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Current Opinion in Supportive and... Jun 2017Pain is one of the most common and feared symptoms associated with a new diagnosis of cancer and its subsequent treatment. Unfortunately, it remains undertreated in... (Review)
Review
PURPOSE OF REVIEW
Pain is one of the most common and feared symptoms associated with a new diagnosis of cancer and its subsequent treatment. Unfortunately, it remains undertreated in around one third of patients. It has been recently postulated that one mechanism for this could be failure to recognize neuropathic pain. One attractive option in both the case of neuropathic pain and pain associated with intolerable side effects of prescribed opioids is the use of 'topiceuticals', as a means of targeted pain relief with potentially fewer side effects. The present review summarizes the evidence base for the various topiceuticals available for the treatment of localized neuropathic pain.
RECENT FINDINGS
The recent evidence base for established treatments such as capsaicin and lignocaine is examined. A variety of novel and previously used therapies are considered.
SUMMARY
The use of topiceuticals in localized neuropathic pain associated with malignancy remain a valuable option with many advantages over systemic treatments. In addition to anecdotal reports of efficacy, there is a growing body of evidence to consider the early use of topical lignocaine and capsaicin in this context. The authors' have proposed a guideline including the use of topiceuticals to aid in the management of neuropathic pain.
Topics: Administration, Cutaneous; Analgesics, Opioid; Anesthetics, Local; Cancer Pain; Capsaicin; Clinical Trials as Topic; Clonidine; Drug Therapy, Combination; Humans; Lidocaine; Menthol; Neuralgia; Pain Management; Pain Measurement
PubMed: 28460372
DOI: 10.1097/SPC.0000000000000271 -
Biomolecules Mar 2023Accumulating evidence has demonstrated the association between alcohol overconsumption and the development of insulin resistance. However, the underlying mechanisms are...
Accumulating evidence has demonstrated the association between alcohol overconsumption and the development of insulin resistance. However, the underlying mechanisms are not completely understood. To investigate the requirement and sufficiency of hepatocyte toll-like receptor 4 (TLR4) in alcohol-induced insulin resistance, we used two mouse models (Tlr4 and Tlr4) that allow ablation of TLR4 only in hepatocytes (Tlr4) and restoration of endogenous TLR4 expression in hepatocytes on a TLR4-null background (Tlr4 × Alb-Cre), respectively. A Lieber-DeCarli feeding model was used to induce glucose intolerance and insulin resistance in mice. Glucose tolerance test, insulin tolerance test, and insulin signaling experiments were performed to examine systemic and tissue-specific insulin sensitivity. We found that alcohol-fed hepatocyte TLR4 deficient mice (Tlr4) had lower blood glucose levels in response to intraperitoneal injection of insulin. Moreover, increased phosphorylation of glycogen synthase kinase-3β (GSK3β) was observed in the liver of Tlr4 mice after chronic alcohol intake. In contrast, when hepatic TLR4 was reactivated in mice (Tlr4 × Alb-Cre), alcohol feeding caused glucose intolerance in these mice compared with littermate controls (Tlr4). In addition, AKT phosphorylation was dramatically reduced in the liver and epididymal white adipose tissue (eWAT) of alcohol-fed Tlr4 × Alb-Cre mice, which was similar to that of mice with whole-body TLR4 reactivation (Tlr4 × Zp3-Cre). Collectively, these findings suggest that hepatocyte TLR4 is both required and sufficient in the development of insulin resistance induced by alcohol overconsumption.
Topics: Animals; Mice; Ethanol; Glucose Intolerance; Hepatocytes; Insulin; Insulin Resistance; Liver; Mice, Inbred C57BL; Toll-Like Receptor 4
PubMed: 36979389
DOI: 10.3390/biom13030454 -
Women's Health Issues : Official... 2022Women are experiencing greater unemployment and increased stress from childcare responsibilities than men during the COVID-19 pandemic. Women with these experiences may...
PURPOSE
Women are experiencing greater unemployment and increased stress from childcare responsibilities than men during the COVID-19 pandemic. Women with these experiences may be at particular risk for mental illness and increased substance use during the COVID-19 pandemic. The purpose of the study was to assess women's substance use, mental health, and experiences of COVID-19 pandemic impacts.
METHODS
A national online survey was administered to adult women from September to November 2020. The survey included questionnaires assessing mental health, loneliness, intolerance for uncertainty, social support, substance use, and intimate partner violence (IPV).
RESULTS
A total of 499 women responded; most were White, college educated, and in their mid-30s. Of the 20.24% who acknowledged at least one IPV problem, 29.7% stated that their IPV problems have gotten worse since the pandemic began, and 16.83% said that they have increased their drug or alcohol use to cope with their relationship problems. Anxiety, perceived daily impact of COVID-19, and lower self-efficacy were significant predictors of COVID-19 anxiety. Those with risky alcohol use had significantly higher anxiety (p = .028) and depression (p = .032) than those with low-risk alcohol use.
CONCLUSIONS
Greater anxiety about COVID-19, greater reported changes in daily life due to the pandemic, and high-risk alcohol use are related to greater mental health-related distress among women. For some, IPV has gotten worse during the pandemic and drug or alcohol use is a coping mechanism.
Topics: Adult; Anxiety; COVID-19; Female; Humans; Intimate Partner Violence; Mental Health; Pandemics; Substance-Related Disorders; Women's Health
PubMed: 35246351
DOI: 10.1016/j.whi.2022.01.004 -
Nutrients Oct 2023Excessive intake of sugar, and particularly fructose, is closely associated with the development and progression of metabolic syndrome in humans and animal models....
Excessive intake of sugar, and particularly fructose, is closely associated with the development and progression of metabolic syndrome in humans and animal models. However, genetic disorders in fructose metabolism have very different consequences. While the deficiency of fructokinase, the first enzyme involved in fructose metabolism, is benign and somewhat desirable, missense mutations in the second enzyme, aldolase B, causes a very dramatic and sometimes lethal condition known as hereditary fructose intolerance (HFI). To date, there is no cure for HFI, and treatment is limited to avoiding fructose and sugar. Because of this, for subjects with HFI, glucose is their sole source of carbohydrates in the diet. However, clinical symptoms still occur, suggesting that either low amounts of fructose are still being consumed or, alternatively, fructose is being produced endogenously in the body. Here, we demonstrate that as a consequence of consuming high glycemic foods, the polyol pathway, a metabolic route in which fructose is produced from glucose, is activated, triggering a deleterious mechanism whereby glucose, sorbitol and alcohol induce severe liver disease and growth retardation in aldolase B knockout mice. We show that generically and pharmacologically blocking this pathway significantly improves metabolic dysfunction and thriving and increases the tolerance of aldolase B knockout mice to dietary triggers of endogenous fructose production.
Topics: Humans; Animals; Mice; Fructose Intolerance; Fructose; Fructose-Bisphosphate Aldolase; Liver Diseases; Digestive System Diseases; Glucose; Mice, Knockout
PubMed: 37892451
DOI: 10.3390/nu15204376 -
Cancers Oct 2019Liver cancer is one of the leading causes of death worldwide due to late diagnosis and scarcity of treatment options. The major risk factor for liver cancer is cirrhosis... (Review)
Review
Liver cancer is one of the leading causes of death worldwide due to late diagnosis and scarcity of treatment options. The major risk factor for liver cancer is cirrhosis with the underlying causes of cirrhosis being viral infection (hepatitis B or C), metabolic deregulation (Non-alcoholic fatty liver disease (NAFLD) in the presence of obesity and diabetes), alcohol or cholestatic disorders. Lysophosphatidic acid (LPA) is a bioactive phospholipid with numerous effects, most of them compatible with the hallmarks of cancer (proliferation, migration, invasion, survival, evasion of apoptosis, deregulated metabolism, neoangiogenesis, etc.). Autotaxin (ATX) is the enzyme responsible for the bulk of extracellular LPA production, and together with LPA signaling is involved in chronic inflammatory diseases, fibrosis and cancer. This review discusses the most important findings and the mechanisms related to ATX/LPA/LPAR involvement on metabolic, viral and cholestatic liver disorders and their progression to liver cancer in the context of human patients and mouse models. It focuses on the role of ATX/LPA in NAFLD development and its progression to liver cancer as NAFLD has an increasing incidence which is associated with the increasing incidence of liver cancer. Bearing in mind that adipose tissue accounts for the largest amount of LPA production, many studies have implicated LPA in adipose tissue metabolism and inflammation, liver steatosis, insulin resistance, glucose intolerance and lipogenesis. At the same time, LPA and ATX play crucial roles in fibrotic diseases. Given that hepatocellular carcinoma (HCC) is usually developed on the background of liver fibrosis, therapies that both delay the progression of fibrosis and prevent its development to malignancy would be very promising. Therefore, ATX/LPA signaling appears as an attractive therapeutic target as evidenced by the fact that it is involved in both liver fibrosis progression and liver cancer development.
PubMed: 31652837
DOI: 10.3390/cancers11111626 -
Molecular Metabolism Dec 2023Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality worldwide. Current strategies to manage ALD focus largely on advanced stage...
Ceramide synthase 6 (CerS6) is upregulated in alcohol-associated liver disease and exhibits sex-based differences in the regulation of energy homeostasis and lipid droplet accumulation.
OBJECTIVE
Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality worldwide. Current strategies to manage ALD focus largely on advanced stage disease, however, metabolic changes such as glucose intolerance are apparent at the earliest stage of alcoholic steatosis and increase the risk of disease progression. Ceramides impair insulin signaling and accumulate in ALD, and metabolic pathways involving ceramide synthase 6 (CerS6) are perturbed in ALD during hepatic steatosis. In this study, we aimed to investigate the role of CerS6 in ALD development and the relevance of CerS6 to human ALD.
METHODS
C57BL/6 WT and CerS6 KO mice of both sexes were fed either a Lieber-DeCarli control (CON) or 15% ethanol (EtOH) diet for six weeks. In vivo metabolic tests including glucose and insulin tolerance tests (GTT and ITT) and energy expenditure were performed. The mice were euthanized, and serum and liver lipids and liver histology were examined. For in vitro studies, CerS6 was deleted in human hepatocytes, VL17A and cells were incubated with EtOH and/or C-ceramides. RNAseq analysis was performed in livers from mice and human patients with different stages of ALD and diseased controls.
RESULTS
After six weeks on an EtOH diet, CerS6 KO mice had reduced body weight, food intake, and %fat mass compared to WT mice. Energy expenditure increased in both male and female KO mice, however, was only statistically significant in male mice. In response to EtOH, WT mice developed mild hepatic steatosis, while steatosis was ameliorated in KO mice as determined by H&E and ORO staining. KO mice showed significantly decreased long-chain ceramide species, especially C-ceramides, in the serum and liver tissues compared to WT mice. CerS6 deletion decreased serum TG and NEFA only in male not female mice. CerS6 deletion improved glucose tolerance and insulin resistance in EtOH-fed mice of both sexes. RNAseq analysis revealed that 74 genes are significantly upregulated and 66 genes are downregulated by CerS6 deletion in EtOH-fed male mice, with key network pathways including TG biosynthetic process, positive regulation of lipid localization, and fat cell differentiation. Similar to RNAseq results, absence of CerS6 significantly decreased mRNA expression of lipid droplet associated proteins in EtOH-fed mice. In vitro, EtOH stimulation significantly increased PLIN2 protein expression in VL17A cells while CerS6 deletion inhibited EtOH-mediated PLIN2 upregulation. C-ceramide treatment significantly increased PLIN2 protein expression compared to CON. Notably, progression of ALD in humans was associated with increased hepatic CerS6 expression.
CONCLUSIONS
Our findings demonstrate that CerS6 deletion improves glucose homeostasis in alcohol-fed mice and exhibits sex-based differences in the attenuation of EtOH-induced weight gain and hepatic steatosis. Additionally, we unveil that CerS6 plays a major role as a regulator of lipid droplet biogenesis in alcohol-induced intra-hepatic lipid droplet formation, identifying it as a putative target for early ALD management.
Topics: Animals; Female; Humans; Male; Mice; Ceramides; Ethanol; Fatty Liver; Glucose; Homeostasis; Insulins; Lipid Droplets; Liver Diseases, Alcoholic; Mice, Inbred C57BL; Perilipin-2
PubMed: 37714377
DOI: 10.1016/j.molmet.2023.101804 -
Frontiers in Molecular Biosciences 2021Aldehyde dehydrogenases engage in many cellular functions, however their dysfunction resulting in accumulation of their substrates can be cytotoxic. ALDHs are... (Review)
Review
Aldehyde dehydrogenases engage in many cellular functions, however their dysfunction resulting in accumulation of their substrates can be cytotoxic. ALDHs are responsible for the NAD(P)-dependent oxidation of aldehydes to carboxylic acids, participating in detoxification, biosynthesis, antioxidant and regulatory functions. Severe diseases, including alcohol intolerance, cancer, cardiovascular and neurological diseases, were linked to dysfunctional ALDH enzymes, relating back to key enzyme structure. An in-depth understanding of the ALDH structure-function relationship and mechanism of action is key to the understanding of associated diseases. Principal structural features 1) cofactor binding domain, 2) active site and 3) oligomerization mechanism proved critical in maintaining ALDH normal activity. Emerging research based on the combination of structural, functional and biophysical studies of bacterial and eukaryotic ALDHs contributed to the appreciation of diversity within the superfamily. Herewith, we discuss these studies and provide our interpretation for a global understanding of ALDH structure and its purpose-including correct function and role in disease. Our analysis provides a synopsis of a common structure-function relationship to bridge the gap between the highly studied human ALDHs and lesser so prokaryotic models.
PubMed: 34055881
DOI: 10.3389/fmolb.2021.659550 -
Journal of Ginseng Research May 2023Hepatic lipid disorder impaired mitochondrial homeostasis and intracellular redox balance, triggering development of non-alcohol fatty liver disease (NAFLD), while...
BACKGROUND
Hepatic lipid disorder impaired mitochondrial homeostasis and intracellular redox balance, triggering development of non-alcohol fatty liver disease (NAFLD), while effective therapeutic approach remains inadequate. Ginsenosides Rc has been reported to maintain glucose balance in adipose tissue, while its role in regulating lipid metabolism remain vacant. Thus, we investigated the function and mechanism of ginsenosides Rc in defending high fat diet (HFD)-induced NAFLD.
METHODS
Mice primary hepatocytes (MPHs) challenged with oleic acid & palmitic acid were used to test the effects of ginsenosides Rc on intracellular lipid metabolism. RNAseq and molecular docking study were performed to explore potential targets of ginsenosides Rc in defending lipid deposition. Wild type and liver specific deficient mice on HFD for 12 weeks were subjected to different dose of ginsenosides Rc to determine the function and detailed mechanism in vivo.
RESULTS
We identified ginsenosides Rc as a novel activator via increasing its expression and deacetylase activity. Ginsenosides Rc defends OA&PA-induced lipid deposition in MPHs and protects mice against HFD-induced metabolic disorder in dosage dependent manner. Ginsenosides Rc (20mg/kg) injection improved glucose intolerance, insulin resistance, oxidative stress and inflammation response in HFD mice. Ginsenosides Rc treatment accelerates -mediated fatty acid oxidation in vivo and in vitro. Hepatic specific deletion abolished ginsenoside Rc-derived protective effects against HFD-induced NAFLD.
CONCLUSION
Ginsenosides Rc protects mice against HFD-induced hepatosteatosis by improving -mediated fatty acid oxidation and antioxidant capacity in a dependent manner, and providing a promising strategy for NAFLD.
PubMed: 37252281
DOI: 10.1016/j.jgr.2020.07.005 -
Cureus May 2022Lactose intolerance (LI) appears usually in later ages when the lactase enzyme becomes deficient or absent in the small intestine. Conflicting results have been reported...
BACKGROUND
Lactose intolerance (LI) appears usually in later ages when the lactase enzyme becomes deficient or absent in the small intestine. Conflicting results have been reported in the literature about the association of lactose intolerance with various gastrointestinal malignancies. Hence, our aim was to study the association between LI, colon cancer (CCa), and gastric cancer (GC) using a large database.
METHODS
A cross-sectional study was performed using the National Inpatient Sample (NIS) database between 2004 and 2014. We identified adult patients (18-90 years) who were diagnosed with LI (study group) using appropriate International Classification of Diseases, Ninth Revision (ICD-9) codes. The control group comprised patients who did not have a diagnosis of LI. We identified the diagnosis of CCa and GC in both study and control groups using the ICD-9 codes. Univariable and multivariable logistic regression analyses were performed to assess the association between LI, CCa, and GC.
RESULTS
The total population comprised 71,360,501 patients, of which 57,909 (0.08%) were diagnosed with LI. LI patients were older (62 vs 51 years) with more females (61.5% vs 60.1%) and less African American patients (11.8% vs 14.3%) (p <0.0001 for all). In addition, LI patients had more smoking (12.4% vs 12%) and obesity (15% vs 8.9%). On the other hand, patients in the LI group had less alcohol use (3.8% vs 4.2%) (p <0.0001). After adjusting for the age, gender, race, smoking, alcohol, obesity, and inflammatory bowel disease, the LI group had a slightly lower rate of CCa (OR 0 .974, 95%CI 0.906-1.048, p = 0.486) and a lower rate of GC (OR: 0.993, 95%CI 0.924-1.068, p =0.853); however, the results were not statistically significant.
CONCLUSION
Patients with lactose intolerance may have a lower risk of colon and gastric cancer. However, these findings were not statistically significant. Further studies are needed to understand this association.
PubMed: 35676992
DOI: 10.7759/cureus.24713