , IFN-γ, IL-1β, IL-8, IL-2, IL-7, IL-5, IL-13, IL, 4, IL-10 IL-12p70, GM-CSF, and IL-6)., Results: Results revealed significantly higher levels of IL-6 in persons with PD when compared to healthy older adults ( p  ​= ​0.005). Moreover, results revealed that higher levels of IL-4 ( p  ​= ​0.011) and lower levels of IFNγ ( p  ​= ​0.003) significantly predicted more severe tremor in persons with PD. No other associations between the peripheral inflammation markers and other motor symptoms were observed., Conclusions: Overall, these results are consistent with a growing body of literature that implicates inflammatory cytokines in the PD, and further suggests that inflammatory cytokines, or lack thereof, may be associated with tremor in persons with PD., (© 2022 The Authors.)

The immune checkpoint blockade (ICB) targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers. However, the low response rate and frequently observed severe side effects limit its broad benefits. It is partially due to less understanding of the biological regulation of PD-L1. Here, we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation. In PD-L1 and PD-L2 highly expressed cancer cells, a new TAD (topologically associating domain) (chr9: 5,400,000-5,600,000) around CD274 and CD273 was discovered, which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2. The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1. After transcription, the PD-L1 is tightly regulated by miRNAs and RNA-binding proteins via the long 3'UTR. At translational level, PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination. In addition, PD-L1 can be secreted via exosome to systematically inhibit immune response. Therefore, fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS-STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure, myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns (mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS-STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism. Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS-STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases., Competing Interests: The authors have no conflicts of interest to declare., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Colostrum, the sole diet for newborns, is an emerging nutraceutical. To date, the chemopreventive effect of Bovine Colostrum against liver injury induced by the potent carcinogen, 7,12-dimethyl-Benz[a]anthracene (DMBA) is unexplored. Humans are daily exposed to DMBA which is a highly lipophilic environmental organic pollutant. The study aimed to investigate the hepatoprotective role of Bovine Colostrum against DMBA-induced hepatotoxicity using a rat model. Fifty male rats were divided into five groups; GI (control), GII (olive oil, vehicle for DMBA), GIII (DMBA), GIV (DMBA + Bovine Colostrum), GV (Bovine Colostrum). After 12 weeks, body weight changes and mortality were calculated. Histological and ultrastructural examinations of liver tissue were performed. Expressions of p53, TGFβ2, TNF-α, S6K2, and c20orf20 were assessed by RT-PCR. Post-treatment with Bovine Colostrum increased both the body weight and the survival rate of rats treated with DMBA. In addition, remarkable protection against the pathological effect of DMBA was noted. Ultrastructurally, Bovine Colostrum ameliorated/prevented most of the toxic effects of DMBA on hepatocytes, including irregularities of nuclear envelope, clumping, and margination of heterochromatin aggregates, segregated nucleoli, and mitochondrial pleomorphism. Bovine Colostrum administration down-regulated p53, C20orf20, and S6K2 mRNA levels, and up-regulated TNF-α and TGFβ2. In conclusion, Bovine Colostrum have a protective effect against DMBA-induced toxicity on the liver of albino rats. Consequently, Bovine Colostrum may prevent polycyclic aromatic hydrocarbons-induced hepatotoxicity and may be useful in promoting human health if supplemented in the diet., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Background: Exposure to particulate matter (PM) emitted from vehicle exhaust might disrupt systemic function and elevate the risk of cardiovascular disease. In this study, we examined the changes of cardiometabolic biomarkers among vehicle inspectors exposed daily to PM0.25 and components., Methods: This cross-sectional study was conducted at two vehicle inspection centers, Pulogadung and Ujung Menteng, located in East Jakarta, Indonesia. The exposed respondents were 43 workers from vehicle inspection centers, and the unexposed group consisted of 22 staff officers working in the same locations. Vehicle exhaust particulate matter was measured for eight hours using a Leland Legacy personal pump attached to a Sioutas Cascade Impactor. The used filters were 25 and 37-mm quartz filters. The particulate matter concentration was analyzed using a gravimetric method, whereas trace elements were analyzed using energy dispersive X-ray fluorescence. An EEL Smoke Stain Reflectometer analyzed black carbon., Results: The personal exposure concentrations of PM0.25 were 10.4-fold higher than those in unexposed groups. Calcium and sulfur were the major components in the obtained dust, and their levels were 3.3- and 7.2-fold higher, respectively, in the exposed group. Based on an independent-samples t -test, high-density lipoprotein, triglyceride, HbA1c, total immunoglobulin E, high-sensitivity C-reactive protein, tumor necrosis factor-alpha, and nitric oxide levels were significantly different between the groups., Conclusions: In summary, it was suggested that PM0.25 exposure from vehicle exhaust might affect cardiometabolic biomarkers change., (© 2020 The Authors.)

Background & Aims: End-ischemic hypothermic oxygenated machine perfusion (HOPE) of the donor liver for 1-2 h mitigates ischemia-reperfusion injury during subsequent liver transplantation. Extended preservation time may be preferred to facilitate difficult recipient hepatectomy or to optimize logistics. We therefore investigated whether end-ischemic dual HOPE (DHOPE) could extend preservation time for up to 24 h using a porcine liver reperfusion model., Methods: Following 30 min warm ischemia, porcine livers were subjected to 2 h static cold storage (SCS), followed by 2 h, 6 h, or 24 h DHOPE (n = 6 per group). Subsequent normothermic reperfusion was performed for 4 h using autologous blood. Two livers preserved by 24 h SCS served as additional controls. A proof of principle confirmation was carried out in 2 discarded human livers subjected to extended DHOPE. Hepatocellular and cholangiocyte injury and function were assessed. Oxidative stress levels and histology were compared between groups., Results: Perfusion flows remained stable during DHOPE, regardless of duration. After normothermic reperfusion, livers perfused for 24 h by DHOPE had similar lactate clearance, blood pH, glucose, and alanine aminotransferase levels, and biliary pH, bicarbonate, and LDH levels, as livers perfused for 2 h and 6 h. Levels of malondialdehyde and high-mobility group box 1 in serum and liver parenchyma were similar for all groups. Histological analysis of bile ducts and liver parenchyma revealed no differences between the groups. Extended DHOPE in discarded human livers preserved hepatocellular and cholangiocyte function and histology after reperfusion. In contrast, livers preserved by 24 h SCS were non-functioning., Conclusion: Extended end-ischemic DHOPE enabled successful preservation of porcine and discarded human donor livers for up to 24 h. Extended DHOPE enables safe extension of preservation time, which may facilitate allocation and transplantation from a logistical perspective, and further expand the donor pool., Lay Summary: It has been suggested that preserving liver grafts with a technique called (dual) hypothermic oxygenated machine perfusion ([D]HOPE) leads to better outcomes after transplantation than if livers are stored on ice, especially if an organ is of lesser quality. In this study, we showed that DHOPE could be used to preserve liver grafts for up to 24 h. This extended procedure could be used globally to facilitate transplantation and expand the donor pool., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Author(s).)

Takotsubo cardiomyopathy is an acute stress-induced heart failure syndrome for which the exact pathogenic mechanisms are unclear, and consequently, no specific treatment exists. In an experimental model of stress-induced takotsubo-like cardiomyopathy, the authors describe the temporal course of a chronic inflammatory response post-induction, with an initial early influx of neutrophils into myocardial tissue followed by macrophages that are typical of a proinflammatory M1 phenotype, and a nonsignificant increase in systemic inflammatory cytokines. Post-mortem myocardium from the more complex clinical takotsubo patients share features of the study's experimental model. These findings suggest modulators of inflammation could be a potential therapeutic option.