Liver cancer in Hidalgo State, Mexico: analysis of the status, risk factors and regional public health policy requirements: a cross-sectional correlational study

ABSTRACT BACKGROUND: In Latin America, liver cancer is one of the top causes of cancer mortality. It is the fifth most common cause of death among malignant tumors in Mexico and is the leading cause in Hidalgo State (43.8% of the population living in poverty). OBJECTIVE: To conduct a correlational analysis on the main risk factors for liver cancer in Hidalgo State, Mexico, including municipal disaggregation and comparison with the national level. DESIGN AND SETTING: Cross-sectional, correlational, descriptive and comparative epidemiological study using Mexican governmental databases covering 1990-2019. METHODS: A comprehensive review of the databases of the General Directorate of Health Information (DGIS) was performed to analyze official death figures, hospital discharges and national and municipal population projections, using specific search criteria defined in the Global Burden of Disease classification, based on the risk factors for liver cancer. RESULTS: Liver cancer rates showed an evident rise in Hidalgo (183%), moving from 21st place in Mexico in 1990 to 9th place in 2019. This increase was correlated with alcoholism. An increasing trend for liver cancer deaths, of 133.89%, is projected for 2030. Females and the population over 60 years of age are more affected. There are some critical regions with liver cancer death rates twice the national rate or more. CONCLUSION: Targeted effective public health strategies should be structured by identifying, characterizing and regionalizing critical marginalized municipalities that are vulnerable to alcoholism and other risk factors for liver cancer. This approach may be helpful for other states in Mexico or similar countries.

Sea urchins: an update on their pharmacological properties.

Sea urchins are a group of benthic invertebrates characterized by having rigid globose bodies, covered in spines, and have an innate immune system that has allowed them to survive in the environment and defend against many pathogens that affect them. They are consumed for their unique flavor, but also for possessing a rich source of bioactive compounds which make them a source for a wide array of medicinal properties. Thus, these may be used to discover and develop new drugs such as anti-bacterials, anti-carcinogenics and anti-virals. Precisely for those reasons, this revision is centered on the known biological activities in various sea urchin species. Recently, the potential pharmacological benefits of nine sea urchin species [Diadema antillarum (Philippi 1845), Echinometra mathaei (de Blainville), Evechinus chloroticus (Valenciennes), Mesocentrotus nudus (Agassiz, 1863), Paracentrotus lividus (Lamarck, 1816), Scaphechinus mirabilis (Agazzis, 1863), Stomopneustes variolaris (Lamarck, 1816), Tripneustes depressus (Agassiz, 1863), and Tripneustes ventricosus (Lamarck, 1816)] have been evaluated. Our work includes a comprehensive review of the anti-fungal, anti-parasitic, anti-inflammatory, hepatoprotective, anti-viral, anti-diabetic, anti-lipidemic, gastro-protective and anti-cardiotoxic effects. Furthermore, we revised the compounds responsible of these pharmacological effects. This work was intended for a broad readership in the fields of pharmacology, drugs and devices, marine biology and aquaculture, fisheries and fish science. Our results suggest that organic extracts, as well as pure compounds obtained from several parts of sea urchin bodies are effective in vitro and in vivo pharmacological models. As such, these properties manifest the potential use of sea urchins to develop emergent active ingredients.

High-Risk HPV with Multiple Infections Promotes CYP2E1, Lipoperoxidation and Pro-Inflammatory Cytokines in Semen of Asymptomatic Infertile Men.

High-risk human papillomavirus (HR-HPV) infection, followed by chronic inflammation and oxidative stress, is a major risk factor of male infertility. In this study, we explored the potential impact of high-risk (HR) HPV genotypes in single infection (SI) and multiple infections (MI) that promote CYP2E1 expression, oxidative damage and pro-inflammatory cytokines, possibly contributing to sperm damage and male infertility. Semen samples from 101 infertile military men were studied. We analyzed seminal parameters, namely, HPV genotyping, cytochrome P450 2E1 (CYP2E1), oxidative stress biomarkers (total antioxidant capacity (TAC), catalase (CAT) and superoxide dismutase (SOD)), lipid peroxidation (LPO), 8-hydroxiguanosine (8-OHdG) and pro-inflammatory cytokines (IFN-γ, IL-1ß, IL-4, IL-6 and IL-8). Eighty-one men (80.2%, 81/101) were positive for HPV infection, and MI-HR-HPV was higher than SI-HR-HPV (63% vs. 37%). HPV-52 was the most frequently detected type (18.5%), followed by HPV-33 (11.1%), and the most frequent combination of genotypes detected was HPV-33,52 (11.1%), followed by HPV-18,31 (6.2%). The group with infected samples presented lower normal morphology and antioxidant levels compared to non-infected samples. In concordance, the infected group showed high levels of LPO, IFN-γ, IL-1ß, IL-4 and IL-6 and downregulation of CAT and SOD enzymes. Interestingly, changes in motility B, low levels of TAC, overexpression of CYP2E1, LPO and IL-8 levels were higher in MI-HR-HPV than SI-HR-HPV, suggesting that HPV infection promotes a chronic inflammatory process and a toxic and oxidative microenvironment, which increases with MI-HPV infections.

Liver cancer in Hidalgo State, Mexico: analysis of the status, risk factors and regional public health policy requirements: a cross-sectional correlational study.

BACKGROUND: In Latin America, liver cancer is one of the top causes of cancer mortality. It is the fifth most common cause of death among malignant tumors in Mexico and is the leading cause in Hidalgo State (43.8% of the population living in poverty). OBJECTIVE: To conduct a correlational analysis on the main risk factors for liver cancer in Hidalgo State, Mexico, including municipal disaggregation and comparison with the national level. DESIGN AND SETTING: Cross-sectional, correlational, descriptive and comparative epidemiological study using Mexican governmental databases covering 1990-2019. METHODS: A comprehensive review of the databases of the General Directorate of Health Information (DGIS) was performed to analyze official death figures, hospital discharges and national and municipal population projections, using specific search criteria defined in the Global Burden of Disease classification, based on the risk factors for liver cancer. RESULTS: Liver cancer rates showed an evident rise in Hidalgo (183%), moving from 21st place in Mexico in 1990 to 9th place in 2019. This increase was correlated with alcoholism. An increasing trend for liver cancer deaths, of 133.89%, is projected for 2030. Females and the population over 60 years of age are more affected. There are some critical regions with liver cancer death rates twice the national rate or more. CONCLUSION: Targeted effective public health strategies should be structured by identifying, characterizing and regionalizing critical marginalized municipalities that are vulnerable to alcoholism and other risk factors for liver cancer. This approach may be helpful for other states in Mexico or similar countries.

Potential Mechanisms of the Improvement of Glucose Homeostasis in Type 2 Diabetes by Pomegranate Juice.

Pomegranate is a polyphenol-rich fruit. Studies have shown that extracts prepared from its juice or from different parts of the pomegranate plant have various biological activities including antioxidant, antimicrobial, anti-inflammatory, anticarcinogenic, cardioprotective, and antidiabetic. The therapeutic potential has been attributed to various phytochemicals, including ellagic acid, punicic acid, flavonoids, anthocyanidins, anthocyanins, flavonols, and flavones. This review focuses on the scientific evidence of pomegranate juice as hypoglycemic, emphasizing the chemical composition and the possible mechanisms of action associated with this effect. Studies were identified using the PubMed, Scopus, and ISI Web of Science databases to identify relevant articles focused on the hypoglycemic effect of pomegranate juice. The physiological responses to pomegranate juice are reported here, including a decrease of oxidative stress damage, an increase of insulin-dependent glucose uptake, maintenance of ß-cell integrity, inhibition of nonenzymatic protein glycation, an increase of insulin sensitivity, modulation of peroxisome proliferator-activated receptor-gamma, inhibition of α-amylase, inhibition of α-glucosidase and dipeptidyl peptidase-4, and decreases in inflammation. Overall, we found a significant hypoglycemic effect of pomegranate in in vitro and in vivo studies and we summarize the potential mechanisms of action.

Proinflammatory and Oxidative Stress States Induced by Human Papillomavirus and Chlamydia trachomatis Coinfection Affect Sperm Quality in Asymptomatic Infertile Men.

Background and Objectives: To investigate the effect of infection with human papillomavirus (HPV) or Chlamydia trachomatis (CT) and HPV + CT coinfection on sperm quality, inflammation, and the state of oxidative stress (OS) in asymptomatic infertile men. Materials and Methods: Semen samples from 84 asymptomatic military infertile men were studied. The polymerase chain reaction (PCR) was used for the molecular detection of HPV and CT. Semen parameters were analyzed according to the World Health Organization guidelines. Inflammation was evaluated by an IL-1ß, IL-6, and IFN-γ enzyme-linked immunosorbent assay (ELISA) and OS by the quantification of lipid peroxidation (LPO), 8-hydroxydeoxyguanosine (8-OHdG), and total antioxidant capacity (TAC). Results: A total of 81 of the 84 (96.4%) samples were positives for the pathogens, with 55/81 (68%) being positive for HPV, 11/81 (13.5%) for CT, and 15/81 (18.5%) for HPV + CT coinfection. Seminal parameters were affected in the infected groups, including pH increases above the normal range in all groups. An abnormal sperm morphology was observed in the HPV and HPV + CT groups. Higher cytokine levels were detected in the HPV group and the highest IL-1ß level was found in the HPV + CT group. No cytokines were detected in the CT group. High LPO and 8-OHdG levels were found in all groups with a lower TAC. Comparisons between groups showed the highest OS state was observed in the HPV group. Conclusions: High HPV infection or coinfection (HVP + CT) in these infertile men suggest compromising male fertility by inducing a proinflammatory state and OS. Infection with CT suggests an alteration of the state of OS by promoting an alkaline pH.

Seminal pro-inflammatory cytokines and pH are affected by Chlamydia infection in asymptomatic patients with teratozoospermia.

INTRODUCTION: Infection and inflammation of the reproductive tract by Chlamydia trachomatis (CT) are recognized as significant risk factors for male infertility. This study aimed to evaluate CT infection and its effects on seminal parameters and cytokines in asymptomatic patients with teratozoospermia. MATERIAL AND METHODS: Semen samples from one hundred four male patients were collected, and CT detection was performed by polymerase chain reaction (PCR). The quality (volume, sperm concentration, pH, motility, morphology, and leucocytes) of the semen was measured by standard procedures recommended by the World Health Organization (WHO). Pro-inflammatory cytokines [interleukin (IL)-1 ß, IL-6, IL-8, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ)], as well as anti-inflammatory cytokines (IL-4, IL-10), were determined by using enzyme-linked immunosorbent assay (ELISA). The frequency of CT infection was expressed as a percentage. Descriptive statistics were used for comparison of cytokines from infertile men, and then the Mann-Whitney U test was applied for the contrast of seminal parameters and cytokines from CT-infected versus non-CT infected men. RESULTS: A ratio of 33/104 (31.7%) patients were positive for CT infection. The ejaculate of positive CT infection was found to have increased pH (pH = 7.65 in non-CT infected vs. 7.94 CT-infected men; p = 0.026). High levels of pro-inflammatory cytokines were found in the population studied; however, infected males were noted to have high levels of IL-1 ß [184.66 (0-3985.33 pg/ml), p = 0.001] and IL-6 [87.8 (0-1042.8 pg/ml), p = 0.001]. CONCLUSIONS: CT infection increased seminal pH, as well as IL-1 ß and IL-6 cytokines, suggesting a potential role of infection and inflammation in asymptomatic patients with teratozoospermia.

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.

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.

Phytosterols and Triterpenoids for Prevention and Treatment of Metabolic-related Liver Diseases and Hepatocellular Carcinoma.

BACKGROUND: Liver ailments are among the leading causes of death; they originate from viral infections, chronic alcoholism, and autoimmune illnesses, which may chronically be precursors of cirrhosis; furthermore, metabolic syndrome may worsen those hepatopathies or cause Non-alcoholic Fatty Liver Disease (NAFLD) that may advance to non-alcoholic steatohepatitis (NASH). Cirrhosis is the late-stage liver disease and can proceed to hepatocellular carcinoma (HCC). Pharmacological treatment options for liver diseases, cirrhosis, and HCC, are limited, expensive, and not wholly effective. The use of medicinal herbs and functional foods is growing around the world as natural resources of bioactive compounds that would set the basis for the development of new drugs. Review and Conclusion: Plant and food-derived sterols and triterpenoids (TTP) possess antioxidant, metabolic-regulating, immunomodulatory, and anti-inflammatory activities, as well as they are recognized as anticancer agents, suggesting their application strongly as an alternative therapy in some chronic diseases. Thus, it is interesting to review current reports about them as hepatoprotective agents, but also because they structurally resemble cholesterol, sexual hormones, corticosteroids and bile acids due to the presence of the steroid nucleus, so they all can share pharmacological properties through activating nuclear and membrane receptors. Therefore, sterols and TTP appear as a feasible option for the prevention and treatment of chronic metabolic-related liver diseases, cirrhosis, and HCC.

Colorectal Cancer: Causes and Evidence of Chemopreventive Treatments.

BACKGROUND: Colorectal cancer (CRC) is the second and third most frequent cancer in women and men, respectively; indeed, CRC is placed as the fourth world's most deadly cancer (after lung, liver, and stomach cancer). The incidence of CRC is strongly influenced by nutrition and the high fat/high carbohydrate Western-style diet. CRC is one of the most intensively studied cancer types, partly because of its high prevalence, but also because of the existence of its precursor lesions, tubular or villous adenomas, and more recently serrated adenomas. The morphological steps in the adenomacarcinoma sequence have been elucidated at a molecular level, which allow the identification of the genes responsible for CRC. Review and Conclusions: The main aim of this review is to provide data regarding the pathophysiological characteristics, molecular mechanisms as well as carcinogenic and chemopreventive agents for CRC, with emphasis on evidence supporting their efficacy. These compounds may modulate multiple signaling pathways involved in cell proliferation and apoptosis in transformed cells, they also enhance the host immune system and favor an effective treatment. Despite promising results from experimental studies, only a limited number of these compounds have been tested in clinical trials. The mechanistic spectrum and specificity of the action of phytochemicals represent a complex and evolving field of research.

Hepatoprotective Effects of Nonpolar Extracts from Inflorescences of Thistles Cirsium vulgare and Cirsium ehrenbergii on Acute Liver Damage in Rat.

BACKGROUND: Drugs for the treatment of liver diseases are scarce and not effective enough. Some species of the genus Cirsium possess hepatoprotective activity. There are no studies on the hepatoprotective effects of nonpolar extracts from inflorescences of thistles Cirsium vulgare and Cirsium ehrenbergii, and there are few reports on their chemical composition. OBJECTIVE: The aim is to obtain the hexane extract from inflorescences of both thistles and to identify preliminarily their main chemical component, and to evaluate the hepatoprotective properties of the extracts. MATERIALS AND METHODS: Hexane extracts were obtained using a Soxhlet apparatus. The chemical composition was analyzed using infrared spectra and gas chromatography-mass spectrometry. Two doses (250 and 500 mg/kg, p.o.) of both extracts were administered to assess their hepatoprotective effect on acute carbon tetrachloride (TC)-induced liver damage in rats using biochemical markers of necrosis, cholestasis, functionality, oxidative stress, and histological analysis. RESULTS: Extracts were shown to have a very similar chemical profile. Their major constituent seems to be lupeol acetate. The two doses of both extracts demonstrated comparable hepatoprotective properties because they significantly diminished all the liver injury indicators (P < 0.05) and were corroborated using histopathology. CONCLUSION: This is the first study on the hepatoprotective effects of nonpolar extracts from inflorescences of thistles C. vulgare and C. ehrenbergii. Hexane extracts administration totally prevented the acute TC-induced liver damage. The preliminary chemical analysis strongly suggests the lupeol acetate as their major constituent. Lupeol and its derivatives have been previously reported as antiinflammatory and hepatoprotective agents. SUMMARY: Hexane extracts of both thistles kept normal liver functionality and glycogen store in carbon tetrachloride-induced acute liver damageHexane extracts of both thistles showed anti-necrotic and anti-cholestatic effects, also diminished the lipid peroxidation and nitric oxide levels on the carbon tetrachloride-induced acute liver damageThe two doses of hexane extracts administered (250 and 500 mg/kg) prevented the liver injury in a very similar extentBoth nonpolar extracts are chemically very similar and their main compound seems to be lupeol acetate. Abbreviations used: TC: Carbon tetrachloride; FT-IR: Fourier transform Infrared spectroscopy; GC-MS: Gas chromatography - Mass spectrometry; V: Vehicle; E: Extract; Ecv: Extract of Cirsium vulgare; Ece: Extract of Cirsium ehrenbergii; AP: Alkaline phosphatase; GGTP: γ-Glutamyl transpeptidase; ALT: Alanine aminotransferase; DB: Direct bilirubin; TB: Total bilirubin; LP: Lipid peroxidation; MDA: Malondialdehyde; NO: Nitric oxide; TNF-α: Tumor necrosis factor-α.

Relaxant and anti-inflammatory effect of two thalidomide analogs as PDE-4 inhibitors in pregnant rat uterus.

The aim of this study was to evaluate the relaxant and anti-inflammatory effects of two thalidomide analogs as phosphodiesterase-4 (PDE-4) inhibitors in pregnant rat uterus. Uteri from Wistar female rats were isolated at 19 day of pregnancy. Uterine samples were used in functional studies to evaluate the inhibitory effects of the thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe), on prostaglandin-F2α (PGF2α)-induced phasic, K+-induced tonic, and Ca2+-induced contractions. Accumulation of cAMP was quantified in uterine homogenates by ELISA. Anti-inflammatory effect was assessed by using ELISA for determination of the pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin (IL)-1ß, and anti-inflammatory IL-10, from uterine explants stimulated with lipopolysaccharide (LPS). Nifedipine, forskolin and rolipram were used as positive controls where required. Both thalidomide analogs induced a significant inhibition of the uterine contractions induced by the pharmaco- and electro-mechanic stimuli. Nifedipine and forskolin were more potent than the analogs to inhibit the uterine contractility, but these were more potent than rolipram, and 4APDPMe was equieffective to nifedipine. Thalidomide analogs increased uterine cAMP-levels in a concentration-dependent manner. The LPS-induced TNFα and IL-1ß uterine secretion was diminished in a concentration-dependent fashion by both analogs, whereas IL-10 secretion was increased significantly. The thalidomide analogs induced utero-relaxant and anti-inflammatory effects, which were associated with the increased cAMP levels as PDE-4 inhibitors in the pregnant rat uterus. Such properties place these thalidomide analogs as potentially safe and effective tocolytic agents in a field that urgently needs improved pharmacological treatments, as in cases of preterm labor.

Evaluation of antioxidant and hepatoprotective effects of white cabbage essential oil.

CONTEXT: There have been no reports of the extraction of essential oil (EO) from white cabbage [Brassica oleracea L. var. capitata (L.) Alef. f. alba DC. (Brassicaceae)] (Bocfal) or its chemical composition, antioxidant activity, or hepatoprotective effects. OBJECTIVE: To extract Bocfal EO, to identify and quantify its chemical components, to assess their antioxidant capacity, and to evaluate the hepatoprotective properties of Bocfal EO. MATERIALS AND METHODS: Bocfal EO was obtained using hydrodistillation (200 mm Hg/58 °C). The chemical composition was analyzed using GC-MS and was quantified using GC-FID. The antioxidant activity of Bocfal EO and its main constituents was evaluated using TBARS in rat brain homogenates. A Bocfal EO hepatoprotective effect (192 mg/kg) on acute carbon tetrachloride (CT)-induced liver damage was determined in rats using biochemical markers and histological analysis. Diallyl disulphide (DADS) (1 mmol/kg) was used as a control for comparison. RESULTS: Bocfal EO contained organic polysulphides (OPSs), such as dimethyl trisulphide (DMTS) 65.43 ± 4.92% and dimethyl disulphide (DMDS) 19.29 ± 2.16% as major constituents. Bocfal EO and DMTS were found to be potent TBARS inhibitors with IC50 values of 0.51 and 3 mg/L, respectively. Bocfal EO demonstrated better hepatoprotective properties than did DADS (p < 0.05), although both slightly affected the hepatic parenchyma per se, as observed using histopathology. DISCUSSION AND CONCLUSION: The antioxidant properties of Bocfal EO and DMTS may be the mechanism of hepatoprotective action; the parenchymal disturbances by Bocfal EO or DADS alone may be related to the high doses used.

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.

Immunomodulatory effects by oral contraceptives in normal and cholestatic female rats: role of cytokines.

Oral contraceptives (OC) may cause intrahepatic cholestasis or increase a pre-established liver damage. OC effects on hepatic injury biochemical markers remain contradictory and the role of cytokines in those processes is fairly unknown. Two doses, simple or double, of the OC combination ethinylestradiol/norgestrel were administered during 14 or 28 days to normal and cholestatic female rats. Liver damage markers and the cytokines tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10) and transforming growth factor-ß (TGF-ß) were determined in plasma and liver. OC caused ambiguous results on cholestasis indicators, even more in cholestatic rats. Necrosis rose during cholestasis while OC lowered it in normal rats. Fibrosis was induced by cholestasis but OC double dose or intake time diminished that. Cholestasis depleted glycogen while OC did not alter it. Double dose or time of administration of OC significantly elevated the lipid peroxidation. Cholestasis modified plasma and liver cytokines but OC remarkably altered them in normal and cholestatic animals. TNF-α as well as IL-10 were increased in both tissues by OC, such rise was higher in normal rats. TGF-ß was augmented by OC and more in cholestatic rats receiving double dose. Thus, OC modified most liver injury markers in normal rats although more pronouncedly in cholestatic ones, as well as increased hepatic oxidative stress. Liver fibrosis was decreased and corroborated by histological analysis even when TGF-ß is elevated by OC. OC strongly immunomodulate cytokines that mediate liver damage or worsen a prior hepatopathy; those processes are influenced by dose, administration time and OC formulation.

Effect of diclofenac with B vitamins on the treatment of acute pain originated by lower-limb fracture and surgery.

The aim of this study was to compare the efficacy of diclofenac, for the treatment of acute pain originated by lower-limb fracture and surgery, with that of diclofenac plus B vitamins. This was a single-center, prospective, randomized, and double-blinded clinical trial. Patients with lower-limb closed fractures rated their pain on a 10 cm visual analog scale (VAS). Patients were then randomized to receive diclofenac or diclofenac plus B vitamins (thiamine, pyridoxine, and cyanocobalamin) intramuscularly twice daily. Patient evaluations of pain intensity were recorded throughout two periods: twenty-four hours presurgery and twenty-four hours postsurgical. One hundred twenty-two patients completed the study. The subjects' assessments of limb pain on the VAS showed a significant reduction from baseline values regardless of the treatment group. Diclofenac plus B vitamins combination was more effective to reduce the pain than diclofenac alone. The results showed that the addition of B vitamins to diclofenac increased its analgesic effect. The novelty of this paper consists in that diclofenac and diclofenac plus B vitamins were useful for treatment of acute pain originated by lower-limb fracture and surgery.

Trolox down-regulates transforming growth factor-beta and prevents experimental cirrhosis.

Cirrhosis is a very common disease and its treatment is limited due to lack of effective drugs. Some studies indicate that this disease is associated with oxidative stress. Therefore, we decided to study the effect of trolox, an effective antioxidant, on experimental cirrhosis. Cirrhosis was induced by CCl4 administration (0.4 g/kg, intraperitoneally, three times per week, for 8 weeks) to Wistar male rats. Trolox was administered daily (50 mg/kg, orally). Fibrosis was assessed histologically and by measuring liver hydroxyproline content. Glutathione, lipid peroxidation and glycogen were measured in liver; serum markers of liver damage were also quantified. Transforming growth factor-beta (TGF-beta) was determined by Western blot and quantified densitometrically. Alkaline phosphatase, gamma-glutamyl transpeptidase and alanine aminotransferase increased in the group receiving CCl4; trolox completely or partially prevented these alterations. Glycogen was almost depleted by CCl4 but was partially preserved by trolox. Lipid peroxidation increased while glutathione decreased by CCl4 administration; trolox corrected both effects. Histology showed thick bands of collagen, necrosis and distortion of the hepatic parenchyma in the CCl4 group, such effects were prevented by trolox. Hydroxyproline content increased 5-fold by CCl4, while the group receiving both CCl4 and trolox showed no significant difference compared to the control group. CCl4 increased 3-fold TGF-beta, while trolox completely prevented this increase. We found that trolox effectively prevented cirrhosis induced with CCl4 in the rat. Our results suggest that the beneficial effects of trolox may be associated to its antioxidant properties and to its ability to reduce the profibrogenic cytokine TGF-beta expression.

Trans-3-phenyl-2-propenoic acid (cinnamic acid) derivatives: structure-activity relationship as hepatoprotective agents.

Among various phenolic compounds, caffeic acid (3,4-dihydroxycinnamic acid) exhibited pharmacological antioxidant, anticancer and antimutagenic activities. The antioxidant properties of phenolic compounds depend on their chemical structure, however, the role of the ethylenic side chain in the radical scavenging activity remains controversial. Thus, the aim of this study consisted to test cinnamic acid and 15 cinnamic acid derivatives in the well known CCl(4)-induced acute liver damage model, which is dependent on oxidative stress mechanisms. Cinnamic acid and 15 cinnamic acid derivatives (50 mg/kg, p.o.) were administered to male Wistar rats intoxicated with CCl(4) (4 g/kg, p.o.). The activities of gamma-glutamyl transpeptidase, alkaline phosphatase and alanine aminotransferase were measured in serum. The lipid peroxidation products were determined in liver. Compounds with a methoxy group at position 3 or 4, or a 3,4-methylenedioxy moiety were the most active ones. Also, we observed that the monosubstituted 3 or 4 hydroxy, or the bulky 3,4 dibenzyloxy substituted compounds showed lower activity. The poorest activity was displayed by disubstituted 3,4-dihydroxy, dimethoxy or diacetyl cinnamic acid derivatives, the ester derived from cinnamic acid with an 8 carbon chain and N-dimethyl substituted compound. Thus, the methoxy substituted group at positions 3 or 4 or the 3,4-methylenedioxy moiety in the caffeic acid derivatives; seem to be the main features required for the hepatoprotection in this model.

Chronic bile duct obstruction induces changes in plasma and hepatic levels of cytokines and nitric oxide in the rat.

Chronic bile duct ligation (BDL) is a useful model of cirrhosis. However, its parallel plasma and liver changes in levels of cytokines and nitric oxide (NO), involved in liver damage, remain unknown. The aims of this work were to quantify both the plasma and hepatic levels of five cytokines and NO in cirrhotic rats, 28 days after bile BDL, and to analyze their relationship with liver damage markers. One group of male Wistar rats was bile duct ligated and another group was sham operated, both groups were sacrificed 28 days after BDL. Plasma and liver cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-6, -1beta, -10 (IL-6, -1beta, -10) and interferon-gamma (IFN-gamma), were measured by ELISA. Plasma and hepatic NO was determined as NO(2)(-)+NO(3)(-) by an enzymatic method. Alkaline phosphatase, gamma-glutamyl transpeptidase, alanine aminotransferase and bilirubins were determined in plasma. Collagen, lipid peroxidation and glycogen were quantified in liver. Two histopathological staining techniques were performed. BDL-induced cirrhosis was corroborated by the elevated liver damage markers and histopathological analysis. Chronic BDL significantly increased (P<0.05) most of plasma and hepatic cytokine levels and diminished the hepatic IFN-gamma amount. NO was increased in both tissues, but such change was only significant in plasma. Biliary cirrhosis produces interesting changes in plasma and hepatic levels of cytokines and NO. This finding in chronic BDL model in rats has not been previously described in both tissues for such cytokines and NO. Cytokines and NO imbalance favor establishment and perpetuation of cirrhosis.