Stat3 is a vital transcription factor that is activated downstream of the gp130 receptor, primarily via IL-6 signaling in adult liver. A new study demonstrates that Stat3 provides hepatoprotection ...against Fas-mediated apoptotic liver damage by two mechanisms: direct inactivation of caspases and reduction of reactive oxygen species.
Atherosclerosis is the primary cause of heart disease and stroke and is thus the underlying pathology of the leading causes of death in the western world. Although risk can be reduced by lowering ...lipid levels, the equally important contribution of inflammation to the development of cardiovascular disease is not adequately addressed by existing therapies. Here, we summarize the evidence supporting a role for inflammation in the pathogenesis of atherosclerosis, discuss agents that are currently in the clinic and provide a perspective on the challenges faced in the development of drugs that target vascular inflammation.
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with adverse clinical outcomes and impaired health-related quality of life (HRQL).
Patients with biopsy-proven non-cirrhotic ...NASH with hepatic fat fraction of ≥10% by magnetic resonance imaging-proton density fat fraction were enrolled in a phase 2, multicenter, double-blind, randomized, placebo-controlled study of resmetirom. HRQL was assessed using Short Form-36 throughout 36 weeks of treatment.
One hundred twenty-five NASH patients were enrolled (50 ± 11 years old, 50% male, 94% white, body mass index 35 ± 6 kg/m
, 39% with diabetes mellitus). Of these, 84 patients received 80 mg of resmetirom daily, and 41 received placebo. At baseline, HRQL scores were not different from general population norms (Physical Component Summary PCS 47.9 ± 9.3 vs 50, Mental Component Summary 50.4 ± 10.0 vs 50; all P > .05). By treatment week 12, patients who received resmetirom experienced improvement of Bodily Pain and Short Form-6D utility scores (P < .05); no HRQL improvement was noted in placebo (all P > .05). Improvement in PCS continued up to week 36 of treatment with resmetirom, again with no improvement in placebo group (all P > .05). Adjusted for the baseline score and clinicodemographic confounders, meeting the endpoint of a decrease in proton density fat fraction of ≥30% by week 12 (met by 54 of 116 treatment completers; 47 of 54 on resmetirom) was independently associated with greater improvements in Physical Functioning and PCS scores at week 36 (P < .05). Patients with improvement in NASH and fibrosis on liver biopsy also showed improvement in components of HRQL.
Patients with NASH treated who improved their hepatic fat fraction and/or Nonalcoholic Fatty Liver Disease Activity Score on serial liver biopsy experienced improvement of HRQL. Further studies are needed to confirm long-term sustainability of that improvement.
gov #NCT02912260.
An estimated 1.4 million persons in the United States identify as transgender or nonbinary, signifying that their gender identity does not correspond with their assigned sex at birth. Individuals ...assigned female at birth may seek gender-affirming hormone therapy with testosterone. No studies have directly examined ovulatory function in transmasculine individuals using injectable testosterone.
Our primary objective was to determine the effect of testosterone on ovulatory suppression in transmasculine individuals. Secondary objectives were to determine predictors of ovulation in transmasculine individuals on testosterone, and to assess the effect of testosterone on antimüllerian hormone.
This prospective observational study recruited participants from a community clinic that provides gender-affirming hormone therapy. Enrolled individuals were assigned female at birth and were currently using or seeking to initiate masculinizing therapy with injectable testosterone esters (transmasculine individuals). Over a 12-week study period, participants collected daily urine samples for pregnanediol-3-glucoronide testing and completed daily electronic bleeding diaries. We assessed monthly serum mid-dosing interval testosterone, estradiol and sex hormone binding globulin, and antimüllerian hormone values at baseline and study end. Ovulation was defined as pregnanediol-3-glucoronide greater than 5 μg/mL for 3 consecutive days. The primary outcome was the proportion of participants who ovulated during the study period. We examined predictors of ovulation such as age, length of time on testosterone, serum testosterone levels, body mass index, and bleeding pattern.
From July to November 2018, we enrolled 32 individuals; 20 completed the study (14 continuing testosterone users, 6 new users). Median age was 23 years (range 18−37 years). Bleeding or spotting during the study period was noted by 41% of participants (13/32). Among continuing users, median testosterone therapy duration was 11 months (range 1−60 months). A single ovulation was observed out of a total of 61 combined months of testosterone use; however, several transient rises in pregnanediol-3-glucoronide followed by bleeding episodes were suggestive of 7 dysfunctional ovulatory cycles among 7 individuals. There was no difference in antimüllerian hormone from baseline to 12 weeks between participants initiating testosterone and continuing users of testosterone. We did not have the power to examine our intended predictors given the low numbers of ovulatory events, but found that longer time on testosterone and presence of vaginal bleeding over 12 weeks were associated with transient rises in pregnanediol-3-glucoronide.
This study suggests that testosterone rapidly induces hypothalamic−pituitary−gonadal suppression, resulting in anovulation in a proportion of new users. Importantly, these data also suggest that some long-term testosterone users break through the hormonal suppression and experience an ovulatory event, thereby raising concerns pertaining to the need for contraception in transmasculine individuals engaged in sexual intercourse with sperm-producing partners. Given the small number of overall participants, this work is hypothesis generating. Larger studies are needed to confirm and to clarify these findings.
Resmetirom (MGL‐3196), a selective thyroid hormone receptor‐β agonist, was evaluated in a 36‐week paired liver biopsy study (NCT02912260) in adults with biopsy‐confirmed nonalcoholic steatohepatitis ...(NASH). The primary endpoint was relative liver fat reduction as assessed by MRI–proton density fat fraction (MRI‐PDFF), and secondary endpoints included histopathology. Subsequently, a 36‐week active treatment open‐label extension (OLE) study was conducted in 31 consenting patients (including 14 former placebo patients) with persistently mild to markedly elevated liver enzymes at the end of the main study. In patients treated with resmetirom (80 or 100 mg orally per day), MRI‐PDFF reduction at OLE week 36 was −11.1% (1.5%) mean reduction (standard error SE; P < 0.0001) and −52.3% (4.4%) mean relative reduction, P < 0.0001. Low‐density lipoprotein (LDL) cholesterol (−26.1% 4.5%, P < 0.0001), apolipoprotein B (−23.8% 3.0%, P < 0.0001), and triglycerides (−19.6% 5.4%, P = 0.0012; −46.1 14.5 mg/dL, P = 0.0031) were reduced from baseline. Markers of fibrosis were reduced, including liver stiffness assessed by transient elastography (−2.1 0.8 mean kilopascals SE, P = 0.015) and N‐terminal type III collagen pro‐peptide (PRO‐C3) (−9.8 2.3 ng/mL, P = 0.0004 (baseline ≥ 10 ng/mL). In the main and OLE studies, PRO‐C3/C3M (matrix metalloproteinase‐degraded C3), a marker of net fibrosis formation, was reduced in resmetirom‐treated patients (−0.76 −1.27, −0.24, P = 0.0044 and −0.68, P < 0.0001, respectively). Resmetirom was well tolerated, with few, nonserious adverse events. Conclusion: The results of this 36‐week OLE study support the efficacy and safety of resmetirom at daily doses of 80 mg and 100 mg, used in the ongoing phase 3 NASH study, MAESTRO‐NASH (NCT03900429). The OLE study demonstrates a potential for noninvasive assessments to monitor the response to resmetirom from an individual patient with NASH.
The unusual regenerative properties of the liver are a logical adaptation by organisms, as the liver is the main detoxifying organ of the body and is likely to be injured by ingested toxins. The ...numerous cytokine- and growth-factor-mediated pathways that are involved in regulating liver regeneration are being successfully dissected using molecular and genetic approaches. So what is known about this process at present and which questions remain?
short interval repeat pregnancy increases maternal and neonatal morbidity, and provision of postpartum contraception provides primary protection against these adverse outcomes. Confusion regarding ...effects on breast feeding and thrombosis risk delaying initiation of contraception in the immediate post-partum interval. Delaying contraception provision until the 6-week postpartum visit misses many women who either do not attend or have resumed ovulation and/or intercourse prior to this visit. Because of this, recent studies have looked into initiation of highly effective contraceptive methods at earlier intervals including immediately postpartum. These data provide strong evidence for immediate post-partum initiation of the most effective long-acting reversible contraception (LARC) methods, intrauterine devices and implants. Areas covered: We review the data for safety and efficacy, timing of initiation, and continuation rates of various contraceptive methods in the postpartum period. We also evaluate effects on initiation and continuation of breastfeeding for each contraceptive method discussed. Expert opinion: It is important to counsel patients antenatally regarding the full spectrum of contraceptive options available with a focus on long-acting reversible contraceptive (LARC) methods. When a woman chooses a LARC method, her provider should consider placement in the immediate postpartum period.
STAT3 is rapidly induced during liver regeneration in an interleukin 6 (IL-6)-dependent fashion, and IL-6 is required for normal liver regeneration. We wanted to know whether STAT3 was also required ...for liver regeneration but disruption of the STAT3 gene during embryonic stages causes lethality. Therefore, an albumin promoter-driven Cre-loxP recombination system was used to create a STAT3 deletion in the adult mouse liver to study the role of STAT3 in liver regeneration. After partial hepatectomy, there was virtually no STAT3 RNA or protein induction in Alb(+) STAT3(fl/fl) livers. STAT3 DNA binding activity was also absent in Alb(+) STAT3(fl/fl) livers. Unlike in control livers, STAT1 was activated in STAT3 conditional-mutant livers posthepatectomy. Hepatocyte DNA synthesis at 40 h posthepatectomy in Alb(+) STAT3(fl/fl) livers was reduced to approximately one-third of the control. Alb(+) STAT3(fl/fl) livers had abnormalities in immediate-early gene activation that largely correlated with but were not identical to those seen in IL-6-/- livers. G(1) phase cyclins including cyclins D1 and E had lower expression levels in Alb(+) STAT3(fl/fl) livers, indicating an abnormal G(1) to S phase transition. Therefore, STAT3 accounts for part of the DNA synthetic response of the hepatocytes during liver regeneration, which cannot be compensated for by induction of STAT1. Normal activation of the MAPK pathway in Alb(+) STAT3(fl/fl) livers reinforces the fact that at least part of the effect of IL-6 on hepatocyte proliferation is not mediated by STAT3. This study provides the first in vivo evidence that STAT3 promotes cell cycle progression and cell proliferation under physiological growth conditions.
Interleukin-6 stimulates liver regeneration and promotes hepatoprotection following experimental liver injury, but underlying mechanisms have not been fully characterized. Because studies suggest ...matrix metalloproteinase-2 (MMP-2) may promote liver injury, we examined whether IL-6 exerted its protective effects via regulation of MMP-2.
MMP-2 was analyzed in livers of IL-6-/- and IL-6+/+ mice following CCl(4) administration. IL-6-/- mice were pretreated with IL-6 and liver histology and MMP-2 expression were examined after liver injury. IL-6-/- mice were treated with an MMP-2 inhibitor and assessment of injury (histology and serum ALT levels), apoptosis by TUNEL assay, and hepatocyte proliferation by BRDU-labeling was performed. These studies were complemented by analysis of cultured stellate cells.
MMP-2 mRNA, protein, and activity was increased in IL-6-/- livers. Restoration of IL-6 signaling in IL-6-/- mice rescued injury and restored MMP-2 expression to wild-type levels. Furthermore, pharmacologic inhibition of MMP-2 decreased hepatocellular injury and apoptosis in IL-6-/- mice. In cultured stellate cells, recombinant IL-6 suppressed endogenous MMP-2 mRNA and protein expression.
IL-6 may be hepatoprotective in acute injury through down-regulation of MMP-2. These findings suggest a role for MMP-2 in amplifying liver injury in vivo.
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