Search

Livedoid vasculopathy is a chronic, recurrent skin disorder. It seriously affects the quality of patients’ life. However, the pathogenesis has not been fully identified yet. Here, this retrospective study describes the successful use of anti-TNF-α agent adalimumab in three cases of refractory livedoid vasculopathy, which has not been reported previously. In addition, we provide some clinical evidence that adalimumab therapy is efficient in improving skin lesions and relieving the pain of livedoid vasculopathy.

Abstract Background TGF-β resistance often develops in breast cancer cells that in turn overproduce this cytokine to create a local immunosuppressive environment that fosters tumor growth and exacerbates the invasive and metastatic behavior of the tumor cells themselves. Smads-mediated cross-talk with the estrogen receptor has been implied to play an important role in development and/or progression of breast cancer. We investigated how TGF-β regulates ERα-induced gene transcription and potential mechanisms of frequent TGF-β resistance in breast cancer. Methods Effect of TGF-β on ERα-mediated gene transcription was investigated in breast cancer cell lines using transient transfection, real-time PCR, sequential DNA precipitation, and small interfering RNA assays. The expression of Smads on both human breast cancer cell lines and ERα-positive human breast cancer tissue was evaluated by immunofluorescence and immunohistochemical assays. Results A complex of Smad3/4 mediates TGF-β inhibition of ERα-mediated estrogenic activity of gene transcription in breast cancer cells, and Smad4 is essential and sufficient for such repression. Either overexpression of Smad3 or inhibition of Smad4 leads to the "switch" of TGF-β from a repressor to an activator. Down-regulation and abnormal cellular distribution of Smad4 were associated with some ERα-positive infiltrating human breast carcinoma. There appears a dynamic change of Smad4 expression from benign breast ductal tissue to infiltrating ductal carcinoma. Conclusion These results suggest that aberrant expression of Smad4 or disruption of Smad4 activity lead to the loss of TGF-β suppression of ERα transactivity in breast cancer cells.

Evidence links osteoporosis and cardiovascular disease but the cellular and molecular mechanisms are unclear. Here we identify skeleton-secreted platelet-derived growth factor-BB (PDGF-BB) as a key mediator of arterial stiffening in response to aging and metabolic stress. Aged mice and those fed high-fat diet (HFD), relative to young mice and those fed normal chow food diet, respectively, had higher serum PDGF-BB and developed bone loss and arterial stiffening. Bone/bone marrow preosteoclasts in aged mice and HFD mice secrete an excessive amount of PDGF-BB, contributing to the elevated PDGF-BB in blood circulation. Conditioned medium prepared from preosteoclasts stimulated proliferation and migration of the vascular smooth muscle cells. Conditional transgenic mice, in which PDGF-BB is overexpressed in preosteoclasts, had 3-fold higher serum PDGF-BB concentration and developed simultaneous bone loss and arterial stiffening spontaneously at a young age. Conversely, in conditional knockout mice, in which PDGF-BB is deleted selectively in preosteoclasts, HFD did not affect serum PDGF-BB concentration; as a result, HFD-induced bone loss and arterial stiffening were attenuated. These studies confirm that preosteoclasts are a main source of excessive PDGF-BB in blood circulation during aging and metabolic stress and establish the role of skeleton-derived PDGF-BB as an important mediator of vascular stiffening., Introduction Accumulating evidence supports a link between bone metabolism and the vascular system. Cross-sectional and longitudinal studies have shown a direct association between osteoporosis and cardiovascular disease (CVD) (1-5), 2 [...]

Microgravity is the primary factor that affects human physiology in spaceflight, particularly bone loss and disturbances of the central nervous system. However, little is known about the cellular and molecular mechanisms of these effects. Here, it is reported that in mice hindlimb unloading stimulates expression of neuropeptide Y (NPY) and tyrosine hydroxylase (TH) in the hypothalamus, resulting in bone loss and altered fat metabolism. Enhanced expression of TH and NPY in the hypothalamus occurs downstream of a reduced prostaglandin E2 (PGE2)‐mediated ascending interoceptive signaling of the skeletal interoception. Sympathetic antagonist propranolol or deletion of Adrb2 in osteocytes rescue bone loss in the unloading model. Moreover, depletion of TH+ sympathetic nerves or inhibition of norepinephrine release ameliorated bone resorption. Stereotactic inhibition of NPY expression in the hypothalamic neurons reduces the food intake with altered energy expenditure with a limited effect on bone, indicating hypothalamic neuroendocrine factor NPY in the facilitation of bone formation by sympathetic TH activity. These findings suggest that reduced PGE2‐mediated interoceptive signaling in response to microgravity or unloading has impacts on the skeletal and central nervous systems that are reciprocally regulated. [ABSTRACT FROM AUTHOR]

Enthesopathy is a disorder of bone, tendon, or ligament insertion. It represents one-fourth of all tendon-ligament diseases and is one of the most difficult tendon-ligament disorders to treat. Despite its high prevalence, the exact pathogenesis of this condition remains unknown. Here, we show that TGF-[beta] was activated in both a semi-Achilles tendon transection (SMTS) mouse model and in a dorsiflexion immobilization (DI) mouse model of enthesopathy. High concentrations of active TGF-[beta] recruited mesenchymal stromal stem cells (MSCs) and led to excessive vessel formation, bone deterioration, and fibrocartilage calcification. Transgenic expression of active TGF-[beta]1 in bone also induced enthesopathy with a phenotype similar to that observed in SMTS and DI mice. Systemic inhibition of TGF-[beta] activity by injection of 1D11, a TGF-[beta]-neutralizing antibody, but not a vehicle antibody, attenuated the excessive vessel formation and restored uncoupled bone remodeling in SMTS mice. 1D11-treated SMTS fibrocartilage had increased proteoglycan and decreased collagen X and matrix metalloproteinase 13 expression relative to control antibody treatment. Notably, inducible knockout of the TGF-[beta] type II receptor in mouse MSCs preserved the bone microarchitecture and fibrocartilage composition after SMTS relative to the WT littermate controls. Thus, elevated levels of active TGF-[beta] in the enthesis bone marrow induce the initial pathological changes of enthesopathy, indicating that TGF-[beta] inhibition could be a potential therapeutic strategy., Introduction The connection of muscles/bones to bones via tendons or ligaments is vital for movement. The entheses, the insertion sites of tendons or ligaments to bones, are essential for a [...]

The aim of this study was to investigate the impact of heat stress on physiological features, together with endogenous hormones and the transcription level of related genes, to estimate the heat resistance ability and stress injury mechanism of different dwarfing apple rootstocks. Among the six rootstocks, the rootstocks of native Shao series (SH series) showed better heat stress resistance than those of Budagovski 9 (B9), Cornell-Geneva 24 (CG24), and Malling 26 (M26) from abroad. Among SH series rootstocks, SH1 and SH6 showed higher heat stress resistance than SH40. M26 demonstrated the lowest adaption ability to heat stress, showing higher leaf conductivity and lower liquid water content (LWC) with the increase in temperature. Heat stress also resulted in the suppression of photosynthesis, which showed no significant restoration after 7-day recovery. It should be noted that although a higher temperature led to a lower LWC and photosynthetic efficiency (Pn) of CG24, there was no significant increase in leaf conductivity, and 7 days after the treatment, the Pn of CG24 recovered. The extremely high temperature tolerance of SH series rootstocks could be related to the greater osmotic adjustment (OA), which was reflected by smaller reductions in leaf relative water content (RWC) and higher turgor potentials and leaf gas exchange compared with the other rootstocks. Determination of hormones indicated multivariate regulation, and it is presumed that a relatively stable expression levels of functional genes under high-temperature stress is necessary for heat stress resistance of rootstocks.