SIRT1 regulates osteoblast senescence through SOD2 acetylation and mitochondrial dysfunction in the progression of Osteoporosis caused by Cadmium exposure.

Environmental Cadmium (Cd) is a toxicant with widespread exposure, documented adverse effects on bone homeostasis, and makes the onset of osteoporosis (OP), one of the age-related chronic diseases an enormous burden to modern societies worldwide. Aging is the largest risk factor for a multitude of age-related diseases and osteoblasts senescence reduces bone formation and is a key factor for osteoporosis. Despite anti-aging molecules the nuclear silent information regulator of transcription 1 (SIRT1) actions in chondrocytes and bone cells are critical for normal skeletal development and homeostasis, much less is known about the role of SIRT1 in osteoporosis. Here, we aim to demonstrate that SIRT1 mediates osteoblasts' senescence response to OP caused by Cd. The senescent osteoblasts accumulation and their viability were analyzed after Cd exposure. To explore the effects and mechanism of SIRT1 in Cd-induced osteoblastic senescence, we generated SIRT1-overexpressed osteoblast and SIRT1 conditional overexpression in the rat femur. Meanwhile, the OP rat model was established by removing bilateral ovaries. We found decreased SIRT1 expression and senescent osteoblasts accumulation after Cd exposure. Meanwhile, Cd exposure increased P53, P16INK4a, and P21CIPI proteins level, triggered DNA damage response (DDR) through the phosphorylation of ATM and H2AX, and caused mitochondrial dysfunction by the increased acetylation of SOD2 and excessive mitophagy. SIRT1 overexpression attenuated DDR and mitochondrial dysfunction and downregulated the increase of hall makers senescence caused by Cd in osteoblasts. We found overexpression of osteoblastic SIRT1 protects against Cd-induced senescence, which is likely driven by ATM-mediated DDR and SOD2ace-mediated mitochondrial dysfunction. Our study demonstrates the mechanism of SIRT1 in mediating bone homeostasis via senescence. Further mechanistic studies using specific SIRT1 mutations elucidating how SIRT1 modulates bone cell senescence, will provide new therapeutic strategies for human osteoporosis.

Reactive Oxygen Species Control Osteoblast Apoptosis through SIRT1/PGC-1α/P53Lys382 Signaling, Mediating the Onset of Cd-Induced Osteoporosis.

The imbalance between osteogenesis and osteoclastogenesis is a feature of bone metabolic disease. Cadmium (Cd) exposure causes human bone loss and osteoporosis (OP) through bioaccumulation of the food chain. However, the impact of Cd on bone tissues and the underlying molecular mechanisms are not well-characterized. In the current study, we found that the Cd concentration in bone tissues of OP patients was higher than normal subjects; meanwhile, the nuclear silent information regulator of transcription 1 (SIRT1) protein expression level was significantly decreased, which is a new star molecule to treat OP. It is further revealed that SIRT1 activation markedly reprograms bone metabolic and stress-response pathways that incline with osteoblast (OB) apoptosis. Suppressing reactive oxygen species (ROS) release with N-acetyl-l-cysteine (NAC) abolished Cd-induced reduction of SIRT1 protein, deacetylation of P53, OB apoptosis, and attenuated OP. Conversely, overexpression of SIRT1 suppressed Cd-induced ROS release. SIRT1 overexpression in vivo and in vitro dampened PGC-1α protein, acetylation of P53 at lysine 382, and caspase-dependent apoptosis. These results reveal that ROS/SIRT1 controls P53 acetylation and coordinates OB apoptosis involved in the onset of OP.

An unexpected visitor and a sword play: a randomized controlled trial of collective narrative therapy groups for primary carers of people with schizophrenia.

BACKGROUND: Most family carer support programs focus on supporting carers with caregiving-related knowledge and skills to help their family members who suffer from schizophrenia in their recovery process while carers' inner resources and preferred identities are less emphasized in the existing studies. AIMS: The present study uses collective narrative therapy groups (CNTG) to promote the inner strengths and agency of family carers and help them to explore their preferred identities while caring for family members with schizophrenia. METHOD: To ensure an evidence-based intervention, 89 Chinese family carers of people with schizophrenia took part in this three-wave longitudinal program evaluation study using a randomized controlled trial design. RESULTS: Compared with the control group, family carers in CNTG reported better family relationships, a lesser caregiving burden, and more perceived inner resources. Repeated one-way ANOVA revealed that CNTG improved family relationships, the caregiving burden, the level of hope and inner resources in the posttest, and a statistically significantly better mental health condition in the follow-up. CONCLUSION: This study shows that collective narrative psychotherapy is effective in supporting family carers of people with schizophrenia in Hong Kong. Based on the research findings, we discuss the strengths of the program and its implications for practitioners.

Outside-in or Inside-out? A Randomized Controlled Trial of Two Empowerment Approaches for Family Caregivers of People with Schizophrenia.

Training-based intervention such as psychoeducational groups has become increasingly popular to empower family caregivers of people with schizophrenia, yet existing supportive programs for caregivers tend to focus more on the needs of the patients rather than the development of the caregivers. This study aimed to compare the outcomes of a skill-based empowerment psychoeducational group and an inner-resource enhancing empowerment narrative therapy group for family caregivers of people with schizophrenia. We conducted a randomized controlled trial with a longitudinal design. The sample consisted of 132 family caregivers who were randomly assigned to eight sessions of the two groups (i.e. a narrative-based group, or a psychoeducational group), or a control group with delayed treatment. Psychometric scales were administrated throughout the project. Both the psychoeducational group and the narrative group showed significant improvements in family relationships, caregiving burden, and coping skills compared with the control group across the three time points (pretest, posttest, and 2-month follow-up). A statistically significant advancement in coping skills was found in the psychoeducational group. The narrative group outperformed the psychoeducational group and the control group in the enhancement of inner resources, perceived control, and level of hope. The findings call for the need of an integrative empowerment approach that both values the inner strength and unique experiences of the caregivers and at the same time provides them with necessary skills and knowledge in taking care of their family members with schizophrenia.

Can We Hit Two Birds with One Stone: An Effectiveness Study of Peer-support Groups for Low-income Spousal and Adult Children Caregivers of Hong Kong Older Adults.

This study aims to assess the effectiveness of peer support groups for low-income older adults' caregivers in the Hong Kong community. It compares the effectiveness of peer support groups on spouse and adult children caregivers. The peer support program was structured into three stages, including six training sessions for peer specialists, eight caregiver support group sessions, and non-structured informal contact. The study adopted a quasi-experiment design supplemented with qualitative data collected from focused group interviews. It involved a user group of 58 participants and a control group of 42 participants. Both quantitative and qualitative data were collected before, after the peer support groups, and at a three-month follow-up. The quantitative results showed that the peer support program was more effective in promoting social support for adult children caregivers but not for spousal caregivers. Three focus group interviews suggested that the community-based peer-support group could be helpful to improve stress management, emotional regulation skills, and social networks of the caregivers. Based on the research findings, we discuss the various needs of spousal and adult children caregivers, provide recommendations for service providers and practitioners to consider homogenous group services to address the diverse needs of spousal and adult children caregivers.

Heterogeneous chromosome 12p deletion is an independent adverse prognostic factor and resistant to bortezomib-based therapy in multiple myeloma.

The deletion of 12p (del(12p)) has been described as a novel negative prognostic marker in multiple myeloma (MM) and has gained increasing attention in recent years. However, its impact on MM is still controversial. In this study, we comprehensively evaluated the clinical impact of 12p13 deletion using fluorescence in situ hybridization (FISH) on 275 newly diagnosed MM cases treated in a prospective, non-randomized clinical trial (BDH 2008/02). The results showed that deletion of 12p13 was detected in 10.5% of newly diagnosed cases and associated with multiple indicators for high tumor burden including ISS III, BM plasmacytosis larger than 50%, and renal lesion. Moreover, the cases with 12p13 deletion typically had higher incidence of del(17p), IGH translocation and t(4;14). Patients with del(12p) conferred significantly adverse prognosis for PFS and OS, even in patients subjected to bortezomib-based therapy. When adjusted to the established prognostic variables including del(13q), del(17p), t(4;14), amp(1q21), ISS stage and LDH, del(12p13) remained the powerful independent adverse factor for PFS (P = 0.007) and OS (P = 0.032). In addition, del(12p13) combined with high ß2-MG, high LDH and bone lesion can further identify subpopulations with high-risk features. Our results strongly supported that del(12p13) can be used as a valuable prognostic marker in MM.

[Prognostic value of serum IL-6 in patients with multiple myeloma].

This study was aimed to evaluate the prognostic value of serum IL-6 (sIL-6) in patients with multiple myeloma (MM). The sIL-6 level in 288 patients with MM was retrospectively analyzed, and the clinical characteristics and prognosis in patients with different IL-6 level were compared. The newly diagnosed patients with MM were divided into two groups: the low sIL-6 group (sIL-6 < 100 pg/ml) and the high sIL-6 group (sIL-6 ≥ 100 pg/ml). The results showed that high sIL-6 level was more common in patients with ECOG score>3, myeloma bone disease (MBD) between grade 2 to 4, and high creatinine level. There was no significant differences in age, abnormal karyotype percentage, chromosome 13q14 abnormality percentage, CD138(+)/CD38(+) cells percentage and the level of calcium, phosphorus, albumin, C-reactive protein, ß2-MG, lactate dehydrogenase, hemoglobin, platelet between the two groups at diagnosis, and also no significant difference in response to initial induction chemotherapy among the two groups. The overall survival was significantly different between the low and high IL-6 groups (P = 0.04, 35 m vs 29 m), but no difference in time to progress between the two groups (P = 1.93, 23 m vs 14 m). It is concluded that the sIL-6 level correlates with the clinical characteristics and prognosis. Radioimmunoassay is an appropriate measurement for human IL-6 in serum, and suitable for clinical application.