Exercise and osteoimmunology in bone remodeling.

Bones can form the scaffolding of the body, support the organism, coordinate somatic movements, and control mineral homeostasis and hematopoiesis. The immune system plays immune supervisory, defensive, and regulatory roles in the organism, which mainly consists of immune organs (spleen, bone marrow, tonsils, lymph nodes, etc.), immune cells (granulocytes, platelets, lymphocytes, etc.), and immune molecules (immune factors, interferons, interleukins, tumor necrosis factors, etc.). Bone and the immune system have long been considered two distinct fields of study, and the bone marrow, as a shared microenvironment between the bone and the immune system, closely links the two. Osteoimmunology organically combines bone and the immune system, elucidates the role of the immune system in bone, and creatively emphasizes its interdisciplinary characteristics and the function of immune cells and factors in maintaining bone homeostasis, providing new perspectives for skeletal-related field research. In recent years, bone immunology has gradually become a hot spot in the study of bone-related diseases. As a new branch of immunology, bone immunology emphasizes that the immune system can directly or indirectly affect bones through the RANKL/RANK/OPG signaling pathway, IL family, TNF-α, TGF-ß, and IFN-γ. These effects are of great significance for understanding inflammatory bone loss caused by various autoimmune or infectious diseases. In addition, as an external environment that plays an important role in immunity and bone, this study pays attention to the role of exercise-mediated bone immunity in bone reconstruction.

The multiple regulatory effects of white adipose tissue on bone homeostasis.

White adipose tissue (WAT) is not only an energy storage reservoir that is critical in energy homeostasis but is also a highly metabolically active endocrine organ. WAT can secrete a variety of adipocytokines, including leptin (LEP), adiponectin (APN), resistin, visfatin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and osteopontin (OPN). It can also synthesize and secrete exosomes, which enhance intercellular communication and participate in various physiological processes in the body. It can also synthesize and secrete exosomes to enhance intercellular communication and participate in a variety of physiological processes in the body. The skeleton is an important organ for protecting internal organs. It forms the scaffolding of the body and gives the body its basic form. It drives muscle contraction to produce movement under the regulation of the nervous system. It is also an important hematopoietic organ; and it is regulated by the cytokines secreted by WAT. As research related to the release of adipocytokines from WAT to affect the skeleton continues to progress, an inextricable link between bone lipid regulation has been identified. In this paper, we review the literature to summarize the structure, function and metabolism of WAT, elaborate the specific molecular mechanisms by which WAT-secreted hormones, cytokines and exosomes regulate skeletal cells, provide a theoretical basis for the in-depth study of WAT cross-organ regulation of bone, and provide new ideas for finding new adipose-secreted targeting factors for the treatment of skeletal diseases.

Ocular immune privilege and retinal pigment epithelial cells.

The ocular tissue microenvironment is immune-privileged and uses multiple immunosuppressive mechanisms to prevent the induction of inflammation. The retinal pigment epithelium plays an essential role in ocular immune privilege. In addition to serving as a blood barrier separating the fenestrated choriocapillaris from the retina, the retinal pigment epithelium is a source of immunosuppressive cytokines and membrane-bound negative regulators that modulate the activity of immune cells within the retina. This article reviews the current understanding of how retinal pigment epithelium cells mediate immune regulation, focusing on the changes under pathologic conditions.

Osteopontin - The stirring multifunctional regulatory factor in multisystem aging.

Osteopontin (OPN) is a multifunctional noncollagenous matrix phosphoprotein that is expressed both intracellularly and extracellularly in various tissues. As a growth regulatory protein and proinflammatory immunochemokine, OPN is involved in the pathological processes of many diseases. Recent studies have found that OPN is widely involved in the aging processes of multiple organs and tissues, such as T-cell senescence, atherosclerosis, skeletal muscle regeneration, osteoporosis, neurodegenerative changes, hematopoietic stem cell reconstruction, and retinal aging. However, the regulatory roles and mechanisms of OPN in the aging process of different tissues are not uniform, and OPN even has diverse roles in different developmental stages of the same tissue, generating uncertainty for the future study and utilization of OPN. In this review, we will summarize the regulatory role and molecular mechanism of OPN in different tissues and cells, such as the musculoskeletal system, central nervous system, cardiovascular system, liver, and eye, during senescence. We believe that a better understanding of the mechanism of OPN in the aging process will help us develop targeted and comprehensive therapeutic strategies to fight the spread of age-related diseases.

VEGF-B is a potent antioxidant.

VEGF-B was discovered a long time ago. However, unlike VEGF-A, whose function has been extensively studied, the function of VEGF-B and the mechanisms involved still remain poorly understood. Notwithstanding, drugs that inhibit VEGF-B and other VEGF family members have been used to treat patients with neovascular diseases. It is therefore critical to have a better understanding of VEGF-B function and the underlying mechanisms. Here, using comprehensive methods and models, we have identified VEGF-B as a potent antioxidant. Loss of Vegf-b by gene deletion leads to retinal degeneration in mice, and treatment with VEGF-B rescues retinal cells from death in a retinitis pigmentosa model. Mechanistically, we demonstrate that VEGF-B up-regulates numerous key antioxidative genes, particularly, Gpx1 Loss of Gpx1 activity largely diminished the antioxidative effect of VEGF-B, demonstrating that Gpx1 is at least one of the critical downstream effectors of VEGF-B. In addition, we found that the antioxidant function of VEGF-B is mediated mainly by VEGFR1. Given that oxidative stress is a crucial factor in numerous human diseases, VEGF-B may have therapeutic value for the treatment of such diseases.

Critical role of caveolin-1 in ocular neovascularization and multitargeted antiangiogenic effects of cavtratin via JNK.

Ocular neovascularization is a devastating pathology of numerous ocular diseases and is a major cause of blindness. Caveolin-1 (Cav-1) plays important roles in the vascular system. However, little is known regarding its function and mechanisms in ocular neovascularization. Here, using comprehensive model systems and a cell permeable peptide of Cav-1, cavtratin, we show that Cav-1 is a critical player in ocular neovascularization. The genetic deletion of Cav-1 exacerbated and cavtratin administration inhibited choroidal and retinal neovascularization. Importantly, combined administration of cavtratin and anti-VEGF-A inhibited neovascularization more effectively than monotherapy, suggesting the existence of other pathways inhibited by cavtratin in addition to VEGF-A. Indeed, we found that cavtratin suppressed multiple critical components of pathological angiogenesis, including inflammation, permeability, PDGF-B and endothelial nitric oxide synthase expression (eNOS). Mechanistically, we show that cavtratin inhibits CNV and the survival and migration of microglia and macrophages via JNK. Together, our data demonstrate the unique advantages of cavtratin in antiangiogenic therapy to treat neovascular diseases.

JAM-C maintains VEGR2 expression to promote retinal pigment epithelium cell survival under oxidative stress.

Junctional adhesion molecule-C (JAM-C) has been shown to play critical roles during development and in immune responses. However, its role in adult eyes under oxidative stress remains poorly understood. Here, we report that JAM-C is abundantly expressed in adult mouse retinae and choroids in vivo and in cultured retinal pigment epithelium (RPE) and photoreceptor cells in vitro. Importantly, both JAM-C expression and its membrane localisation are downregulated by H2O2-induced oxidative stress. Under H2O2-induced oxidative stress, JAM-C is critically required for the survival of human RPE cells. Indeed, loss of JAM-C by siRNA knockdown decreased RPE cell survival. Mechanistically, we show that JAM-C is required to maintain VEGFR2 expression in RPE cells, and VEGFR2 plays an important role in keeping the RPE cells viable since overexpression of VEGFR2 partially restored impaired RPE survival caused by JAM-C knockdown and increased RPE survival. We further show that JAM-C regulates VEGFR2 expression and, in turn, modulates p38 phosphorylation. Together, our data demonstrate that JAM-C plays an important role in maintaining VEGR2 expression to promote RPE cell survival under oxidative stress. Given the vital importance of RPE in the eye, approaches that can modulate JAM-C expression may have therapeutic values in treating diseases with impaired RPE survival.

PDGF-CC underlies resistance to VEGF-A inhibition and combinatorial targeting of both suppresses pathological angiogenesis more efficiently.

Anti-VEGF-A therapy has proven to be effective for many neovascular diseases. However, drug resistance to anti-VEGF-A treatment can develop. Also, not all patients with neovascular diseases are responsive to anti-VEGF-A treatment. The mechanisms underlying these important issues remain unclear. In this study, using different model systems, we found that inhibition of VEGF-A directly upregulated PDGF-CC and its receptors in multiple cell types in pathological angiogenesis in vitro and in vivo. Importantly, we further revealed that combinatorial targeting of VEGF-A and PDGF-CC suppressed pathological angiogenesis more efficiently than monotherapy. Given the potent angiogenic activity of PDGF-CC, our findings suggest that the development of resistance to anti-VEGF-A treatment may be caused by the compensatory upregulation of PDGF-CC, and combined inhibition of VEGF-A and PDGF-CC may have therapeutic advantages in treating neovascular diseases.

Protective effects of appropriate Zn(2+) levels against UVB radiation-induced damage in human lens epithelial cells in vitro.

As one of the crucial factors of cataract formation, ultraviolet B (UVB) can lead to apoptosis of human lens epithelial cells. Zinc, a cell-protective metal against various toxic compounds, plays an important role in protecting target cells from damage. Nevertheless, it is still unclear whether zinc exhibits protective effect on human lens epithelial cells (HLE B-3) against UVB-induced damage. In this study, we investigated the protective effect of zinc chloride (ZnCl2) on UVB-induced HLE B-3 cell damage, explored the molecular mechanisms using real-time cell electronic sensing system, flow cytometry, real-time quantitative PCR and enzyme-linked immunosorbent assay techniques. The results show that ZnCl2 is a potential inhibitor of UVB-induced HLE B-3 cell damage, and the underlying mechanisms are involved in decreasing the overproduction of reactive oxygen species and mitochondrial dysfunction, promoting intracellular calcium homeostasis recovery, and thus maintaining cell normal physiological functions. Taken together, our findings suggest that appropriate zinc levels have potential for protecting HLE B-3 cells against UVB-induced damage, and this finding may be clinically useful.

Ranibizumab alone or in combination with photodynamic therapy vs photodynamic therapy for polypoidal choroidal vasculopathy: a systematic review and Meta-analysis.

AIM: To compare the efficacy of intravitreal ranibizumab (IVR) alone or in combination with photodynamic therapy (PDT) vs PDT in patients with symptomatic polypoidal choroidal vasculopathy (PCV). METHODS: A systematic search of a wide range of databases (including PubMed, EMBASE, Cochrane Library and Web of Science) was searched to identify relevant studies. Both randomized controlled trials (RCTs) and non-RCT studies were included. Methodological quality of included literatures was evaluated according to the Newcastle-Ottawa Scale. RevMan 5.2.7 software was used to do the Meta-analysis. RESULTS: Three RCTs and 6 retrospective studies were included. The results showed that PDT monotherapy had a significantly higher proportion in patients who achieved complete regression of polyps than IVR monotherapy at months 3, 6, and 12 (All P≤0.01), respectively. However, IVR had a tendency to be more effective in improving vision on the basis of RCTs. The proportion of patients who gained complete regression of polyps revealed that there was no significant difference between the combination treatment and PDT monotherapy. The mean change of best-corrected visual acuity (BCVA) from baseline showed that the combination treatment had significant superiority in improving vision vs PDT monotherapy at months 3, 6 and 24 (All P<0.05), respectively. In the mean time, this comparison result was also significant at month 12 (P<0.01) after removal of a heterogeneous study. CONCLUSION: IVR has non-inferiority compare with PDT either in stabilizing or in improving vision, although it can hardly promote the regression of polyps. The combination treatment of PDT and IVR can exert a synergistic effect on regressing polyps and on maintaining or improving visual acuity. Thus, it can be the first-line therapy for PCV.

Disrupted calcium homeostasis is involved in elevated zinc ion-induced photoreceptor cell death.

Zinc (Zn), the second abundant trace element in living organisms, plays an important role in regulating cell metabolism, signaling, proliferation, gene expression and apoptosis. Meanwhile, the overload of Zn will disrupt the intracellular calcium homeostasis via impairing mitochondrial function. However, the specific molecular mechanism underlying zinc-induced calcium regulation remains poorly understood. In the present study, using zinc chloride (ZnCl2) as a stressor, we investigated the effect of exogenous Zn(2+) in regulating murine photoreceptor cell viability, reactive oxygen species (ROS), cell cycle distribution and calcium homeostasis as well as plasma membrane calcium ATPase (PMCA) isoforms (PMCA1 and PMCA2, i.e., ATP2B1, ATP2B2) expression. We found that the exogenous Zn(2+) in the exposure range (31.25-125.0 µmol/L) results in the overgeneration of ROS, cell cycle arrest at G2/M phases, elevation of cytosolic [Ca(2+)], inactivation of Ca(2+)-ATPase and reduction of both PMCA1 and PMCA2 in 661 W cells, and thus induces cell death. In conclusion, ZnCl2 exposure can elevate the cytosolic [Ca(2+)], disrupt the intracellular calcium homeostasis, further initiate Ca(2+)-dependent signaling pathway in 661 W cells, and finally cause cell death. Our results will facilitate the understanding of cell death induced by the zinc ion-mediated calcium homeostasis disruption.

UVB irradiation enhances TiO2 nanoparticle-induced disruption of calcium homeostasis in human lens epithelial cells.

Currently, titanium dioxide nanoparticles (TiO2 NPs) have been widely used in various applications including cosmetics, food additives and biomedicine. However, there are few reports available using TiO2 NPs to treat ocular diseases. Posterior capsular opacification (PCO) is the most frequent complication after cataract surgery, which is induced by the proliferation and migration of lens epithelial cells. Thus, inhibiting the proliferation of lens epithelial cells will efficiently reduce the occurrence of PCO. In this study, we investigated the effects of TiO2 NPs on HLE B-3 cells with or without ultraviolet B (UVB) irradiation in vitro. We found that TiO2 NPs can inhibit HLE B-3 cell growth, cause the elevation of intracellular [Ca(2+)], produce excessive reactive oxygen species (ROS), further reduce Ca(2+)-ATPase activity and decrease the expression of plasma membrane calcium ATPase 1 (PMCA1), finally disrupt the intracellular calcium homeostasis and induce cell damage. Importantly, UVB irradiation can apparently enhance these effects on HLE B-3 cells in the presence of TiO2 NPs. Taken together, the generation of excessive ROS and the disruption of intracellular calcium homeostasis may be both involved in TiO2 nanoparticle-induced HLE B-3 cell damage under UVB irradiation.

Zinc chloride inhibits human lens epithelial cell migration and proliferation involved in TGF-ß1 and TNF-α signaling pathways in HLE B-3 cells.

Zinc is one of the most abundant essential elements in the human body, which is an essential, coenzyme-like component of many enzymes, and is indispensable to their functions. However, high levels of zinc ions can lead to cell damage. In the present study, we explored the effects of high concentrations of zinc chloride (ZnCl2) on lens epithelial cell proliferation and migration and further investigated the effects of different concentrations of ZnCl2 on caspase-9 and caspase-12, transforming growth factor-beta 1 (TGF-ß1), and tumor necrosis factor-alpha (TNF-α). We found that ZnCl2 could inhibit human lens epithelial (HLE) B-3 cell migration and induce apoptosis/necrosis. In addition, ZnCl2 can efficiently decrease the expressions of caspase-9 and caspase-12, increase the expression of TNF-α at both gene and protein levels, and thus induces cell death. Taken together, our results indicate that ZnCl2 can inhibit HLE B-3 cell migration and proliferation by decreasing the expression of TGF-ß1 and increasing the expression of TNF-α and finally lead to HLE B-3 cell death.

Zinc oxide nanoparticles inhibit Ca2+-ATPase expression in human lens epithelial cells under UVB irradiation.

Epidemiological and experimental studies have revealed that lens epithelial cells exposed to ultraviolet B (UVB) light could be induced apoptosis, and lens epithelial cell apoptosis can initiate cataractogenesis. Posterior capsular opacification (PCO), the most frequent complication after cataract surgery, is induced by the proliferation, differentiation, migration of lens epithelial cells. Thus, inhibiting the proliferation of lens epithelial cells could reduce the occurrence of PCO. It is reported that zinc oxide (ZnO) nanoparticles have great potential for the application of biomedical field including cancer treatment. In the present study, we investigated the cytotoxic effect of ZnO nanoparticles on human lens epithelial cell (HLEC) viability. In addition, changes in cell nuclei, apoptosis, reactive oxygen species and intracellular calcium ion levels were also investigated after cells treated with ZnO nanoparticles in the presence and absence of UVB irradiation. Meanwhile, the expression of plasma membrane calcium ATPase 1 (PMCA1) was also determined at gene and protein levels. The results indicate that ZnO nanoparticles and UVB irradiation have synergistic inhibitory effect on HLEC proliferation in a concentration-dependent manner. ZnO nanoparticles can increase the intracellular calcium ion level, disrupt the intracellular calcium homeostasis, and decrease the expression level of PMCA1. UVB irradiation can strengthen the effect of reduced expression of PMCA1, suggesting that both UVB irradiation and ZnO nanoparticles could exert inhibitory effect on HLECs via calcium-mediated signaling pathway. ZnO nanoparticles have great potential for the treatment of PCO under UVB irradiation.

UVB irradiation-induced dysregulation of plasma membrane calcium ATPase1 and intracellular calcium homeostasis in human lens epithelial cells.

Ultraviolet B (UVB) could lead to the apoptosis of human lens epithelial cell and be hypothesized to be one of the important factors of cataractogenesis. In the human lens, Ca(2+)-ATPase is a major determinant of calcium homeostasis. Plasma membrane calcium ATPase1 (PMCA1) is a putative "housekeeping" isoform and is widely expressed in all tissues and cells, which plays an important role in calcium homeostasis. However, the effects of UVB-irradiation on the expression of PMCA1 and the cellular calcium homeostasis are still unclear. In the present study, we cultured human lens epithelial cells (HLE B-3) in vitro and investigated the effects of UVB irradiation on the expression of PMCA1 and the intracellular calcium homeostasis using real-time cell electronic sensing system, flow cytometry, fluo-3/AM probes, real-time quantitative PCR, and enzyme-linked immunosorbent assay techniques. We found that UVB irradiation could induce human lens epithelial cell death, cause intracellular calcium ion (Ca(2+)) elevation, inhibit Ca(2+)-ATPase activity and decrease the expression of PMCA1 at gene and protein levels, suggesting that the downregulation of PMCA1 and the disruption of calcium homeostasis may play important roles in UVB-induced HLE B-3 cell apoptosis.