Farnesoid X receptor agonist attenuates subchondral bone osteoclast fusion and osteochondral pathologies of osteoarthritis via suppressing JNK1/2/NFATc1 pathway.

Osteoarthritis (OA) is a prevalent degenerative disease of the joint, featured by articular cartilage destruction and subchondral bone marrow lesions. Articular cartilage and subchondral bone constitute an osteochondral unit that guarantees joint homeostasis. During OA initiation, activated osteoclasts in subchondral bone ultimately result in impaired capacities of the subchondral bone in response to mechanical stress, followed by the degradation of overlying articular cartilage. Thus, targeting osteoclasts could be a potential therapeutic option for treating OA. Here, we observed that farnesoid X receptor (FXR) expression and osteoclast fusion and activity in subchondral bone were concomitantly changed during early-stage OA in the OA mouse model established by anterior cruciate ligament transection (ACLT). Then, we explored the therapeutic effects of FXR agonist GW4064 on the osteochondral pathologies in ACLT mice. We showed that GW4064 obviously ameliorated subchondral bone deterioration, associated with reduction in tartrate-resistant acid phosphatase (TRAP) positive multinuclear osteoclast number, as well as articular cartilage degradation, which were blocked by the treatment with FXR antagonist Guggulsterone. Mechanistically, GW4064 impeded osteoclastogenesis through inhibiting subchondral bone osteoclast fusion via suppressing c-Jun N-terminal kinase (JNK) 1/2/nuclear factor of activated T-cells 1 (NFATc1) pathway. Taken together, our results present evidence for the protective effects of GW4064 against OA by blunting osteoclast-mediated aberrant subchondral bone loss and subsequent cartilage deterioration. Therefore, GW4064 demonstrates the potential as an alternative therapeutic option against OA for further drug development.

Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists.

Although several potent bile acid Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1) dual agonists such as INT-767 have been reported, no non-bile acid FXR/TGR5 dual agonist has been investigated to date. Therefore, we attempted to discover potent non-bile acid FXR/TGR5 dual agonists and identified some non-bile acid FXR/TGR5 dual agonists, such as isonicotinamide derivatives in vitro assay. Compound 20p was evaluated in C57BL/6J mice, that were administered a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) consisting of 60 kcal% fat and 0.1% methionine by weight for one week. Compound 20p dose-dependently induced small heterodimer partner (SHP) mRNA and decreased cytochrome P450 7A1 (CYP7A1) in the liver at 10 and 30 mg/kg, respectively, which were used as FXR agonist markers. Compound 20p significantly increased the plasma levels of GLP-1 as a TGR5 agonist, and a high concentration of GLP-1 lowered blood glucose levels. We confirmed that compound 20p was a non-bile acid FXR/TGR5 dual agonist.

Novel FXR agonist nelumal A suppresses colitis and inflammation-related colorectal carcinogenesis.

FXR is a member of the nuclear receptor superfamily and bile acids are endogenous ligands of FXR. FXR activation has recently been reported to inhibit intestinal inflammation and tumour development. This study aimed to investigate whether the novel FXR agonist nelumal A, the active compound of the plant Ligularia nelumbifolia, can prevent colitis and colorectal carcinogenesis. In a mouse colitis model, dextran sodium sulfate-induced colonic mucosal ulcer and the inflammation grade in the colon significantly reduced in mice fed diets containing nelumal A. In an azoxymethane/dextran sodium sulfate-induced mouse inflammation-related colorectal carcinogenesis model, the mice showed decreased incidence of colonic mucosal ulcers and adenocarcinomas in nelumal A-treated group. Administration of nelumal A also induced tight junctions, antioxidant enzymes, and FXR target gene expression in the intestine, while it decreased the gene expression of bile acid synthesis in the liver. These findings suggest that nelumal A effectively attenuates colonic inflammation and suppresses colitis-related carcinogenesis, presumably through reduction of bile acid synthesis and oxidative damage. This agent may be potentially useful for treatment of inflammatory bowel diseases as well as their related colorectal cancer chemoprevention.

The protective effect of obeticholic acid on lipopolysaccharide-induced disorder of maternal bile acid metabolism in pregnant mice.

The disorder of bile acid metabolism is a common feature during pregnancy, which leads to adverse birth outcomes and maternal damage effects. However, the cause and therapy about the disorder of bile acid metabolism are still poor. Microbial infection often occurs in pregnant women, which can induce the disorder of bile acid metabolism in adult mice. Here, this study observed the acute effect of lipopolysaccharide (LPS) on maternal bile acid of pregnant mice at gestational day 17 and the protective effect of obeticholic acid (OCA) pretreatment, a potent agonist of bile acid receptor farnesoid X receptor (FXR). The results showed LPS significantly increased the level of maternal serum and disordered bile acids components of maternal serum and liver, which were ameliorated by OCA pretreatment with obviously reducing the contents of CA, TCA, DCA, TCDCA, CDCA, GCA and TDCA in maternal serum and DCA, TCA, TDCA, TUDCA, CDCA and TCDCA in maternal liver. Furthermore, we investigated the effects of OCA on LPS-disrupted bile acid metabolism in maternal liver. LPS disrupted maternal bile acid profile by decreasing transport and metabolism with hepatic tight junctions of bile acid in pregnant mice. OCA obviously increased the protein level of nuclear FXR and regulated its target genes involving in the metabolism of bile acid, which was characterized by the lower expression of bile acid synthase CYP7A1, the higher expression of CYP3A and the higher mRNA level of transporter Mdr1a/b. This study provided the evidences that LPS disrupted bile acid metabolism in the late stage of pregnant mice and OCA pretreatment played the protective role on it by activating FXR.

Cold-inducible RNA binding protein agonist enhances the cardioprotective effect of UW solution during extended heart preservation.

In heart transplantation, time restriction is an unavoidable thorny problem during cardiac transport. Cold storage is an important organ preservation method in donor heart transport. Cold-inducible RNA binding protein (CIRBP) has been proven to play a protective role under cold stress. In this study, we investigated the role of CIRBP in hypothermic cardioprotection during heart preservation in UW solution and explored a new approach to extend the heart preservation time. Cirbp-knockout (Cirbp-/- ), Cirbp-transgenic (Cirbp-Tg), and wild-type rats were, respectively, randomized into two groups based on various heart preservation times (6 or 12-hour group) (n = 8 per group). After preservation in UW solution, all hearts were mounted on a Langendorff apparatus and underwent measurement of cardiac parameters, histological analysis, and molecular study. Within the 6-hour preservation group, no significant difference was found in cardiac functions and histological changes between different rat species. However, after 12 hours of preservation, Cirbp-/- rat hearts showed more apoptosis and worse cardiac function, but less apoptosis and better cardiac function were observed in Cirbp-Tg rat hearts. Furthermore, we found CIRBP-mediated cardiac ubiquinone (CoQ10 ) biosynthesis plays an important role in extending heart preservation, and ubiquinone biosynthesis protein COQ9 was an essential down-stream regulator during this process. Finally, we found that zr17-2, a CIRBP agonist, could enhance the expression of CIRBP, which further enhances the synthesis of CoQ10 and promotes scavenging of reactive oxygen species and ATP production to extend heart preservation. This study demonstrated that CIRBP-enhanced CoQ10 biosynthesis during hypothermic heart preservation and zr17-2-supplemented UW solution could be a promising approach to ameliorate heart damage and extend heart preservation during cardiac transport.

Obeticholic acid and INT-767 modulate collagen deposition in a NASH in vitro model.

Pharmacological treatments for non-alcoholic steatohepatitis (NASH) are still unsatisfactory. Fibrosis is the most significant predictor of mortality and many anti-fibrotic agents are under evaluation. Herein, we assessed in vitro the effects of the FXR agonist obeticholic acid (OCA) and the dual FXR/TGR5 agonist INT-767 in a well-established co-culture NASH model. Co-cultures of human hepatoma and hepatic stellate (HSCs) cells were exposed to free fatty acids (FFAs) alone or in combination with OCA or INT-767. mRNA expression of HSCs activation markers and FXR engagement were evaluated at 24, 96 and 144 hours. Collagen deposition and metalloproteinase 2 and 9 (MMP2-9) activity were compared to tropifexor and selonsertib. FFAs induced collagen deposition and MMP2-9 activity reduction. Co-treatment with OCA or INT-767 did not affect ACTA2 and COL1A1 expression, but significantly reduced FXR and induced SHP expression, as expected. OCA induced a dose-dependent reduction of collagen and induced MMP2-9 activity. Similarly, INT-767 induced collagen reduction at 96 h and a slight increase in MMP2-9. Tropifexor and Selonsertib were also effective in collagen reduction but showed no modulation of MMP2-9. All tested compounds reduced collagen deposition. OCA exerted a more potent and long-lasting effect, mainly related to modulation of collagen turn-over and MMP2-9 activity.

ß-aminoisobutyric acid protects against vascular inflammation through PGC-1ß-induced antioxidative properties.

BACKGROUD: Among various myocyte-derived bioactive molecules (myokines), ß-aminoisobutyric acid (BAIBA) is a unique myokine that attenuates skeletal muscle insulin resistance and inflammation, increases browning of white adipose tissue, and enhances hepatic fatty acid oxidation, resulting in upregulated energy expenditure of the whole body. In the present study, we investigated the effects of BAIBA on the vascular endothelial cell function. METHODS: The mRNA levels of proinflammatory molecules, antioxidants, and their related transcription regulators were examined by quantitative RT-PCR in BAIBA-treated human aortic or umbilical vein endothelial cells (HAEC or HUVEC, respectively), with or without tumor necrosis factor (TNF)-α stimulation. The protein expression and phosphorylation of AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) were determined by Western blot analysis. RESULTS: BAIBA pretreatment significantly suppressed the mRNA levels of the adhesion molecules in the TNF-α-stimulated HAEC and HUVEC. BAIBA treatment significantly increased the mRNA levels of antioxidant molecules, catalase, superoxide dismutases, thioredoxin, and gamma-glutamylcysteine ligases, together with mitochondrial biogenesis-related molecules, nuclear respiratory factor 1, and mitochondrial transcription factor A. In addition, BAIBA treatment significantly increased the transcription factors that regulated these genes [i.e., peroxisome proliferator-activated receptor (PPAR)-δ, PPAR-γ, estrogen-related receptor α (ERRα), and peroxisome proliferator-activated receptor gamma coactivator (PGC)-1ß]. Adenovirus-mediated PGC-1ß overexpression significantly increased the mRNA levels of all antioxidant molecules. The phosphorylation levels of AMPK and eNOS were unaltered by BAIBA. CONCLUSIONS: In vascular endothelial cells, BAIBA had antiatherogenic effects through the PGC-1ß-ERRα/PPAR-δ and PPAR-γ pathway. This can explain the beneficial effects of exercise on vascular endothelial function.

The Mechanism of CIRP in Regulation of STAT3 Phosphorylation and Bag-1/S Expression Upon UVB Radiation.

Cold-inducible RNA binding protein (CIRP) is a stress-inducible protein, which could be activated by various cellular stresses, such as hypothermia, hypoxia and UV irradiation. Our previous study indicated that UVB radiation (3 mJ cm-2 ) induces CIRP expression, which promotes keratinocytes growth, survival and eventually transformation via activation of STAT3-Bag-1/S signaling cascade. However, the mechanism(s) of CIRP in regulating p-STAT3 activation and Bag-1/S expression have not been fully elucidated. In this study, we demonstrate that repeated exposure of UVB radiation (3 mJ cm-2 ) or overexpression of CIRP could lead to an elevation of the phosphorylation of Janus kinase (JAK) family proteins (JAK2 and JAK3) in HaCaT cells. The increased phosphorylation of the JAKs correlates to an increased phosphorylation of STAT3 (p-STAT3) in the cells; inhibiting JAKs using JAK inhibitor I lead to a reduction of STAT3 phosphorylation and Bag-1/S expression in wild type HaCaT and CIRP stably transfected HaCaT cells with or without UVB exposure. Furthermore, our data indicated that inhibiting the downstream factor of CIRP, NF-κB, using BAY 11-7085 could also decrease the p-STAT3. These results lead us to propose that CIRP mediates the activation of STAT3-Bag-1/S signaling cascade via activating the JAKs and NF-κB signaling pathways.

Regulation of Luteinizing Hormone Receptor mRNA Expression in the Ovary: The Role of miR-122.

The expression of luteinizing hormone receptor (LHR) in the mammalian ovary is regulated in response to changes in the secretion of follicle-stimulating hormone and luteinizing hormone by the anterior pituitary, at least in part, through posttranscriptional mechanisms. The steady-state levels of LHR mRNA are maintained by controlling its rate of degradation by an RNA-binding protein designated as LHR mRNA-binding protein (LRBP). LRBP forms a complex with LHR mRNA and targets it for degradation in the p bodies. miR-122, an 18 nucleotide noncoding RNA, regulates the expression of LRBP. Thus, the levels of miR-122 determine the cellular levels of LHR mRNA expression. This phenomenon has been examined during the induction of LHR mRNA expression that occurs during follicle maturation in response to rising levels of FSH. In this situation, miR-122 and LRBP levels decrease as LHR mRNA expression undergoes downregulation in response to preovulatory LH surge. miR-122 expression as well as LRBP levels show robust increases. The mechanism of induction of LRBP by miR-122 has also been discussed.

Post-transcriptional regulation of ERBB2 by miR26a/b and HuR confers resistance to tamoxifen in estrogen receptor-positive breast cancer cells.

Tamoxifen-resistant (TAMR) estrogen receptor-positive (ER+) breast cancer is characterized by elevated Erb-B2 receptor tyrosine kinase 2 (ERBB2) expression. However, the underlying mechanisms responsible for the increased ERBB2 expression in the TAMR cells remain poorly understood. Herein, we reported that the ERBB2 expression is regulated at the post-transcriptional level by miR26a/b and the RNA-binding protein human antigen R (HuR), both of which associate with the 3'-UTR of the ERBB2 transcripts. We demonstrated that miR26a/b inhibits the translation of ERBB2 mRNA, whereas HuR enhances the stability of the ERBB2 mRNA. In TAMR ER+ breast cancer cells with elevated ERBB2 expression, we observed a decrease in the level of miR26a/b and an increase in the level of HuR. The forced expression of miR26a/b or the depletion of HuR decreased ERBB2 expression in the TAMR cells, resulting in the reversal of tamoxifen resistance. In contrast, the inactivation of miR26a/b or forced expression of HuR decreased tamoxifen responsiveness of the parental ER+ breast cancer cells. We further showed that the increase in HuR expression in the TAMR ER+ breast cancer cells is attributable to an increase in the HuR mRNA isoform with shortened 3'-UTR, which exhibits increased translational activity. This shortening of the HuR mRNA 3'-UTR via alternative polyadenylation (APA) was observed to be dependent on cleavage stimulation factor subunit 2 (CSTF2/CstF-64), which is up-regulated in the TAMR breast cancer cells. Taken together, we have characterized a model in which the interplay between miR26a/b and HuR post-transcriptionally up-regulates ERBB2 expression in TAMR ER+ breast cancer cells.

Induction of farnesoid X receptor signaling in germ-free mice colonized with a human microbiota.

The gut microbiota influences the development and progression of metabolic diseases partly by metabolism of bile acids (BAs) and modified signaling through the farnesoid X receptor (FXR). In this study, we aimed to determine how the human gut microbiota metabolizes murine BAs and affects FXR signaling in colonized mice. We colonized germ-free mice with cecal content from a mouse donor or feces from a human donor and euthanized the mice after short-term (2 weeks) or long-term (15 weeks) colonization. We analyzed the gut microbiota and BA composition and expression of FXR target genes in ileum and liver. We found that cecal microbiota composition differed between mice colonized with mouse and human microbiota and was stable over time. Human and mouse microbiota reduced total BA levels similarly, but the humanized mice produced less secondary BAs. The human microbiota was able to reduce the levels of tauro-ß-muricholic acid and induce expression of FXR target genes Fgf15 and Shp in ileum after long-term colonization. We show that a human microbiota can change BA composition and induce FXR signaling in colonized mice, but the levels of secondary BAs produced are lower than in mice colonized with a mouse microbiota.

Splicing factor transformer-2ß (Tra2ß) regulates the expression of regulator of G protein signaling 4 (RGS4) gene and is induced by morphine.

Regulator of G protein signaling 4 (RGS4) is a critical modulator of G protein-coupled receptor (GPCR)-mediated signaling and plays important roles in many neural process and diseases. Particularly, drug-induced alteration in RGS4 protein levels is associated with acute and chronic effects of drugs of abuse. However, the precise mechanism underlying the regulation of RGS4 expression is largely unknown. Here, we demonstrated that the expression of RGS4 gene was subject to regulation by alternative splicing of the exon 6. Transformer-2ß (Tra2ß), an important splicing factor, bound to RGS4 mRNA and increased the relative level of RGS4-1 mRNA isoform by enhancing the inclusion of exon 6. Meanwhile, Tra2ß increased the expression of full-length RGS4 protein. In rat brain, Tra2ß was co-localized with RGS4 in multiple opioid action-related brain regions. In addition, the acute and chronic morphine treatment induced alteration in the expression level of Tra2ß in rat locus coerulus (LC) in parallel to that of RGS4 proteins. It suggests that induction of this splicing factor may contribute to the change of RGS4 level elicited by morphine. Taken together, the results provide the evidence demonstrating the function of Tra2ß as a new mediator in opioid-induced signaling pathway via regulating RGS4 expression.

Activation of the nuclear receptor FXR enhances hepatocyte chemoprotection and liver tumor chemoresistance against genotoxic compounds.

The success of pharmacological treatments in primary liver cancers is limited by the marked efficacy of mechanisms of chemoresistance already present in hepatocytes. The role of the nuclear receptor FXR is unclear. Although, in non-treated liver tumors, its expression is reduced, the refractoriness to anticancer drugs is high. Moreover, the treatment with cisplatin up-regulates FXR. The aim of this study was to investigate whether FXR is involved in stimulating chemoprotection/chemoresistance in healthy and tumor liver cells. In human hepatocytes, the activation of FXR with the agonist GW4064 resulted in a significant protection against cisplatin-induced toxicity. In human hepatoma Alexander cells, with negligible endogenous expression of FXR, GW4064 also protected against cisplatin-induced toxicity, but only if they were previously transfected with FXR/RXR. Investigation of 109 genes potentially involved in chemoresistance revealed that only ABCB4, TCEA2, CCL14, CCL15 and KRT13 were up-regulated by FXR activation both in human hepatocytes and FXR/RXR-expressing hepatoma cells. In both models, cisplatin, even in the absence of FXR agonists, such as bile acids and GW4064, was able to up-regulate FXR targets genes, which was due to FXR-mediated trans-activation of response elements in the promoter region. FXR-dependent chemoprotection was also efficient against other DNA-damaging compounds, such as doxorubicin, mitomycin C and potassium dichromate, but not against non-genotoxic drugs, such as colchicine, paclitaxel, acetaminophen, artesunate and sorafenib. In conclusion, ligand-dependent and independent activation of FXR stimulates mechanisms able to enhance the chemoprotection of hepatocytes against genotoxic compounds and to reduce the response of liver tumor cells to certain pharmacological treatments.

Inhibitory effects of bile acids and synthetic farnesoid X receptor agonists on rotavirus replication.

Rotaviruses (group A rotaviruses) are the most important cause of severe gastroenteritis in infants and children worldwide. Currently, an antiviral drug is not available and information on therapeutic targets for antiviral development is limited for rotavirus infection. Previously, it was shown that lipid homeostasis is important in rotavirus replication. Since farnesoid X receptor (FXR) and its natural ligands bile acids (such as chenodeoxycholic acid [CDCA]) play major roles in cholesterol and lipid homeostasis, we examined the effects of bile acids and synthetic FXR agonists on rotavirus replication in association with cellular lipid levels. In a mouse model of rotavirus infection, effects of oral administration of CDCA on fecal rotavirus shedding were investigated. The results demonstrate the following. First, the intracellular contents of triglycerides were significantly increased by rotavirus infection. Second, CDCA, deoxycholic acid (DCA), and other synthetic FXR agonists, such as GW4064, significantly reduced rotavirus replication in cell culture in a dose-dependent manner. The reduction of virus replication correlated positively with activation of the FXR pathway and reduction of cellular triglyceride contents (r(2) = 0.95). Third, oral administration of CDCA significantly reduced fecal virus shedding in mice (P < 0.05). We conclude that bile acids and FXR agonists play important roles in the suppression of rotavirus replication. The inhibition mechanism is proposed to be the downregulation of lipid synthesis induced by rotavirus infection.

Discovery and characterization of potent and selective 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acids as S1P1 agonists.

S1P(1) receptor driven lymphopenia has proven utility in the treatment of an array of autoimmune disease states. As a part of our efforts to develop potent and selective S1P(1) receptor agonists, we have identified a novel chemical series of 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acid S1P(1) receptor agonists.

Transcriptional activation of apolipoprotein CIII expression by glucose may contribute to diabetic dyslipidemia.

OBJECTIVE: Hypertriglyceridemia and fatty liver are common in patients with type 2 diabetes, but the factors connecting alterations in glucose metabolism with plasma and liver lipid metabolism remain unclear. Apolipoprotein CIII (apoCIII), a regulator of hepatic and plasma triglyceride metabolism, is elevated in type 2 diabetes. In this study, we analyzed whether apoCIII is affected by altered glucose metabolism. METHODS AND RESULTS: Liver-specific insulin receptor-deficient mice display lower hepatic apoCIII mRNA levels than controls, suggesting that factors other than insulin regulate apoCIII in vivo. Glucose induces apoCIII transcription in primary rat hepatocytes and immortalized human hepatocytes via a mechanism involving the transcription factors carbohydrate response element-binding protein and hepatocyte nuclear factor-4α. ApoCIII induction by glucose is blunted by treatment with agonists of farnesoid X receptor and peroxisome proliferator-activated receptor-α but not liver X receptor, ie, nuclear receptors controlling triglyceride metabolism. Moreover, in obese humans, plasma apoCIII protein correlates more closely with plasma fasting glucose and glucose excursion after oral glucose load than with insulin. CONCLUSIONS: Glucose induces apoCIII transcription, which may represent a mechanism linking hyperglycemia, hypertriglyceridemia, and cardiovascular disease in type 2 diabetes.

S1P(1) receptor agonists: Assessment of selectivity and current clinical activity.

Interest in sphingosine-1-phosphate (S1P)(1) receptor agonists has increased steadily since the discovery that the mechanism of action of fingolimod (FTY-720)-induced lymphopenia is linked to the S1P GPCR family. Fingolimod is an agonist at four out of the five S1P family receptors. Adoptive cell transfer experiments and selective S1P(1) receptor agonists provided evidence that the S1P(1) receptor is the main target responsible for trapping lymphocytes in secondary lymphoid tissue. This readily accessible, translatable biomarker has been correlated with efficacy in rodent models of immune disease. Novartis AG filed for regulatory approval for fingolimod in the US and EU for the treatment of multiple sclerosis in December 2009. In addition, more selective compounds targeting S1P receptors from several companies have entered clinical trials. These compounds can be categorized into two classes of S1P(1) receptor agonists: amino alcohol prodrugs and second-generation direct agonists. This review focuses on the development of these compounds and the role of S1P receptor family selectivity.

Acetyl-L-carnitine supplementation to old rats partially reverts the age-related mitochondrial decay of soleus muscle by activating peroxisome proliferator-activated receptor gamma coactivator-1alpha-dependent mitochondrial biogenesis.

The age-related decay of mitochondrial function is a major contributor to the aging process. We tested the effects of 2-month-daily acetyl-L-carnitine (ALCAR) supplementation on mitochondrial biogenesis in the soleus muscle of aged rats. This muscle is heavily dependent on oxidative metabolism. Mitochondrial (mt) DNA content, citrate synthase activity, transcript levels of some nuclear- and mitochondrial-coded genes (cytochrome c oxidase subunit IV [COX-IV], 16S rRNA, COX-I) and of some factors involved in the mitochondrial biogenesis signaling pathway (peroxisome proliferator-activated receptor gamma [PPARgamma] coactivator-1alpha [PGC-1alpha], mitochondrial transcription factor A mitochondrial [TFAM], mitochondrial transcription factor 2B [TFB2]), as well as the protein content of PGC-1alpha were determined. The results suggest that the ALCAR treatment in old rats activates PGC-1alpha-dependent mitochondrial biogenesis, thus partially reverting the age-related mitochondrial decay.

Challenges and opportunities in clinical trials for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is the most common fatal neuromuscular disease of infancy. SMA type I is the most severe and mortality is usually due to respiratory failure. In type II the disability is of later onset and less severe, and prognosis has improved primarily due to supportive care. Type III is the mildest form with onset usually of weakness in adolescence or young adulthood. SMA is an autosomal recessive disorder with deletions or mutations of the gene at the 5 q11 locus. There is no specific prevention or treatment, but current progress toward potential therapies has been substantial and several candidates including histone deacetylase (HDAC) inhibitors are under consideration for further evaluation. The authors sought to address the challenges and opportunities for testing new therapies for SMA.