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Hypoxia is a pathological condition common to many diseases, although multiple organ injuries induced by hypoxia are often overlooked. There is increasing evidence to suggest that the hypoxic environment may activate innate immune cells and suppress adaptive immunity, further stimulating inflammation and inhibiting immunosurveillance. We found that dysfunctional immune regulation may aggravate hypoxia-induced tissue damage and contribute to secondary injury. Among the diverse mechanisms of hypoxia-induced immune dysfunction identified to date, the role of programmed death-ligand 1 (PD-L1) has recently attracted much attention. Besides leading to tumour immune evasion, PD-L1 has also been found to participate in the progression of the immune dysfunction which mediates hypoxia-induced multiple organ injury. In this review, we aimed to summarise the role of immune dysfunction in hypoxia-induced multiple organ injury, the effects of hypoxia on the cellular expression of PD-L1, and the effects of upregulated PD-L1 expression on immune regulation. Furthermore, we summarise the latest information pertaining to the involvement, diagnostic value, and therapeutic potential of immunosuppression induced by PD-L1 in various types of hypoxia-related diseases, including cancers, ischemic stroke, acute kidney injury, and obstructive sleep apnoea. Video Abstract., (© 2021. The Author(s).)

Background: Traditional atherosclerotic risk factors predict long-term cardiovascular disease events but are poor predictors of near-term events., Objective: To determine whether elevated levels of D-dimer and biomarkers of inflammation were more closely associated with near-term than long-term mortality in patients with lower-extremity peripheral arterial disease (PAD) and whether greater increases in biomarker levels were associated with higher mortality rates during the first year after the increase than during later years., Design: Prospective cohort study with a mean follow-up of 3.4 years., Setting: Academic medical center., Patients: 377 men and women with PAD., Measurements: Mortality within 1 year after biomarker measurement, 1 to 2 years after biomarker measurement, and 2 to 3 years after biomarker measurement. Cox regression analyses were used to evaluate associations of biomarkers levels and changes in biomarkers with cardiovascular and all-cause mortality. Hazard ratios were calculated for each 1-unit increase in log1.5(biomarker level). Analyses were adjusted for age, sex, race, comorbid conditions, ankle-brachial index, and other confounders., Results: Seventy-six patients (20%) died during follow-up. Higher levels of D-dimer, C-reactive protein, and serum amyloid A were associated with higher all-cause mortality among patients who died within 1 year after biomarker measurement (hazard ratio, 1.20 [95% CI, 1.08 to 1.33], 1.13 [CI, 1.05 to 1.21], and 1.12 [CI, 1.04 to 1.20], respectively; P < 0.001, P < 0.001, and P = 0.003) and among patients who died 1 to 2 years after biomarker measurement (hazard ratio, 1.14 [CI, 1.02 to 1.27], 1.15 [CI, 1.06 to 1.24], and 1.13 [CI, 1.04 to 1.24]; P = 0.022, P = 0.001, and P = 0.005]). However, higher levels of each biomarker were not associated with all-cause mortality for deaths occurring 2 to 3 years after biomarker measurement. Similar results were observed for cardiovascular mortality. Greater increases in each biomarker were associated with higher all-cause and cardiovascular mortality during the following year., Limitation: The small number of deaths limited the statistical power of the analyses., Conclusion: Among persons with PAD, circulating levels of D-dimer and inflammatory markers are higher in the 1 to 2 years before death than in periods more remote from death. Increasing levels of D-dimer and inflammatory biomarkers are independently associated with higher mortality in persons with PAD.

This study aimed to clarify the intervention effect of salidroside (SAL) on lung injury caused by PM 2.5 in mice and illuminate the function of SIRT1-PGC-1ɑ axis. Specific pathogen-free (SPF) grade male C57BL/6 mice were randomly assigned to the following groups: control group, SAL group, PM 2.5 group, SAL+PM 2.5 group. On the first day, SAL was given by gavage, and on the second day, PM 2.5 suspension was given by intratracheal instillation. The whole experiment consist of a total of 10 cycles, lasting 20 days. At the end of treatment, blood samples and lung tissues were collected and analyzed. Observation of pathological changes in lung tissue using inverted microscopy and transmission electron microscopy. The expression of inflammatory, antioxidants, apoptosis, and SIRT1-PGC-1ɑ proteins were detected by Western blotting. Exposure to PM 2.5 leads to obvious morphological and pathologica changes in the lung of mice. PM 2.5 caused a decline in levels of antioxidant-related enzymes and protein expressions of HO-1, Nrf2, SOD2, SIRT1 and PGC-1ɑ, and an increase in the protein expressions of IL-6, IL-1β, Bax, caspase-9 and cleaved caspase-3. However, SAL reversed the aforementioned changes caused by PM 2.5 by activating the SIRT1-PGC-1α pathway. SAL can activate SIRT1-PGC-1ɑ to ameliorate PM 2.5 -induced lung injury. [ABSTRACT FROM AUTHOR]

Background: While observational studies and experimental data suggest a link between oral lichen planus (OLP) and oral cavity cancer (OCC), the causal relationship and the role of inflammatory cytokines remain unclear. Methods: This study employed a univariable and multivariable Mendelian Randomization (MR) analysis to investigate the causal relationship between OLP and the risk of OCC. Additionally, the potential role of inflammatory cytokines in modulating this association was explored. Instrumental variables were derived from genetic variants associated with OLP (n = 377,277) identified in Finngen R9 datasets, with 41 inflammatory cytokines as potential mediators, and OCC (n = 4,151) as the outcome variable. Analytical methods including Inverse Variance Weighted (IVW), Weighted Median, MR-Egger, and MR-PRESSO were utilized to assess the causal links among OLP, inflammatory cytokines, and OCC risk. Multivariable MR (MVMR) was then applied to quantify the mediating effects of these cytokines in the relationship between OLP and increased OCC risk. Results: MR analysis provided strong evidence of a causal relationship between OLP (OR = 1.417, 95% CI = 1.167–1.721, p < 0.001) and the risk of OCC. Furthermore, two inflammatory cytokines significantly influenced by OLP, IL-13 (OR = 1.088, 95% CI: 1.007–1.175, P = 0.032) and IL-9 (OR = 1.085, 95% CI: 1.005–1.171, P = 0.037), were identified. Subsequent analysis revealed a significant causal association only between IL-13 (OR = 1.408, 95% CI: 1.147–1.727, P = 0.001) and higher OCC risk, establishing it as a potential mediator. Further, MVMR analysis indicated that IL-13 (OR = 1.437, 95% CI = 1.139–1.815, P = 0.002) mediated the relationship between OLP and OCC, accounting for 8.13% of the mediation. Conclusion: This study not only elucidates the potential causal relationship between OLP and the risk of OCC but also highlights the pivotal mediating role of IL-13 in this association. [ABSTRACT FROM AUTHOR]

Autophagy is a critical cytoprotective mechanism that takes a hand in innate or adaptive immune responses. Hypoxia is a common pathophysiological mechanism that can lead to systemic pathological reactions. In recent years, the impact of hypoxia on the central nervous system has attracted more attention. In the past, autophagy was thought to be directly involved in the apoptosis of nerve cells under hypoxia. An increasing amount of evidence shows that the neuroinflammatory response plays an indispensable role in the neural damage caused by hypoxia. There are many mechanisms related to the neuroinflammatory response induced by hypoxia, among which autophagy is an important aspect, but the role of autophagy is still unclear. This article focuses on how autophagy flux of central immune cells is modified under hypoxic conditions, and how this autophagy affects neuroinflammatory response. [ABSTRACT FROM AUTHOR]

Many studies have shown that endothelial dysfunction is associated with a variety of cardiovascular diseases. The endothelium is one of the primary targets of circulating microvesicles. Besides, microRNAs emerge as important regulators of endothelial cell function. As a delivery system of microRNAs, microvesicles play an active and important role in regulating vascular endothelial function. In recent years, some studies have shown that microvesicles containing microRNAs regulate the pathophysiological changes in vascular endothelium, such as cell apoptosis, proliferation, migration and inflammation. These studies have provided some clues for the possible roles of microvesicles and microRNAs in vascular endothelial dysfunction‐associated diseases, and opened the door towards discovering potential novel therapeutic targets. In this review, we provide an overview of the main characteristics of microvesicles and microRNAs, summarizing their potential role and mechanism in endothelial dysfunction, and discussing the clinical application and existing problems of microvesicles for better translational applications. [ABSTRACT FROM AUTHOR]

Cell‐derived microvesicles are membrane vesicles produced by the outward budding of the plasma membrane and released by almost all types of cells. These have been considered as another mechanism of intercellular communication, because they carry active molecules, such as proteins, lipids and nucleic acids. Furthermore, these are present in circulating fluids, such as blood and urine, and are closely correlated to the progression of pathophysiological conditions in many diseases. Recent studies have revealed that microvesicles have a dual effect of damage and protection of receptor cells. However, the nature of the active molecules involved in this effect remains unclear. The present study mainly emphasized the mechanism of microvesicles and the active molecules mediating the different biological effects of receptor cells by affecting autophagy, apoptosis and inflammation pathways. The effective ways of blocking microvesicles and its active molecules in mediating cell damage when microvesicles exert harmful effects were also discussed. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To determine whether higher levels of inflammatory blood markers, D-dimer, and homocysteine were associated with greater impairment in lower extremity functioning in persons with peripheral arterial disease (PAD). DESIGN: Cross-sectional. SETTING: Three Chicago-area medical centers. PARTICIPANTS: Four hundred twenty-three persons with PAD (ankle–brachial index (ABI) <0.90). MEASUREMENTS: Lower extremity performance was assessed using the 6-minute walk and with usual- and fast-paced 4-m walking speed. Blood markers were D-dimer, C-reactive protein (CRP), interleukin-6 (IL-6), soluble vascular cellular adhesion molecule-1 (sVCAM-1), soluble intracellular adhesion molecule-1 (sICAM-1), and homocysteine. Calf muscle area was measured using computed tomography. RESULTS: Adjusting for confounders, higher levels of D-dimer ( P<.001), IL-6 ( P<.001), sVCAM-1 ( P=.006), CRP ( P=.01), homocysteine ( P=.004), and sICAM-1 ( P=.046) were associated with poorer 6-minute walk performance. Higher levels of D-dimer ( P<.001), IL-6 ( P=.003), sVCAM-1 ( P=.001), and homocysteine ( P=.005) were associated with slower usual-paced 4-m walking speed. Higher levels of D-dimer, sVCAM-1, sICAM-1, IL-6, and homocysteine were associated with slower fast-paced walking speed. Results were attenuated after additional adjustment for calf muscle area. CONCLUSION: Higher levels of inflammation and D-dimer were associated with poorer lower extremity performance in participants with PAD, independent of confounders including ABI. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress is recognized as a contributing factor to various ocular neurovascular pathologies including retinitis pigmentosa, glaucoma, and diabetic retinopathy (DR). ER stress in particular is implicated in the development of DR, which is significantly influenced by inflammation driven retinal vascular degeneration and dysfunction. Ultimately, loss of vision occurs if left untreated. However, the identity of the target cells and their temporal involvement in diabetes-mediated dysfunction need further investigation. Early diabetes-induced stress in photoreceptor cells is proposed as the driver of inflammatory mediated neurovascular changes during diabetes. Although tunicamycin induced ER stress results in photoreceptor loss, its consequences for retinal vascular degeneration and retinal ganglion (RGC) and pigment epithelium (RPE) cell loss remains unclear. Here we show intravitreal delivery of tunicamycin primarily induced ER stress in photoreceptor cells resulting in their loss by apoptosis. This was concomitant with induced expression of the unfolded protein response marker CHOP in these cells. We also demonstrated significant degeneration of retinal capillaries following the loss of photoreceptor cells with minimal impact on loss of RGC and RPE cells. However, activation of retinal microglial and Muller cells were noticeable. Thus, our data support the notion that ER stress mediated dysfunction and/or loss of photoreceptor cells in response to inflammation and oxidative stress could precede retinal vascular and neuronal dysfunction and degeneration. • Photoreceptor cells exhibit a selective sensitivity to tunicamycin induced ER stress. • Tunicamycin induced ER stress leads to activation of retinal microglial and Muller cells. • Tunicamycin induced ER stress results in retinal vascular degeneration without affecting RGC and RPE cells. [ABSTRACT FROM AUTHOR]

• Silencing VCAM-1 and BMSCs synergistically improve cardiac function of MI rats. • Injection with BMSCs and sh-VCAM-1 increases CPR and survival rate of MI rats. • Injection with BMSCs and sh-VCAM-1 reduce the IS and myocardial apoptosis. • sh-VCAM-1 could inhibit the NF-κB signaling pathway. • sh-VCAM-1 enhances the therapeutic effects of BMSCs by NF-κB pathway. Bone mesenchymal stem cells (BMSCs) has been well known to exert therapeutic potential for patients with myocardial infarction (MI). VCAM-1 can promote the migration of lymphocytes to the inflammatory zone. In the present study, we tried to explore whether VCAM-1 silenced-BMSCs have better therapeutic effects on MI. BMSCs were isolated and cultured followed by treatment of a lentivirus silencing VCAM-1 and NF-κB activator (PMA). Besides, MI rat models were also established and injected with treated BMSCs to detect the effect of VCAM-1 silenced-BMSCs in MI, as evidenced by detection of cardiac function, survival of rats within 72 h, infarct size and myocardial cell apoptosis. Moreover, the expression of NF-κB-regulated gene products was also determined. The implantation of sh-VCAM-1 BMSCs into MI rats resulted in more reductions in myocardial infarct size as well as myocardial cell apoptosis, improved cardiac function, the number of survived rats within 72 h, and survival time within 72 h compared with the individual treatments of either BMSCs or control. In addition, transplanted BMSCs down-regulated the expression of NF-κB-p65, MMP-9, TNF-α, and Bax, and up-regulated VEGF and Bcl-2 in myocardial tissue, which could be further enhanced by sh-VCAM-1 and rescued by PMA. Our study demonstrated that silencing VCAM-1 in BMSCs could inhibit inflammation and apoptosis, thus improving cardiac function in MI. [ABSTRACT FROM AUTHOR]

Objectives: This study determined whether increased levels of inflammatory blood markers, D-dimer, and homocysteine were associated with smaller calf skeletal muscle area, increased calf muscle percent fat, reduced calf muscle density, and poorer calf strength in persons with lower extremity peripheral arterial disease (PAD). Background: Elevated levels of inflammatory markers and D-dimer are associated with greater functional impairment and functional decline in persons with PAD. Mechanisms of these associations are unknown. Methods: Participants were 423 persons with PAD. Calf muscle area, percent fat, and density were measured with computed tomography. Physical activity levels were measured objectively over 7 days with the Caltrac (Muscle Dynamics Fitness Network, Inc., Rocklin, California) vertical accelerometer. Isometric plantarflexion strength was measured. Analyses were adjusted for age, gender, race, comorbidities, the ankle-brachial index, and other potential confounders. Results: Higher levels of D-dimer (p = 0.014), C-reactive protein (CRP) (p = 0.002), interleukin (IL)-6 (p < 0.001), and soluble vascular cellular adhesion molecule (sVCAM)-1 (p = 0.008) were associated with smaller calf muscle area. Higher sVCAM-1 (p = 0.004) and IL-6 (p = 0.017) were associated with higher calf muscle percent fat. Higher D-dimer (p < 0.001), sVCAM-1 (p < 0.001), and homocysteine (p = 0.014) were associated with lower calf muscle density. These associations were generally unchanged after additional adjustment for physical activity. Higher sVCAM-1 (p = 0.013) was associated with lower calf strength. Conclusions: These data show, for the first time, that higher levels of inflammation, D-dimer, and homocysteine are associated with more adverse calf muscle characteristics in persons with PAD. These associations may contribute to previously established associations between elevated biomarkers and functional impairment and functional decline in PAD. [Copyright &y& Elsevier]