Molecular Pharmacology of Vitamin C and Relevance to Health and Obesity-A Narrative Review.

The role of food constituents as pharmacological agents is an important consideration in health and obesity. Vitamin C acts as a small molecule antioxidant but is also a co-factor for numerous transition metal-dependent enzymes involved in healthy weight and energy metabolism. Vitamin C cannot be manufactured by humans and is mainly obtained from the dietary intake of fresh fruit and vegetables. There is great variability between different nutritional guidelines in the recommended daily allowance of vitamin C. Vitamin C deficiency results from an inadequate intake of vitamin C-containing foods and also increased utilization by oxidative and carbonyl stress. Risk factors for vitamin C deficiency include cigarette smoking, malnutrition, obesity, type 2 diabetes mellitus, age, race, sex, social isolation, major surgery, and Western-type diets. Despite the common belief that vitamin C deficiency is rare in affluent countries, surveys of large populations and specific patient groups suggest otherwise. Patients with obesity typically consume highly processed, energy-dense foods which contain inadequate micronutrients. As obesity increases, larger amounts of oral vitamin C are required to achieve adequate plasma and tissue concentrations, as compared to persons with a healthy weight. This is important in the control of oxidative stress and the maintenance of homeostasis and organ function. In this narrative review, the dosage, absorption, distribution, excretion, and catabolism of vitamin C are reviewed, together with the latest findings on vitamin C pharmacology in patients with obesity.

Cellular Senescence and Extracellular Vesicles in the Pathogenesis and Treatment of Obesity-A Narrative Review.

This narrative review explores the pathophysiology of obesity, cellular senescence, and exosome release. When exposed to excessive nutrients, adipocytes develop mitochondrial dysfunction and generate reactive oxygen species with DNA damage. This triggers adipocyte hypertrophy and hypoxia, inhibition of adiponectin secretion and adipogenesis, increased endoplasmic reticulum stress and maladaptive unfolded protein response, metaflammation, and polarization of macrophages. Such feed-forward cycles are not resolved by antioxidant systems, heat shock response pathways, or DNA repair mechanisms, resulting in transmissible cellular senescence via autocrine, paracrine, and endocrine signaling. Senescence can thus affect preadipocytes, mature adipocytes, tissue macrophages and lymphocytes, hepatocytes, vascular endothelium, pancreatic ß cells, myocytes, hypothalamic nuclei, and renal podocytes. The senescence-associated secretory phenotype is closely related to visceral adipose tissue expansion and metaflammation; inhibition of SIRT-1, adiponectin, and autophagy; and increased release of exosomes, exosomal micro-RNAs, pro-inflammatory adipokines, and saturated free fatty acids. The resulting hypernefemia, insulin resistance, and diminished fatty acid ß-oxidation lead to lipotoxicity and progressive obesity, metabolic syndrome, and physical and cognitive functional decline. Weight cycling is related to continuing immunosenescence and exposure to palmitate. Cellular senescence, exosome release, and the transmissible senescence-associated secretory phenotype contribute to obesity and metabolic syndrome. Targeted therapies have interrelated and synergistic effects on cellular senescence, obesity, and premature aging.

ADOPTERs of Innovation in a Crisis: The History of Vera Gedroits, Kanehiro Takaki and the Russo-Japanese War of 1904-1905.

The 1904-1905 Russo-Japanese War was the first "modern" conflict, using rapid-firing artillery and machine guns, fought over imperial ambitions in Korea and Manchuria. During the war, Princess Vera Gedroits pioneered early laparotomy for penetrating abdominal wounds with unprecedented success. Her techniques were then adopted by the Russian Society of Military Doctors. However, Allied forces took 10 years to adopt operative management of penetrating abdominal wounds over conservative management. Gedroits was later appointed in Kyiv as the world's first female Professor of Surgery. Kanehiro Takaki, a Japanese Naval surgeon, showed in 1884 a diet of barley, meat, milk, bread, and beans, rather than polished white rice, eliminated beriberi in the Japanese Navy. Despite this success, the Japanese Army failed to change the white rice rations until March 1905. During the 1904-1905 Russo-Japanese War, an estimated 250,000 Japanese soldiers developed beriberi, of whom 27,000 died. Japan's 1905 defeat of Russia sowed the seeds of discontent with Tsar Nicholas' rule, culminating in the 1917 Russian Revolution. Although the Russian Navy was destroyed, Japan ceded North Sakhalin Island to Russia in peace negotiations, and Russia seized Manchuria, South Sakhalin, and the Kuril Islands in 1945. We highlight the contributions of Gedroits and Takaki, 2 intellectual prodigies who respectively pioneered rapid triage and surgical management of trauma and a cure for beriberi. We aim to show how both these surgeons challenged entrenched dogma and the cultural and political zeitgeist, and risked their professional reputations and their lives in being ADOPTERs of innovation during a crisis.

NETosis in Surgery: Pathophysiology, Prevention, and Treatment.

OBJECTIVE: To provide surgeons with an understanding of the latest research on NETosis, including the pathophysiology and treatment of conditions involving neutrophil extracellular traps (NETs) in the care of surgical patients. BACKGROUND: A novel function of neutrophils, the formation of NETs, was described in 2004. Neutrophils form mesh-like structures of extruded decondensed chromatin, comprising DNA and histones decorated with bactericidal proteins. These NETs exert antimicrobial action by trapping microorganisms and preventing their wider dissemination through the body. RESULTS: A narrative review of the existing literature describing NETosis was conducted, including NET pathophysiology, conditions related to NET formation, and treatments relevant to surgeons. CONCLUSIONS: In addition to its canonical antimicrobial function, NETosis can exacerbate inflammation, resulting in tissue damage and contributing to numerous diseases. NETs promote gallstone formation and acute pancreatitis, impair wound healing in the early postoperative period and in chronic wounds, and facilitate intravascular coagulation, cancer growth, and metastasis. Agents that target NET formation or removal have shown promising efficacy in treating these conditions, although large clinical trials are required to confirm these benefits.

Molecular Mechanisms of Western Diet-Induced Obesity and Obesity-Related Carcinogenesis-A Narrative Review.

The present study aims to provide a narrative review of the molecular mechanisms of Western diet-induced obesity and obesity-related carcinogenesis. A literature search of the Cochrane Library, Embase and Pubmed databases, Google Scholar and the grey literature was conducted. Most of the molecular mechanisms that induce obesity are also involved in the twelve Hallmarks of Cancer, with the fundamental process being the consumption of a highly processed, energy-dense diet and the deposition of fat in white adipose tissue and the liver. The generation of crown-like structures, with macrophages surrounding senescent or necrotic adipocytes or hepatocytes, leads to a perpetual state of chronic inflammation, oxidative stress, hyperinsulinaemia, aromatase activity, activation of oncogenic pathways and loss of normal homeostasis. Metabolic reprogramming, epithelial mesenchymal transition, HIF-1α signalling, angiogenesis and loss of normal host immune-surveillance are particularly important. Obesity-associated carcinogenesis is closely related to metabolic syndrome, hypoxia, visceral adipose tissue dysfunction, oestrogen synthesis and detrimental cytokine, adipokine and exosomal miRNA release. This is particularly important in the pathogenesis of oestrogen-sensitive cancers, including breast, endometrial, ovarian and thyroid cancer, but also 'non-hormonal' obesity-associated cancers such as cardio-oesophageal, colorectal, renal, pancreatic, gallbladder and hepatocellular adenocarcinoma. Effective weight loss interventions may improve the future incidence of overall and obesity-associated cancer.

Systematic Review and Meta-Analysis of the Impact of Bariatric Surgery on Future Cancer Risk.

The study aimed to perform a systematic review and meta-analysis of the evidence for the prevention of future cancers following bariatric surgery. A systematic literature search of the Cochrane Library, Embase, Scopus, Web of Science and PubMed databases (2007-2023), Google Scholar and grey literature was conducted. A meta-analysis was performed using the inverse variance method and random effects model. Thirty-two studies involving patients with obesity who received bariatric surgery and control patients who were managed with conventional treatment were included. The meta-analysis suggested bariatric surgery was associated with a reduced overall incidence of cancer (RR 0.62, 95% CI 0.46-0.84, p < 0.002), obesity-related cancer (RR 0.59, 95% CI 0.39-0.90, p = 0.01) and cancer-associated mortality (RR 0.51, 95% CI 0.42-0.62, p < 0.00001). In specific cancers, bariatric surgery was associated with reduction in the future incidence of hepatocellular carcinoma (RR 0.35, 95% CI 0.22-0.55, p < 0.00001), colorectal cancer (RR 0.63, CI 0.50-0.81, p = 0.0002), pancreatic cancer (RR 0.52, 95% CI 0.29-0.93, p = 0.03) and gallbladder cancer (RR 0.41, 95% CI 0.18-0.96, p = 0.04), as well as female specific cancers, including breast cancer (RR 0.56, 95% CI 0.44-0.71, p < 0.00001), endometrial cancer (RR 0.38, 95% CI 0.26-0.55, p < 0.00001) and ovarian cancer (RR 0.45, 95% CI 0.31-0.64, p < 0.0001). There was no significant reduction in the incidence of oesophageal, gastric, thyroid, kidney, prostate cancer or multiple myeloma after bariatric surgery as compared to patients with morbid obesity who did not have bariatric surgery. Obesity-associated carcinogenesis is closely related to metabolic syndrome; visceral adipose dysfunction; aromatase activity and detrimental cytokine, adipokine and exosomal miRNA release. Bariatric surgery results in long-term weight loss in morbidly obese patients and improves metabolic syndrome. Bariatric surgery may decrease future overall cancer incidence and mortality, including the incidence of seven obesity-related cancers.