Although calcium overload dysregulation has been implicated in cellular senescence, its role in ionizing radiation (IR)-induced osteocyte senescence, a key pathogenic mechanism underlying radiotherapy-associated bone injury, remains poorly explored. This study investigated whether IR-induced osteocyte senescence is mediated through the Ca2+-NFATc1-ATF3 pathway. Exposure to 2 Gy X-rays impaired osteocyte homeostasis, manifesting as reduced viability and proliferation, G2/M phase arrest, and dendritic retraction. IR also induced persistent DNA damage response and senescence-associated phenotypes, including increased γ-H2AX foci, SA-β-gal activity, condensed punctate DAPI-dense nuclear foci, p16/p21 expression, and pro-inflammatory SASP profile. Intracellular Ca2+ levels surged within 6 h post-irradiation and remained elevated for at least 72 h in a dose-dependent manner. Pharmacological Ca2+ modulation with BAPTA-AM or verapamil attenuated IR-induced intracellular Ca2+ accumulation, G2/M arrest, SA-β-gal positivity, p21/p53 upregulation, and SASP secretion. Conditioned medium from irradiated osteocytes inhibited BMSC-mediated osteogenesis and enhanced BMM-driven osteoclastogenesis, whereas Ca2+ modulation partially mitigated these paracrine effects. Mechanistically, IR promoted NFATc1 nuclear translocation and ATF3 upregulation. Collectively, these findings support an important role for pathological intracellular Ca2+ elevation in IR-induced osteocyte senescence and suggest that the Ca2+-NFATc1-ATF3 axis may represent a potential therapeutic target for mitigating radiation-associated disruption of bone homeostasis.

Various stressors such as ionizing radiation (IR), chemotherapeutic agents, oxidative stress, and inflammatory responses can trigger the stress-induced premature senescence (SIPS) of cells in the bone microenvironment, including osteocytes. However, little is known about the mechanisms underlying the senescent cellular regulation of the differentiation potential and bone homeostasis. Here, we report a secretory change in senescent osteocytes activated by IR, its subsequent impact on osteogenic and osteoclastic differentiation, and the inflammatory cascade response. It was observed that osteocytes exhibited altered biological function, persistent and incomplete DNA damage repair, and characteristic senescence phenotypes after exposure to IR in vitro. Meanwhile, a concomitant increase in the CC chemokine ligand 3 (CCL3), a key component of the senescence-associated secretory phenotype (SASP), was observed in the IR-induced senescent osteocytes, which could further downregulate the osteogenic differentiation and enhance the osteoclastic differentiation in cell supernatant co-culture experiments. Notably, the enhancement of the PI3K/Akt/NF-κB signaling pathway in IR-induced senescent osteocytes appears to be an essential driver of the imbalance between the osteogenic and osteoclastic differentiation potentials. Taken together, these data suggest a novel role of CCL3 in IR-induced bone homeostatic imbalance through SASP cascade secretion, mediated by the PI3K/Akt/NF-κB signaling pathway.

Background and Objectives: Damage to normal bone tissue following therapeutic irradiation (IR) represents a significant concern, as IR-induced bone microenvironment disruption can cause bone loss and create a more favorable environment for tumor metastases. The aim of the present study was to explore the cellular regulatory mechanism of IR-induced bone microenvironment disruption to effectively prevent radiotherapy-associated adverse effects in the future. Materials and Methods: In this study, a mouse model of local IR was established via local irradiation of the left hind limb of BALB/c mice with 12 Gy X-rays, and an in vitro osteocyte (OCY) model was established by exposing osteocyte-like MLO-Y4 cells to 2, 4, and 8 Gy irradiation to analyze multicellular biological injuries and cellular senescence. Small interfering RNA (siRNA) transfection at the cellular level and a selective antagonist intervention C-176 at the animal level were used to explore the potential role of the stimulator of interferon genes (STING) on IR-induced bone microenvironment disruption. Results: The results showed that 12 Gy local IR induces multicellular dysfunction, manifested as ascension of OCYs exfoliation, activation of osteoclastogenesis, degeneration of osteogenesis and fate conversion of adipogenesis, as well as cellular senescence and altered senescence-associated secretory phenotype (SASP) secretion. Furthermore, the expression of STING was significantly elevated, both in the primary OCYs harvested from locally irradiated mice and in vitro irradiated MLO-Y4 cells, accompanied by the markedly upregulated levels of phosphorylated TANK-binding kinase 1 (P-TBK1), RANKL and sclerostin (SOST). STING-siRNA transfection in vitro restored IR-induced upregulated protein expression of P-TBK1 and RANKL, as well as the mRNA expression levels of inflammatory cytokines, such as IL-1α, IL-6 and NF-κB, accompanied by the alleviation of excessive osteoclastogenesis. Finally, administration of the STING inhibitor C-176 mitigated IR-induced activation of osteoclastogenesis and restraint of osteogenesis, ameliorating the IR-induced biological damage of OCYs, consistent with the inhibition of P-TBK1, RANKL and SOST. Conclusions: The STING-P-TBK1 signaling pathway plays a crucial role in the regulation of the secretion of inflammatory cytokines and osteoclastogenesis potential in IR-induced bone microenvironment disruption. The selective STING antagonist can be used to intervene to block the STING pathway and, thereby, repair IR-induced multicellular biological damage and mitigate the imbalance between osteoclastogenesis and osteoblastgenesis.

The present study aimed to investigate the efficacy of Iodine-125 (I-125) brachytherapy in a mouse model of non-small cell lung cancer, to further explore the efficacy and appropriate method of implantation of the I-125 radioactive seed. This study also aimed to determine the impact of brachytherapy on bone metabolism. A total of 18 mice were used to establish H1299 xenograft models, and were randomly assigned to three groups. These included non-radioactive seed implantation (Sham IM), fractionated I-125 seed implantation (Fractionated IM) and single I-125 seed implantation (Single IM) groups. Mice were euthanized after 28 days of implantation. H&E staining, Ki67 immunohistochemistry, CD31 morphometric analysis and TUNEL immunofluorescence assays were respectively used to determine the histopathological changes, proliferation, micro-angiogenesis and apoptosis of tumors. In addition, bone volume and microstructure were evaluated using trabecular bone area (Tb.Ar), trabecular thickness (Tb.Th), trabecular number (Tb.N) and cortical thickness. Bone metabolic status was analyzed using histomorphometric staining of tartrate-resistant acid phosphate (TRAP) and alkaline phosphatase (ALP) expression in the femur, and using an ELISA assay to determine the expression of C-telopeptide of type 1 collagen (CTX-1) and procollagen type 1 n-terminal propeptide (P1NP) in the serum. Moreover, reverse transcription-quantitative PCR and western blotting were carried out for the analysis of bone remodeling-related gene expression in the bone tissue. Results of the present study demonstrated that compared with the Sham IM group, both the I-125 seed implantation groups, including Fractionated IM and Single IM, demonstrated significant therapeutic effects in both tumor volume and weight. More specifically, the most significant therapeutic effects on tumor inhibition were observed in the Fractionated IM group. Results of Ki67 and CD31 immunohistochemical staining suggested a notable reduction in tumor cell proliferation and micro-angiogenesis, and results of the TUNEL assay demonstrated an increase in tumor cell apoptosis. Although the cortical bone appeared thinner and more fragile in both I-125 seed implantation groups, no notable adverse changes in the morphology of the cancellous bone were observed, and the index of Tb.Ar, Tb.Th and Tb.n was not significantly different among Sham IM and I-125 implantation groups. However, alterations in bone metabolism were characterized by a decrease in CTX-1 and P1NP expression, accompanied by an increase in TRAP activity and a decrease in ALP activity. Results of the present study also demonstrated the notable suppression of osteocalcin and runt-related transcription factor 2. I-125 seed implantation may be an effective and safe antitumor strategy. Moreover, the use of fractionated implantation patterns based on tumor shape exhibited improved therapeutic effect on tumor suppression when the total number of I-125 seeds was equivalent along with reduced complications associated with bone loss.

Cadmium exposure is associated with renal dysfunction and bone damage. Chronic kidney disease and bone loss are also related to parathyroid hormone (PTH). However, whether cadmium exposure affect PTH level is not completely understood. In this study, we observed the association between environmental cadmium exposure and PTH levels in a Chinese population. A ChinaCd study was performed in China in 1990s which included 790 subjects living in heavily, moderately and low cadmium polluted area. 354 of them (121 men and 233 women) also had the data of serum PTH. The cadmium levels in blood (BCd) and urine (UCd) were determined by flame atomic absorption spectrometry. Serum PTH was detected by immunoradiometric assay. Renal function was assessed based on urinary N-acetyl-β-d-glucosaminidase (UNAG), β2-microglobulin (UBMG) and urinary albumin (UALB). The median BCd and UCd levels were 4.69 μg/L and 5.50 μg/g creatinine. The BCd, UCd, UNAG, UBMG and UALB levels in subjects with low PTH (< 5.0 ng/L) were significantly higher than those with PTH ≥ 5.0 ng/L (p < 0.05 or p < 0.01). Spearman correlation analysis also showed that UCd level was negatively correlated to PTH levels (r = −0.17, p = 0.008) in women. A weak correlation was also observed between PTH level and BCd in women (r = −0.11, p = 0.09) and UBMG in total population (r = −0.114, p = 0.07). Univariable and mutivariable logistic regression analysis both demonstrated that high BCd (> 10 μg/L) (odds ratio (OR) = 2.26, 95% confidence interval (CI):1.10–4.63; OR = 2.36, 95%CI: 1.11–5.05) and UCd level (> 20 μg/g cr) (OR = 2.84, 95% CI:1.32–6.10; OR = 2.97, 95%CI: 1.25-7.05) were associated with high risk of low PTH. Our data showed that environmental cadmium exposure was associated with low PTH level.

The imbalance that occurs in bone remodeling induced by irradiation (IR) is the disruption of the balance between bone formation and bone resorption. In this study, primary osteocytes (OCYs) of femoral and tibial origin were cultured and irradiated. It was observed that irradiated OCY showed extensive DNA damage, which led to the initiation of a typical phenotype of cellular senescence, including the secretion of senescence-associated secretory phenotype (SASP), especially the C-C motif chemokine ligand 5 (CCL5). In order to explore the regulation of osteoclastogenic potential by IR-induced senescent OCYs exocytosis factor CCL5, the conditioned medium (CM) of OCYs was co-cultured with RAW264.7 precursor cells. It was observed that in the irradiated OCY co-cultured group, the migration potential increased compared with the vehicle culture group, accompanied by an enhancement of typical mature OCs; the expression of the specific function of enzyme tartrate-resistant acid phosphatase (TRAP) increased; and the bone-destructive function was enhanced. However, a neutralizing antibody to CCL5 could reverse the extra-activation of osteoclastogenesis. Accordingly, the overexpression of p-STAT3 in irradiated OCY was accompanied by CCL5. It was concluded that CCL5 is a potential key molecule and the interventions targeting CCL5 could be a potential strategy for inhibiting osteoclastogenesis and restoring bone remodeling.

Fatty pancreas(FP)is not uncommon as a component of obesity-related metabolic syndrome.It is not only closely related to metabolic syndrome-related diseases, but also plays a causative role in the risk of pancreatitis, pancreatic cancer and pancreatic fistula.Compared with metabolic dysfunction-associated fatty liver disease(MAFLD), current status is not optimistic about the degree of attention and awareness of FP that even occurs earlier than MAFLD.This editorial outlines several important issues of FP in pathogenesis, pathophysiology, correlation with other clinical diseases, diagnosis, prevention and treatment status, and summarizes the limitations and controversies of the current understanding in FP, in order to attract attention to its basic and clinical research.

Low hemoglobin (Hb) level or anemia is associated with osteoporosis and bone fracture. Cadmium (Cd) and lead (Pb) exposure are also risk factors of osteoporosis and anemia. However, the role of anemia in Cd/Pb related bone loss remains unclear. The aim of present study was to investigate the association between Hb level and bone loss in a population with environmental lead and cadmium exposure. One hundred and ninety-four women and 108 men with different levels of Cd/Pb exposure were included in our study. The Cd/Pb exposure was determined using graphite-furnace atomic absorption spectrometry. Forearm bone mineral density (BMD) was determined by peripheral dual-energy X-ray absortiometry. Hb concentration was determined using an automatic blood cellcounter. A logistic model was established to predict the risk of osteoporosis. The BMDs of women that had the highest quartile BCd and BPb were markedly lower than that with the lowest quartile (p < 0.05). The BMD and the prevalence of osteoporosis in men with anemia were lower and higher than that with normal Hb (p < 0.05), respectively. In men, age, BPb and anemia were independent risk factors for osteoporosis. The odds ratio (OR) of men with anemia was 11.28 (95%confidence interval (CI):1.94-65.54) and 19.56 (95%CI: 2.98-128.78) compared to those with normal Hb after adjusting for potential cofounders. No such association was found in women. The area under the curve was 0.88 (95%CI: 0.82-0.96) in predicting osteoporosis using the logistic model in men. Linear discriminant analysis also showed that 90.7% of osteoporosis was correctly classified. Our data show that anemia is associated with incident of osteoporosis in men but not in women that environmentally exposed to Pb and Cd.

Background: Cadmium exposure is associated with bone loss. However, the mechanisms involved have not yet been fully understood. Leucine-rich repeat containing GPCR-4 (LGR4) can bind with the receptor activator of nuclear factors Kappa B ligand (RANKL) and inhibit osteoclast formation. In addition, Lgr4 plays an important role in maintaining osteoblast activity. In the present study the effect of cadmium exposure on bone was investigated in terms of Lgr4 expression.Methods: Raw 264.7 cells and primary osteoblasts were exposed to cadmium (0-60 nM/L). The effects of cad-mium on osteoclast formation and osteoblast activity were investigated. Osteoclast differentiation-related (Traf6, NFATc1) and osteoblast-related (RANKL; osteoprotegerin, OPG) gene and protein expression were determined. Lgr4 expression in osteoclasts and osteoblasts were also determined. A rat model was established to show the effects of cadmium (50 mg/L) on bone loss and Lgr4 expression in vivo. Results: Cadmium exposure inhibited osteoblast activities and stimulated osteoclast formation. Cadmium expo-sure also inhibited Lgr4 expression in both osteoclasts and osteoblasts. Low dose of RANKL added to the culture medium could promote osteoclast formation in cadmium-pretreated RAW264.7 cells. Blocking Lgr4 in osteo-clasts only slightly inhibited cadmium-induced osteoclast formation in cadmium-pretreated RAW264.7 cells. Cadmium significantly upregulated the AKT/ERK signaling pathway. An in vivo study showed that cadmium exposure promoted osteoclast formation and inhibited Lgr4 expression.Conclusions: Our data indicates that cadmium may induce bone loss by inhibiting Lgr4-related bone formation and promoting Lgr4-related osteoclast formation.

Purpose This study aimed to investigate the therapeutic potential of tumor suppression and mechanism for different implantation modes of iodine-125 (I-125) seeds irradiation in a mice xenograft model, and its skeletal complications. Materials and methods A total of 24 mice carrying A549 lung tumor-derived xenografts were randomly assigned to four groups, including non-radioactive (sham) seeds implantation, I-125 seeds fractional implantation, I-125 seeds single implantation and I-125 seeds single implantation combined with anlotinib. Ki67 immunohistochemistry, TUNEL immunofluorescence and CD31 morphometric analysis were used to determine the proliferation index, rate of apoptotic cells and microvessel density, respectively. Additionally, the side effects on the skeletal system in mice treated with I-125 seeds implantation were evaluated by histomorphometric staining with tartrate-resistant acid phosphate (TRAP) and alkaline phosphatase (ALP) expression in femur, tartrate-resistant acid phosphatase 5b (TRACP-5b) and procollagen type I N-terminal propeptide (PINP) levels in serum were evaluated by enzyme-linked immunosorbent assay (ELISA). Results The I-125 seeds single and fractionated implantation had similar therapeutic effects and complications when the total number of I-125 seeds was the same. A single implantation of I-125 seeds with or without anlotinib could analogously inhibit the tumor growth in xenografts mice, while the single implantation combined with anlotinib had more effective in tumor inhibition. The results of Ki67, TUNEL and CD31 staining confirmed an evident reduction in tumor cell proliferation and angiogenesis, as well as an increase in apoptosis. A relatively integrated bone metabolism was indicated after I-125 seeds single implantation with or without anlotinib, and the results were similar in I-125 seeds fractional implantation, including a reduction in the number of TRAP-positive cells and an increase in ALP expression level. Additionally, the serum TRACP-5b activity was decreased and the serum PINP concentration was increased following I-125 seeds implantation. Conclusions Single and fractionated implantation pattern of I-125 radioactive seeds had similar therapeutic efficacy against tumor growth, while brachytherapy with I-125 seeds implantation may be an effective and safe treatment strategy for its potential protection against cancer treatment-induced bone loss.

Objective: The association between cadmium exposure and osteoporosis has been rarely reported in longitudinal studies. In this study, we investigated the association between osteoporosis and cadmium exposure and developed predictive models in women in a longitudinal cohort.Materials and Methods: In total, 488 women living in southeastern China were included at baseline (1998). Cadmium in blood (BCd) and urine (UCd) and also renal dysfunction biomarkers and bone mineral density (BMD) were determined both at baseline and follow-up. A total of 307 subjects were finally included after excluding subjects that did not have exposure or effect biomarkers. Osteoporosis was defined based on T score ≤ −2.5. Multiple linear regression and multivariate logistic analysis were used to show the association between baseline data and follow-up osteoporosis. Based on the identified associated factors, nomograms were developed to graphically calculate the individual risk of osteoporosis.Results: The baseline BMD in subjects with osteoporosis was significantly lower than that in subjects without osteoporosis (0.59 vs. 0.71 g/cm2, p < 0.05). The prevalence of low bone mass at baseline was higher in subjects with osteoporosis than in those without osteoporosis (23.5 vs. 7.2%, p = 0.001). Logistic regression analysis demonstrated that age [odds ratio (OR) = 1.21, 95% confidence interval (CI): 1.16–1.27], UCd (OR = 1.03, 95% CI: 1.002–1.06) and the presence of low BMD (OR = 3.84, 95% CI: 1.49–9.89) were independent risk factors for osteoporosis. For those subjects with normal baseline BMD, age, UCd, and baseline BMD were also independent risk factors for osteoporosis. The OR value was 1.16 (95% CI: 1.10–1.22) for age, 2.27 (95% CI: 1.03–4.99) for UCd > 10 μg/g creatinine, and 0.39 (95% CI: 0.21–0.72) for BMDbaseline. We developed two nomograms to predict the risk of osteoporosis. The area under the curve was 0.88 (95% CI: 0.84–0.92) for total population and was 0.88 (95% CI: 0.84–0.92) for subjects with normal baseline BMD, respectively.Conclusion: Baseline age, UCd, and BMD were associated with follow-up osteoporosis in women. Nomograms showed good performance in predicting the risk of osteoporosis.

Cellular senescence and its senescence-associated secretory phenotype (SASP) are widely regarded as promising therapeutic targets for aging-related diseases, such as osteoporosis. However, the expression pattern of cellular senescence and multiple SASP secretion remains unclear, thus leaving a large gap in the knowledge for a desirable intervention targeting cellular senescence. Therefore, there is a critical need to understand the molecular mechanism of SASP secretion in the bone microenvironment that can ameliorate aging-related degenerative pathologies including osteoporosis. In this study, osteocyte-like cells (MLO-Y4) were induced to cellular senescence by 2 Gy γ-rays; then, senescence phenotype changes and adverse effects of SASP on bone marrow mesenchymal stem cell (BMSC) differentiation potential were investigated. The results revealed that 2 Gy irradiation could hinder cell viability, shorten cell dendrites, and induce cellular senescence, as evidenced by the higher expression of senescence markers p16 and p21 and the elevated formation of senescence-associated heterochromatin foci (SAHF), which was accompanied by the enhanced secretion of SASP markers such as IL-1α, IL-6, MMP-3, IGFBP-6, resistin, and adiponectin. When 0.8 μM JAK1 inhibitors were added to block SASP secretion, the higher expression of SASP was blunted, but the inhibition in osteogenic and adipogenic differentiation potential of BMSCs co-cultured with irradiated MLO-Y4 cell conditioned medium (CM- 2 Gy) was alleviated. These results suggest that senescent osteocytes can perturb BMSCs' differential potential via the paracrine signaling of SASP, which was also demonstrated by in vivo experiments. In conclusion, we identified the SASP factor partially responsible for the degenerative differentiation of BMSCs, which allowed us to hypothesize that senescent osteocytes and their SASPs may contribute to radiation-induced bone loss.

目的 探讨残疾老年人营养风险的发生率及其影响因素.方法 通过整群抽样法,对上海市普陀区783例60岁及以上社区残疾人开展面对面问卷调查和人体测量.结果 社区残疾老年人营养不良风险的发生率为16.2％.二分类logistic回归结果显示患有两种及以上的慢性病(OR=2.45)、抑郁(OR=3.45)、近一年有跌倒史(OR=1.80)、握力降低(OR=1.58)是社区残疾老年人营养风险发生的独立影响因素.结论 自身患多种慢性病、抑郁、近一年有跌倒和握力降低的社区残疾老年人容易发生营养不良风险.

The association between internal cadmium exposure and chronic kidney disease (CKD) has been investigated before. However, few studies have shown the association between dietary cadmium intake and CKD. In this study, we show the association between life-time dietary cadmium intake and CKD based on a follow-up study. At baseline, we collected blood and urine samples for assays of cadmium and renal effect biomarkers. A questionnaire and food survey was given to each subject to collect diet and lifestyle information for the estimation of cadmium intake. Dietary cadmium, cadmium in blood and urine were regarded as exposure markers. Life-time dietary cadmium intake was estimated based on an individual’s daily cadmium intake and exposure time. At follow-up, 467 persons (163 men and 304 women) were finally included. CKD at follow-up was considered if the estimated glomerular filtration rate (eGFR) was less than 60 mL/min/1.73 m2. The eGFR level in subjects in the highest quartile of total dietary cadmium intake (>9.34 g) was significantly lower than in those with a moderate or low intake (p < 0.01). eGFR was negatively associated with total dietary cadmium intake (β = -0.42, 95% confidence interval (CI): -0.77 to -0.07) after adjustment with confounders. Logistic regression further showed that the risk of CKD in subjects with a high total dietary cadmium intake (>2.2 g) was higher than in those with a low intake (odds ratio (OR) = 18.16, 95%CI: 1.75–188.85). A similar association was found between the baseline urinary albumin (UALB) level and CKD incidence. A predictive model based on UALB and life-time dietary cadmium intake showed an acceptable performance (the area under the curve was 0.77 (95%CI: 0.65–0.88)). Our data show that high dietary cadmium exposure was associated with CKD after controlling for renal tubular dysfunction and internal cadmium exposure.

Cadmium exposure may increase the risk of osteoporosis. However, there is no quick method to get bone mineral density (BMD) unless dual-energy X-ray absorptiometry (DXA) examinations were performed. In the present study, we aimed to identify associated factors to osteoporosis and fracture in a Chinese female population with cadmium exposure and develop nomograms to predict the risk. A total of 488 women was included in this study. Cadmium in blood (BCd) and urine (UCd) were determined as exposure biomarkers. BMD was determined using single-photon absorptiometry. Urinary N-acetyl-β-d-glucosaminidase (UNAG) and urinary albumin (UALB) were determined as renal function biomarkers. Osteoporosis was defined if T-score < − 2.5. Multiple logistic regression showed that age, BCd, and menopausal status were independent risk factors for osteoporosis. The odds (OR) value was 1.19 (95% confidence interval (CI): 1.14–1.25) for age, 1.05 (95% CI: 1.004–1.10) for BCd, and 4.75 (95% CI: 1.65–13.69) for menopausal status after adjusting with cofounders. Age and UCd were the independent risk factors for bone fracture. Nomograms were developed based on the associated factors. Age was the main determinant for osteoporosis or fracture. Receiver operating curve showed acceptable performance in predicting osteoporosis (area under the curve (AUC) = 0.93, 95CI: 0.90–0.96) and fracture (AUC = 0.67, 95% CI: 0.58–0.75). Linear discriminant analysis (LDA) further showed that 88.9% of osteoporosis and 68.4% of fractures were correctly classified. Our study develops nomograms that may be used to predict cadmium-induced osteoporosis or fracture if BMD data is not available.

Irradiation-induced bone remodeling imbalances arise as a consequence of the dysregulation of bone formation and resorption. Due to the abundance of osteocytes, their long life and their dual-regulatory effects on both osteoblast and osteoclast function, they serve as critical coordinators of bone remolding. In the present study, femur and tibia-derived primary osteocytes were cultured and irradiated to observe the functional changes and the cellular senescence phenotype in vitro. Irradiation directly reduced cell viability, affected the crucial dendritic morphology and altered the expression of functional proteins, including upregulation of receptor activator of nuclear factor-kappa B ligand and sclerostin, and downregulation of osteoprotegerin. Irradiated osteocytes were shown to exhibit notable DNA damage, which resulted in the initiation of a typical cellular senescence phenotype. Furthermore, it was found that irradiation-induced prematurely senescent osteocytes stimulate molecular secretion, referred to as senescence-associated secretory phenotype (SASP), which may be involved in modulation of the bone microenvironment, including the promotion of osteoclastogenesis. Taken together, the results showed that irradiation triggered osteocyte senescence and the acquisition of an associated secretory phenotype. This further resulted in an imbalance of bone remodeling through senescent influence on proliferation, morphology and marker protein production, but also indirectly via a paracrine pathway through SASP secretion. The results of the present study may highlight the potential of SASP-targeted interventions for the management of radiation-induced bone loss.

Background: The associations between cadmium exposure and chronic kidney disease have rarely been reported in longitudinal studies. In this study, we investigated the associations between the estimated glomerular filtration rate and cadmium exposure in a cross-sectional study in a longitudinal cohort. Materials and methods: In total, 790 subjects (>= 35 years of age) living in southeastern China were included at 1998. Cadmium in blood (BCd) and urine (UCd) as well as renal dysfunction biomarkers, urinary N-acetyl-13 dglucosaminidase (UNAG) and albumin (UALB), were determined. 497 subjects were followed at 2006 and a total of 456 subjects were finally included after excluding subjects that did not have exposure or effects biomarkers. The BCd, UCd, UNAG and UALB were determined using baseline methods. At follow-up, the estimated glomerular filtration rate (eGFR) was computed using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Single nucleotide polymorphisms (SNPs) in metallothioneins 1A (MT1A) rs11076161 and MT2A rs28366003 in blood sample were detected using TaqMan allelic discrimination assays. Results: The median of UCd and BCd at baseline was 5.38 mu g/g cr and 4.69 mu g/L, respectively, and the median UCd and BCd at follow-up was 4.88 mu g/g cr and 2.20 mu g/L at follow-up. The mean eGFR at follow-up was 88.0 mL/min/1.73 m2 and 15 subjects had new onset of eGFR <60 mL/min/1.73 m2. The eGFR at follow-up was associated with baseline age (13 = -0.66, 95% confidence interval (CI): 0.80 to -0.52), BCd (13 = -0.46, 95% CI: 0.68 to -0.25) and UALB (13 = -0.29, 95% CI: 0.41 to -0.16) after adjusting for confounders. Subgroup analysis in subjects who had low baseline UALB or subjects with or without hypertension showed similar results. A logistic regression model further showed that baseline BCd and UALB were independent risk factors for follow-up CKD. The odds ratios (ORs) were 1.09 (95% CI:1.03-1.16) for UALB, 1.16 (95% CI:1.01-1.33) for BCd, and 6.74 (0.87-29.63) for current hypertension. Baseline BCd, UALB and current hypertension were used to construct the nomogram. Linear discriminant analysis (LCA) showed that 87.6% of CKD was accurately predicted based on the three factors. Conclusion: Baseline age, BCd and UALB were associated with follow-up eGFR, and baseline BCd and UALB were predictive factors for incidence of CKD.

The role of cellular senescence induced by radiation in bone loss has attracted much attention. As one of the common complications of anticancer radiotherapy, irradiation-induced bone deterioration is common and clinically significant, but the pathological mechanism has not been elucidated. This study was performed to explore the cellular senescence and senescence-associated secretory phenotype (SASP) induction of bone marrow-derived mesenchymal stem cells (BMSCs) by irradiation and its role in osteogenic differentiation dysfunction. It was observed that irradiated BMSCs lost typical fibroblast-like morphology, exhibited suppressed viability and differentiation potential accompanied with senescence phenotypes, including an increase in senescence-associated β-galactosidase (SA-β-gal) staining-positive cells, and upregulated senescence-related genes p53/p21, whereas no changes happened to p16. Additionally, DNA damage γ-H2AX foci, G0/G1 phase of cell cycle arrest, and cellular and mitochondrial reactive oxygen species (ROS) increased in an irradiation dose-dependent manner. Meanwhile, the JAK1/STAT3 pathway was activated and accompanied by an increase in SASP secretion, such as IL-6, IL-8, and matrix metalloproteinase-9 (MMP9), whereas 0.8 μM JAK1 inhibitor (JAKi) treatment effectively inhibited the JAK pathway and SASP production. Furthermore, conditioned medium (CM) from irradiation-induced senescent (IRIS) BMSCs exhibited a markedly reduced ability in osteogenic differentiation and marker gene expression of osteoblasts, whereas CM with JAKi intervention may effectively improve these deterioration effects. In conclusion, irradiation could provoke BMSC senescence and SASP secretion and further aggravate osteogenic differentiation dysfunction via paracrine signaling, whereas SASP targeting may be a possible intervention strategy for alleviating irradiation-induced bone loss.

Our study aimed to investigate the prevalence and associated factors of sarcopenia in the disabled elderly in communities in Shanghai, China. A cross-sectional study was conducted in 2018. Five hundred and seventy two participants (≥60 years) were recruited through cluster sampling from Putuo District of Shanghai. Sarcopenia was defined according to the updated consensus of the European Sarcoma Working Group in 2019. The sarcopenia, depression, and nutrition status were assessed by using SARC-F, the Short Version of the Center for Epidemiological Studies Depression Scale (CES-D-10), and the Mini Nutritional Assessment-Short form (MNA-SF), respectively Physical activity was also assessed. Our results showed the prevalence of sarcopenia was 0.5%, but the prevalence of low handgrip strength was 37.2% (male, 5.5%; female, 39.1%). The modified Poisson regression model was used to evaluate the relationship among related variables and low handgrip strength. The risk for low handgrip strength was higher in the physically disabled subjects than in the visually disabled ones (aPR: 1.69, 95% CI: 1.88-2.42). Depressive symptoms (aPR: 1.31, 95% CI: 1.04-1.62) and PASE score (aPR: 0.99, 95% CI: 0.99-1.00) were independently associated with low handgrip strength. In summary, the prevalence of EWGSOP2-defined sarcopenia is low and the prevalence of declined muscle strength is high in the disabled elderly. The elderly participants with a physical disability had a higher prevalence of low hand handgrip strength than those with a visual disability. More studies with a larger sample size and longitudinal follow-up are needed to confirm our findings.

The original version of this article unfortunately contained a mistake.