The purpose of this study was to explore whether conjugated linoleic acid (CLA) could alleviate fatty liver hemorrhagic syndrome (FLHS) induced by estradiol benzoate intramuscular injection in laying hens. One hundred male Hy-Line white chickens were randomly divided into two groups, namely, the control (CON) and estradiol benzoate (E) groups, and both groups were fed the same basal diet. After injections of estradiol benzoate at 2 mg/kg every two days for a total of 7 times, chickens in the E group showed FLHS symptoms, including liver enlargement, hemorrhage, and steatosis. Then half of the chickens in the E group received an additional diet containing 5000 mg/kg CLA for 8 weeks. The results of morphological observations, hematoxylin and eosin staining, and Oil Red O staining showed that CLA alleviated liver enlargement, hemorrhage, and lipid accumulation in FLHS chickens. Additionally, we measured liver function and lipid metabolism indicators, including ALT, AST, TG, TCH, HDL-C, and LDL-C, which further suggested that CLA mitigated the disturbance of serum and liver metabolism in FLHS chickens. Mechanistically, CLA inhibited hepatic de novo lipogenesis, cholesterol synthesis, and TG accumulation and increased TG hydrolysis in FLHS chickens by regulating the gene expression of CD36, ACC, FAS, SCD 1, DGAT2, LIPE, ATGL, CPT1A, SREBP-1c, SREBP-2, PPARγ, and PPARα. Furthermore, CLA ameliorated hepatic oxidative stress and inhibited NF-κB signaling pathway-mediated inflammation in FLHS chickens. In conclusion, CLA regulated lipid metabolism, thus further alleviating oxidative stress and inflammation to alleviate FLHS induced by estrogen in chickens.

Metabolic diseases, such as obesity, metabolic syndrome (MetS) and type 2 diabetes (T2D), are now a widespread pandemic in the developed world. These pathologies show sex differences in their development and prevalence, and sex steroids, mainly estrogen and testosterone, are thought to play a prominent role in this sexual dimorphism. The influence of sex hormones on these pathologies is not only reflected in differences between men and women, but also between women themselves, depending on the hormonal changes associated with the menopause. The observed sex differences in gut microbiota composition have led to multiple studies highlighting the interaction between steroid hormones and the gut microbiota and its influence on metabolic diseases, ultimately pointing to a new therapy for these diseases based on the manipulation of the gut microbiota. This review aims to shed light on the role of sexual hormones in sex differences in the development and prevalence of metabolic diseases, focusing on obesity, MetS and T2D. We focus also the interaction between sex hormones and the gut microbiota, and in particular the role of microbiota in aspects such as gut barrier integrity, inflammatory status, and the gut-brain axis, given the relevance of these factors in the development of metabolic diseases.

Epidemiological studies support the idea that multiple sclerosis (MS) is a multifactorial disease, overlapping genetic, epigenetic, and environmental factors. A better definition of environmental risks is critical to understand both etiology and the sex-related differences of MS. Exposure to endocrine-disrupting compounds (EDCs) fully represents one of these risks. EDCs are natural or synthetic exogenous substances (or mixtures) that alter the functions of the endocrine system. Among synthetic EDCs, exposure to bisphenol A (BPA) has been implicated in the etiology of MS, but to date, controversial data has emerged. Furthermore, nothing is known about bisphenol S (BPS), one of the most widely used substitutes for BPA. As exposure to bisphenols will not disappear soon, it is necessary to clarify their role also in this pathological condition defining their role in disease onset and course in both sexes. In this study, we examined, in both sexes, the effects of perinatal exposure to BPA and BPS in one of the most widely used mouse models of MS, experimental autoimmune encephalomyelitis (EAE). Exposure to bisphenols seemed to be particularly deleterious in males. In fact, both BPA- and BPS-treated males showed anticipation of the disease onset and an increased motoneuron loss in the spinal cord. Overall, BPA-treated males also displayed an exacerbation of EAE course and an increase in inflammation markers in the spinal cord. Analyzing the consequences of bisphenol exposure on EAE will help to better understand the role of both xenoestrogens and endogenous estrogens on the sexually dimorphic characteristics of MS.

Vaginal bleeding of the newborn is described as a normal phenomenon, occurring physiologically in a subset of baby girls as a response to decreased oestrogen levels in the postnatal period compared with in utero exposure. Here, we present the case of heavy vaginal bleeding prompting an evaluation via transabdominal ultrasound, which was ultimately diagnostic for uterus didelphys. We suggest that neonates with uterus didelphys are predisposed to heavy bleeding due to relatively larger amount of the endometrial tissue in two cavities. While diagnosis of Müllerian anomalies is typically made in adulthood, an earlier diagnosis facilitates timely medical and surgical intervention and prompts screening for concurrent and associated conditions. In summary, we recommend routine consideration of transabdominal ultrasound to investigate abnormal vaginal bleeding in the newborn.

Taurine is an end-product of cysteine metabolism, while cysteine dioxygenase (CDO) and cysteine sulfinate decarboxylase (CSAD) are key enzymes regulating taurine synthesis. Sex steroids, including estrogens and androgens, are associated with liver physio-pathological processes, however, we still do not know whether taurine and sex steroids interact in regulating liver physiology and hepatic diseases, and whether there are sex differences although our recent study shows the estrogen is involved in regulating taurine synthesis in mouse liver. The present study was thus proposed to identify whether 17-beta estradiol and testosterone play their roles by regulating CDO and CSAD expression and taurine synthesis in male mouse liver. Our results demonstrated that testosterone did not have significant influence on CDO expression, but significantly enhanced CSAD, androgen receptor (AR) expressions and taurine levels in mouse liver, cultured hepatocytes and HepG2 cells, whereas these effects were abrogated by AR antagonist flutamide. Further, our results showed that testosterone increased CSAD-promoter-luciferase activity through direct interacting of AR DNA binding domain with CSAD promoter. These findings firstly demonstrate that testosterone acts as important factor to regulate sulfur amino acid metabolism and taurine synthesis through AR/CSAD signaling pathway. In addition, the in vivo and in vitro experiments showed that 17-beta estradiol has no significant effects on liver CSAD expression and taurine synthesis in male mice and suggest that the effects of sex steroids on the taurine synthesis in mouse liver has sex differences. These results are crucial for understanding the physiological functions of taurine/androgen and their interacting mechanisms in liver.

To probe the diagnostic value of transvaginal color Doppler ultrasonography plus serum β-human chorionic gonadotropin (β-HCG) dynamic monitoring in intrauterine residue after medical abortion.In total, 200 pregnant women undergoing medical abortion in our institution from January 2017 to December 2019 were picked, and assigned to either group A (n = 75, with residue) or group B (n = 125, without residue). We detected serum β-HCG, progesterone (P), follicle stimulating estrogen (FSH) levels and ultrasonic indicators endometrial thickness (ET), peak systolic velocity (PSV), resistance index (RI) values, dissected correlation of indicators using logistic linear regression analysis, and prospected the diagnostic value of relevant indicators in intrauterine residue after medical abortion utilizingreceiver operating characteristic curve.At 7 days after abortion (T3), total vaginal bleeding and visual analogue scalescore in group A were saliently higher in contrast to group B (P < .05). At 72 hours after abortion (T2) and T3, serum β-HCG, P and FSH levels declined strikingly in both groups, but group B held plainly higher decrease rate than group A (P HC.05). At T3, ET and PSV levels in both groups considerably waned, whereas RI levels notedly waxed, and group B owned markedly higher decrease/increase than group A (P wa.05). At T3, serum β-HCG in group A possessed positive association with serum P, FSH, intrauterine ET, PSV levels separately (P HC.05), whereas negative link with RI levels (P , .05). The specificity and sensitivity of β-HCG, P, FSH, β-HCG/ET, β-HCG/PSV and β-HCG/RI in the diagnosis of intrauterine residue after medical abortion were high (P < .05).Serum β-HCG dynamic monitoring plus transvaginal color Doppler ultrasonography is of great value in diagnosing intrauterine residue after medical abortion. Serum β-HCG, P, FSH levels can be combined with the results of intrauterine ET, PSV, RI values, so as to boost the diagnostic accuracy of the intrauterine residue after medical abortion.

This study was designed to investigate a possible interaction between 17β‑estradiol and glutamate receptors of the paragigantocellularis lateralis (LPGi) nucleus on pain coping behavior using the formalin test in ovariectomized (OVX) rats. The results showed that intra‑LPGi injection of 17β‑estradiol declined flexing behavior in both phases of the formalin test. Still, it only diminished the late phase of licking behavior in the OVX rats. NMDA receptor antagonist, AP5, reversed the analgesic effect of 17β‑estradiol on flexing behavior in both phases of the formalin test in the OVX rats. The 17β‑estradiol‑induced anti‑nociceptive effect on the flexing duration was prevented by CNQX (AMPA receptor antagonist) only in the early phase of the formalin test in the OVX rats. AP5 and CNQX reduced the anti‑nociceptive effect of 17β‑estradiol in the late phase, but not the early phase of licking response in the OVX rats. These results suggested: (i) The intra‑LPGi injection of 17β‑estradiol is satisfactory in producing modest analgesia on the formalin‑induced inflammatory pain in the OVX rats; (ii) Co‑treatment of glutamate receptors (NMDA and AMPA) antagonists and 17β‑estradiol in the LPGi nucleus decrease the analgesic effect of 17β‑estradiol in the OVX rats; (iii) There is a possible association between 17β‑estradiol and glutamate receptors of the LPGi nucleus on pain coping behavior in the OVX rats.

A protocol for metal and oxidant free photoredox catalyzed trifluoromethylation of 2H-indazoles was developed by using Eosin Y as the photocatalyst and recoverable ionic liquids as the solvents. A series of trifluoromethylated products were obtained in moderate to good yields in this protocol under mild conditions. The reaction proceeded via a free-radical mechanism with a broad substrate range, excellent regioselectivity, and good functional group tolerance. Furthermore, the utility of this protocol was demonstrated by the synthesis of a highly selective ligand for estrogen receptor beta (ERβ) and the drug granisetron. The protocol provides a mild and environmentally friendly solution for trifluoromethylation reaction.

Recent evidence shows the cardiometabolic effects of estrogen administration in postmenopausal women. Women have a cardiometabolic advantage during their reproductive years, which is lost at menopause due to declining estradiol (E2). E2, also known as 17-beta-estradiol, has diverse effects in its target tissues, including the cardiovascular (CV) system, through genomic and non-genomic signaling. Metabolic changes characteristic of menopause include a worsening lipid profile, changes in body fat distribution, epicardial and pericardial fat deposition, increased susceptibility to weight gain, and increased blood pressure, resulting in an increased risk of accelerated cardiovascular disease (CVD) development. E2 mediates its cardioprotective actions by increasing mitochondrial biogenesis, angiogenesis, and vasodilation, decreasing reactive oxygen species (ROS) and oxidative stress, and modulating the renin-angiotensin-aldosterone system (RAAS). In this review, we assess whether it is prudent to develop an approach to managing postmenopausal women based on modifying the patient's CV risk that includes human-identical hormone replacement therapy (HRT), modulation of RAAS, and stimulating mitochondrial biogenesis. Further research is needed to assess the safety and benefit of HRT to reduce cardiometabolic risk.

Female adolescent athletes are at a higher risk of tearing their anterior cruciate ligament (ACL) than male counterparts. While most work related to hormones has focused on the effects of estrogen to understand the increased risk of ACL injury, there are other understudied factors, including testosterone. The purpose of this study was to determine how surgical castration in the male porcine model influences ACL size and function across skeletal growth. Thirty-six male Yorkshire crossbreed pigs were raised to 3 (juvenile), 4.5 (early adolescent), and 6 months (adolescent) of age. Animals were either castrated (barrows) within 1-2 weeks after birth or were left intact (boars). Post-euthanasia, joint and ACL size were assessed via MRI, and biomechanics were assessed via a robotic testing system. Joint size increased throughout age, yet barrows had smaller joints than boars (p<0.001 for all measures). ACL cross-sectional area (CSA), length, volume, and stiffness all increased with age (p<0.0001), as did ACL anteromedial (AM) bundle percent contribution to resisting applied loads (p=0.012). Boar ACL and AM bundle volumes were 18% (p=0.003) and 24% (p=0.004) larger than barrows across ages. However, CSA, stiffness, and bundle contribution were similar between boars and barrows (p>0.05). The barrows had smaller temporal increases in AM bundle percent function than boars, but these data were highly variable. Thus, early and sustained loss in testosterone leads to subtle differences in ACL morphology, but may not influence measures associated with increased injury risk, such as CSA or bundle forces in response to applied loads.

The injectable progestin depot-medroxyprogesterone acetate (DMPA) is a popular contraceptive choice in sub-Saharan Africa although mouse models indicate it weakens genital epithelial integrity and barrier function and increases susceptibility to genital infection. The intravaginal ring NuvaRing® is another contraceptive option that like DMPA suppresses hypothalamic pituitary ovarian (HPO) axis function with local release of progestin (etonogestrel) and estrogen (ethinyl estradiol). As we previously reported that treating mice with DMPA and estrogen averts the loss of genital epithelial integrity and barrier function induced by DMPA alone, in the current investigation we compared genital levels of the cell-cell adhesion molecule desmoglein-1 (DSG1) and genital epithelial permeability in rhesus macaques (RM) treated with DMPA or a NuvaRing®re-sized for RM (N-IVR). While these studies demonstrated comparable inhibition of the HPO axis with DMPA or N-IVR, DMPA induced significantly lower genital DSG1 levels and greater tissue permeability to intravaginally administered low molecular mass molecules. By identifying greater compromise of genital epithelial integrity and barrier function in RM administered DMPA vs. N-IVR, our results add to the growing body of evidence that indicate DMPA weakens a fundamental mechanism of anti-pathogen host defense in the female genital tract.

Trade-offs between metabolic and reproductive processes are important for survival, particularly in mammals that gestate their young. Puberty and reproduction, as energetically taxing life stages, are often gated by metabolic availability in animals with ovaries. How the nervous system coordinates these trade-offs is an active area of study. We identify somatostatin neurons of the tuberal nucleus (TN SST ) as a node of the feeding circuit that alters feeding in a manner sensitive to metabolic and reproductive states in mice. Whereas chemogenetic activation of TN SST neurons increased food intake across sexes, selective ablation decreased food intake only in female mice during proestrus. Interestingly, this ablation effect was only apparent in animals with a low body mass. Fat transplantation and bioinformatics analysis of TN SST neuronal transcriptomes revealed white adipose as a key modulator of the effects of TN SST neurons on food intake. Together, these studies point to a mechanism whereby TN SST hypothalamic neurons modulate feeding by responding to varying levels of circulating estrogens differentially based on energy stores. This research provides insight into how neural circuits integrate reproductive and metabolic signals, and illustrates how gonadal steroid modulation of neuronal circuits can be context-dependent and gated by metabolic status.

Estrogenic overstimulation is carcinogenic to the human breast. Personal care products (PCPs) commonly contain xenoestrogens (XE), such as parabens and phthalates. Here, we identified the adverse effects of persistent exposure to such PCPs directly within human estrogen responsive breast tissue of subjects enrolled in a regimen of reduced XE use (REDUXE). Pre- and post-intervention fine needle aspirates (FNAs) of the breast were collected from healthy volunteers who discontinued the use of paraben and phthalate containing PCPs over a 28 d period. Based on high-dimensional gene expression data of matched FNA pairs of study subjects, we demonstrate a striking reversal of cancer-associated phenotypes, including the PI3K-AKT/mTOR pathway, autophagy, and apoptotic signaling networks within breast cells of REDUXE compliant subjects. These, and other altered phenotypes were detected together with a significant reduction in urinary parabens and phthalate metabolites. Moreover, in vitro treatment of paired FNAs with 17β-estradiol (E2), displayed a 'normalizing' impact of REDUXE on gene expression within known E2-modulated pathways, and on functional endpoints, including estrogen receptor alpha: beta ratio, and S-phase fraction of the cell cycle. In a paradigm shifting approach facilitated by community-based participatory research, REDUXE reveals unfavorable consequences from exposure to XEs from daily-use PCPs. Our findings illustrate the potential for REDUXE to suppress pro-carcinogenic phenotypes at the cellular level towards the goal of breast cancer prevention.

The formation of osteoclasts and their hyperactive bone resorption are related to the aggregation of intracellular reactive oxygen species (ROS). Flavonoids, derived from plant active ingredients, can alleviate the symptoms of osteoporosis (OP). Isosinensetin (Iss) is a flavonoid with antioxidant effects obtained mainly from citrus fruits, and its effect on osteoclastogenesis has not been reported. In this study, we investigated the antioxidant activity of Iss on osteoclast differentiation and function, as well as the therapeutic impact of Iss on OP. We found that Iss inhibited osteoclastogenesis and suppressed the bone resorption function of osteoclasts. Additionally, Iss reduced receptor activator of nuclear factor-κB ligand (RANKL)-induced intracellular ROS. Using quantitative real-time polymerase chain reaction and western blot, we further found that Iss inhibited osteoclast-specific genes and related proteins, while promoting the expression of antioxidant enzyme-related genes and proteins. Mechanistically, Iss reduces intracellular ROS by activating nuclear factor-erythroid 2-related factor 2 (Nrf2) and its related antioxidant enzymes and inhibits the downstream nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways of ROS, which in turn inhibits nuclear factor of activated T cells 1 (NFATc1), and ultimately inhibits osteoclastogenesis. In vivo, by micro-computed tomography (Micro-CT) assay and histological analyses, we found that Iss could reduce bone loss in ovariectomized (OVX) mice. Therefore, Iss has the potential as an OP preventative and therapeutic drug option.

Acute gallstone pancreatitis is a rare occurrence in pregnancy and the postpartum period. However, gallstone pancreatitis should be considered in a differential diagnosis for right upper quadrant (RUQ) pain in this population, as the risk of biliary stasis and gallstone formation increases in pregnancy due to high levels of circulating estrogen causing increased cholesterol formation and delayed gallbladder emptying. Although gallstones are the most common cause of acute pancreatitis in pregnancy, alcohol use and hypertriglyceridemia may also be considered. In this case report, we present a G1P0 female pregnant with monochorionic diamniotic twins who developed postpartum acute gallstone pancreatitis status post Cesarean section.

The role of steroid hormones against infectious diseases has been extensively studied. From immunomodulatory action to direct inhibition of microorganism growth, hormones D3 (VD3) and 17β-estradiol (E2), and the genetic pathways modulated by them, are key targets for a better understanding pathogenesis of infectious respiratory diseases (IRD) such as tuberculosis (TB) and the coronavirus disease-19 (COVID-19). Currently, the world faces two major public health problems, the outbreak of COVID-19, accounting for more than 6 million so far, and TB, more than 1 million deaths per year. Both, although resulting from different pathogens, the Mtb and the SARS-CoV-2, respectively, are considered serious and epidemic. TB and COVID-19 present similar infection rates between men and women, however the number of complications and deaths resulting from the two infections is higher in men when compared to women in childbearing age, which may indicate a role of the sex hormone E2 in the context of these diseases. E2 and VD3 act upon key gene pathways as important immunomodulatory players and supporting molecules in IRDs. This review summarizes the main roles of these hormones (VD3 and E2) in modulating immune and inflammatory responses and their relationship with TB and COVID-19.

Drugs that kill tumors through multiple mechanisms have the potential for broad clinical benefits. Here, we first developed an in silico multiomics approach (BipotentR) to find cancer cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway and then used it to identify 38 candidate immune-metabolic regulators. We show the tumor activities of these regulators stratify patients with melanoma by their response to anti-PD-1 using machine learning and deep neural approaches, which improve the predictive power of current biomarkers. The topmost identified regulator, ESRRA, is activated in immunotherapy-resistant tumors. Its inhibition killed tumors by suppressing energy metabolism and activating two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization, and (ii) antigen-presentation stimulation, recruiting CD8+ T cells into tumors. We also demonstrate a wide utility of BipotentR by applying it to angiogenesis and growth suppressor evasion pathways. BipotentR (http://bipotentr.dfci.harvard.edu/) provides a resource for evaluating patient response and discovering drug targets that act simultaneously through multiple mechanisms.

A rising number of researchers are interested in thiophene-based analogs as they have wide possibilities of biological potential in the largely developing chemical world of the heterocyclic moiety. It also occupies a central position in synthetic organic chemistry and is of the highest theoretical and practical importance. It became an important moiety for researchers to discover combinatorial libraries and implement the efforts in search of the lead entity. Moreover, it helps medicinal chemists to improve sophisticated molecules with a broad range of pharmacological activities. Thiophene and its synthetic derivatives are a prominent heterocyclic compound class with intriguing uses in medical chemistry. It has been manifesting to be an effective drug in current respective diseases scenario. It has been discovered that thiophene has an extensive spectrum of pharmacological potential with numerous applications in academic interest, in the pharmaceutical industry, material science, and medicinal chemistry. Antimitotic, Antimicrobial, Anti-inflammatory, Anticonvulsant, Antipsychotic, Antiarrhythmic, Anti-anxiety, Antifungal, Antioxidant, Estrogen receptor regulating, and Anti-cancer are one of the pharmacological and physiological activities of thiophene moiety. However, there are some marketed formulations available such as Thiophenfurin, Teniposide, Cefoxitin, Ticaconazole, Sertaconazole, Suprofen, ketotifen, Brinzolamide, Dorzolamide, Tiotropium which contain thiophene nucleus. Thus, in a nutshell, gathering recent data is necessary to comprehend the present scenario of thiophene moiety for scientific research purposes and highlights a broad view of the biological potential of compounds having a thiophene nucleus.

The spironolactone derivative drospirenone is combined with ethinylestradiol or estetrol in combined oral contraceptives. Formulations with 17-β-estradiol are used to treat climacteric symptoms. A drospirenone-only formulation has been introduced for contraception. Here, the pharmacological properties of drospirenone, the impact of the different formulations on metabolic and laboratory parameters, and the resulting clinical implications are reviewed. Ethinylestradiol, an inhibitor of CYP metabolic enzymes, changes the pharmacokinetics of drospirenone, leading to a higher drospirenone exposure with ethinylestradiol/drospirenone compared to the drospirenone-only preparation. In addition, several metabolic alterations have been described. The impact of estetrol is less pronounced, and for 17-β-estradiol/drospirenone and drospirenone-only, decreased triglyceride and cholesterol levels were observed. Ethinylestradiol induces various pro-coagulatory factors, leading to hypercoagulability. The effect is significantly reduced with estetrol, and no influence was observed with the drospirenone-only preparation. The anti-mineralocorticoid activity of drospirenone seems to positively counteract the renin-angiotensin-aldosterone-system-activating action of ethinylestradiol. There is no influence on blood pressure with ethinylestradiol/drospirenone and estetrol/drospirenone formulations, while in clinical trials, a reduction has been observed with 17-β-estradiol/drospirenone and drospirenone-only. Anti-aldosterone activity via non-renal mineralocorticoid receptors is associated with cardiovascular health, while interactions with parathyroid hormone signaling impact bone structure and vascular calcification. Though the clinical relevance is unclear for drospirenone, data in this context are reviewed. To sum up, the advantages of drospirenone in hormonal contraception and treatment of menopausal symptoms have been demonstrated for all the formulations described here. Combination with estrogen confers benefits and risks, which must be considered.