Beneficial and Deleterious Effects of Female Sex Hormones, Oral Contraceptives, and Phytoestrogens by Immunomodulation on the Liver.

The liver is considered the laboratory of the human body because of its many metabolic processes. It accomplishes diverse activities as a mixed gland and is in continuous cross-talk with the endocrine system. Not only do hormones from the gastrointestinal tract that participate in digestion regulate the liver functions, but the sex hormones also exert a strong influence on this sexually dimorphic organ, via their receptors expressed in liver, in both health and disease. Besides, the liver modifies the actions of sex hormones through their metabolism and transport proteins. Given the anatomical position and physiological importance of liver, this organ is evidenced as an immune vigilante that mediates the systemic immune response, and, in turn, the immune system regulates the hepatic functions. Such feedback is performed by cytokines. Pro-inflammatory and anti-inflammatory cytokines are strongly involved in hepatic homeostasis and in pathological states; indeed, female sex hormones, oral contraceptives, and phytoestrogens have immunomodulatory effects in the liver and the whole organism. To analyze the complex and interesting beneficial or deleterious effects of these drugs by their immunomodulatory actions in the liver can provide the basis for either their pharmacological use in therapeutic treatments or to avoid their intake in some diseases.

Inhibition of Uterine Contractility by Thalidomide Analogs via Phosphodiesterase-4 Inhibition and Calcium Entry Blockade.

Uterine relaxation is crucial during preterm labor. Phosphodiesterase-4 (PDE-4) inhibitors have been proposed as tocolytics. Some thalidomide analogs are PDE-4 inhibitors. The aim of this study was to assess the uterus-relaxant properties of two thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe) and were compared to rolipram in functional studies of spontaneous phasic, K⁺-induced tonic, and Ca2+-induced contractions in isolated pregnant human myometrial tissues. The accumulation of cAMP was quantified in HeLa cells. The presence of PDE-4B2 and phosphorylated myosin light-chain (pMLC), in addition to the effect of thalidomide analogs on oxytocin-induced pMLC, were assessed in human uterine myometrial cells (UtSMCs). Thalidomide analogs had concentration-dependent inhibitory effects on spontaneous and tonic contractions and inhibited Ca2+-induced responses. Tonic contraction was equipotently inhibited by 4APDPMe and rolipram (IC50 = 125 ± 13.72 and 98.45 ± 8.86 µM, respectively). Rolipram and the thalidomide analogs inhibited spontaneous and tonic contractions equieffectively. Both analogs increased cAMP accumulation in a concentration-dependent manner (p < 0.05) and induced changes in the subcellular localization of oxytocin-induced pMLC in UtSMCs. The inhibitory effects of thalidomide analogs on the contractions of pregnant human myometrium tissue may be due to their PDE-4 inhibitory effect and novel mechanism as calcium-channel blockers.

Prebiotics and Probiotics: Effects on Dyslipidemia and NAFLD/NASH and the Associated Mechanisms of Action.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is now considered the most common chronic liver disease worldwide. NAFLD is related to changes in lipid metabolism and is characterized by the increase or accumulation of fat in hepatocytes that may progress to nonalcoholic steatohepatitis (NASH), which leads to the appearance of inflammatory processes. Treatment consists of changes in diet, physical activity, and weight control; however, these disorders represent a health problem and require the development of novel alternatives to treatment and prevention. NAFLD/NASH are strongly associated with other disorders, such as metabolic syndrome (MetS); in fact, NAFLD is considered the hepatic manifestation of MetS. These disorders are related to other components of MetS, including dyslipidemia, which is characterized by an imbalance in blood cholesterol and triglyceride levels. Prebiotics and probiotics benefit from treating and preventing several ailments, including liver diseases. Specifically, in dyslipidemia, NAFLD, and NASH, probiotics play a fundamental role in conducting the biotransformation of primary bile acids into secondary bile acids, which generally have important activity as immunomodulators and metabolism regulators. The mechanisms of action of pre and probiotics involve the activity of bile acid receptors, such as FXR and TGR-5, and the events resulting from their activation. Therefore, prebiotics and probiotics may be reasonable options to prevent and treat metabolic- related liver diseases.

Plants of the Rubiaceae Family with Effect on Metabolic Syndrome: Constituents, Pharmacology, and Molecular Targets.

Metabolic syndrome (MetS) predisposes individuals to chronic non-communicable diseases (NCDs) like type 2 diabetes (T2D), non-alcoholic fatty liver disease, atherosclerosis, and cardiovascular disorders caused by systemic inflammation, intestinal dysbiosis, and diminished antioxidant ability, leading to oxidative stress and compromised insulin sensitivity across vital organs. NCDs present a global health challenge characterized by lengthy and costly pharmacological treatments. Complementary and alternative medicine using herbal therapies has gained popularity. Approximately 350,000 plant species are considered medicinal, with 80% of the world's population opting for traditional remedies; however, only 21,000 plants are scientifically confirmed by the WHO. The Rubiaceae family is promissory for preventing and treating MetS and associated NCDs due to its rich content of metabolites renowned for their antioxidative, anti-inflammatory, and metabolic regulatory properties. These compounds influence transcription factors and mitigate chronic low-grade inflammation, liver lipotoxicity, oxidative stress, and insulin resistance, making them a cost-effective non-pharmacological approach for MetS prevention and treatment. This review aims to collect and update data that validate the traditional uses of the Rubiaceae family for treating MetS and associated NCDs from experimental models and human subjects, highlighting the mechanisms through which their extracts and metabolites modulate glucose and lipid metabolism at the molecular, biochemical, and physiological levels.

Arsenic exposure and non-carcinogenic health effects.

Inorganic arsenic (iAs) exposure is a serious health problem that affects more than 140 million individuals worldwide, mainly, through contaminated drinking water. Acute iAs poisoning produces several symptoms such as nausea, vomiting, abdominal pain, and severe diarrhea, whereas prolonged iAs exposure increased the risk of several malignant disorders such as lung, urinary tract, and skin tumors. Another sensitive endpoint less described of chronic iAs exposure are the non-malignant health effects in hepatic, endocrine, renal, neurological, hematological, immune, and cardiovascular systems. The present review outlines epidemiology evidence and possible molecular mechanisms associated with iAs-toxicity in several non-carcinogenic disorders.

Dietary chia seeds (Salvia hispanica) improve acute dyslipidemia and steatohepatitis in rats.

Chia seeds (Salvia hispanica L.) are rich in omega fatty acids. Dyslipidemia and steatohepatitis are diseases that require effective treatments in obese and non-obese patients. The aim was to evaluate the effect of chia intake on acute tyloxapol (TI)-induced dyslipidemia, on acute carbon tetrachloride (TC)-induced steatohepatitis, and on mixed damage (TC+TI) in non-obese rats. Four experimental groups were fed for 4 weeks a diet with established rodent food (DE), and four groups were fed a diet with 15% added chia (DC). Plasma samples were analyzed for total cholesterol, triglycerides, glucose, biochemical liver damage markers, and tumor necrosis factor-α (TNF-α). Liver samples were used to quantify glycogen, catalase, lipid peroxidation, and TNF-α. A histopathological analysis was performed. DC intake partially or totally prevented steatohepatitis, and reduced lipids in the dyslipidemic groups. The hypolipidemic and hepatoprotective effects of chia may be correlated to its high content of α-linolenic acid (omega-3) and phenolics. PRACTICAL APPLICATIONS: Metabolic syndrome is associated with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which are currently the most common causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. Dyslipidemia is a significant risk factor for NAFLD and NASH. Non-obese patients may have NAFLD or NASH. Metabolic syndrome and dyslipidemia are more strongly associated with NAFLD in non-obese than in obese patients. This is the first study evaluating the hypolipidemic and hepatoprotective effects of chia seed intake on acute dyslipidemia and/or steatohepatitis caused by the individual or combined administration of the inducers tyloxapol and carbon tetrachloride, respectively, in non-obese rats. The pharmacological effects of dietary chia are correlated to its high content of omega-3 and omega-6 (1:1), protein, dietary fiber, and phenolics. The results suggest that inclusion of chia in diets of non-obese patients with dyslipidemia and/or NAFLD/NASH may improve their health state and preventing cirrhosis or HCC.

Potassium channel blockers inhibit the triggers of attacks in the calcium channel mouse mutant tottering.

Humans with the disorder episodic ataxia type 2 (EA2) and the tottering mouse mutant exhibit episodic attacks induced by emotional and chemical stress. Both the human and mouse disorders result from mutations in CACNA1A, the gene encoding the alpha(1)2.1 subunit of Ca(v)2.1 voltage-gated calcium channels. These mutations predict reduced calcium currents, particularly in cerebellar Purkinje cells, where these channels are most abundant. 4-Aminopyridine (4-AP), a nonselective blocker of K(v) voltage-gated potassium channels, alleviates attacks of ataxia in EA2 patients. To test the specificity of the effect for K(v) channels, aminopyridine analogs were assessed for their ability to ameliorate attacks of dyskinesia in tottering mice. 4-AP and 3,4-diaminopyridine (3,4-DiAP), which have relatively high affinities for K(v) channels, reduced the frequency of restraint- and caffeine-induced attacks. Furthermore, microinjection of 3,4-DiAP into the cerebellum completely blocked attacks in tottering mice. Other aminopyridine analogs reduced attack frequency but, consistent with their lower affinities for K(v) channels, required comparatively higher doses. These results suggest that aminopyridines block tottering mouse attacks via cerebellar K(v) channels. That both stress- and caffeine-induced attacks were blocked by aminopyridines suggests that these triggers act via similar mechanisms. Although 4-AP and 3,4-DiAP were effective in preventing attacks in tottering mice, these compounds did not affect the severity of "breakthrough" attacks that occurred in the presence of a drug. These results suggest that the aminopyridines increase the threshold for attack initiation without mitigating the character of the attack, indicating that attack initiation is mediated by mechanisms that are independent of the neurological phenotype.