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Cachexia, a complex wasting syndrome, significantly affects the quality of life and treatment options for cancer patients. Studies have reported a strong correlation between high platelet count and decreased survival in cachectic individuals. Therefore, this study aimed to investigate the immunopathogenesis of cancer cachexia using the ApcMin/+ mouse model of spontaneous colorectal cancer. The research focused on identifying cellular elements in the blood at different stages of cancer cachexia, assessing inflammatory markers and fibrogenic factors in the skeletal muscle, and studying the behavioral and metabolic phenotype of ApcMin/+ mice at the pre-cachectic and severely cachectic stages. Platelet measurements were also obtained from other animal models of cancer cachexia - Lewis Lung Carcinoma and Colon 26 adenocarcinoma. Our study revealed that platelet number is elevated prior to cachexia development in ApcMin/+ mice and can become activated during its progression. We also observed increased expression of TGFβ2, TGFβ3, and SMAD3 in the skeletal muscle of pre-cachectic ApcMin/+ mice. In severely cachectic mice, we observed an increase in Ly6g, CD206, and IL-10 mRNA. Meanwhile, IL-1β gene expression was elevated in the pre-cachectic stage. Our behavioral and metabolic phenotyping results indicate that pre-cachectic ApcMin/+ mice exhibit decreased physical activity. Additionally, we found an increase in anemia at pre-cachectic and severely cachectic stages. These findings highlight the altered platelet status during early and late stages of cachexia and provide a basis for further investigation of platelets in the field of cancer cachexia.

Abstract Background Quercetin is an organic flavonoid present in several fruits and vegetables. The anti-inflammatory, antiviral, antioxidant, cardio-protective, anti-carcinogenic and neuroprotective properties demonstrated by this dietary supplement endorses it as a possible treatment for inflammatory diseases and cancer. Unfortunately, conflicting research has cast uncertainties on the toxicity of quercetin. The main purpose of this study was to determine if quercetin has any toxic properties in mice at doses that have shown efficacy in pre-clinical studies regarding cancer, cancer therapy, and their off-target effects. Methods A sub-chronic toxicity study of quercetin was examined in male and female CD2F1 mice. Three different doses of quercetin (62, 125, and 250 mg/kg of diet) were infused into the AIN-76A purified diet and administered to mice ad libitum for 98 days. Body weight (BW), food consumption, water intake, body composition, blood count, behavior, and metabolic phenotype were assessed at various timepoints during the course of the experiment. Tissue and organs were evaluated for gross pathological changes and plasma was used to measure alkaline phosphatase (AP), aspartate transaminase (AST), and alanine transaminase (ALT). Results We found that low (62 mg/kg of diet), medium (125 mg/kg of diet), and high (250 mg/kg of diet) quercetin feeding had no discernible effect on body composition, organ function, behavior or metabolism. Conclusions In summary, our study establishes that quercetin is safe for use in both female and male CD2F1 mice when given at ~ 12.5, 25, or 50 mg/kg of BW daily doses for 14 weeks (i.e. 98 days). Further studies will need to be conducted to determine any potential toxicity of quercetin following chronic ingestion.

(1) Background: Gastrointestinal pain and fatigue are the most reported concerns of patients with inflammatory bowel disease (IBD). Commonly prescribed drugs focus on decreasing excessive inflammation. However, up to 20% of IBD patients in an “inactive” state experience abdominal pain. The medicinal herb Ojeok-san (OJS) has shown promise in the amelioration of visceral pain. However, no research on OJS has been conducted in preclinical models of IBD. The mechanism by which OJS promotes analgesia is still elusive, and it is unclear if OJS possesses addictive properties. (2) Aims: In this study, we examined the potential of OJS to promote analgesic effects and rewarding behavior. Additionally, we investigated if tumor necrosis factor alpha (TNFα) from macrophages is a primary culprit of IBD-induced nociception. (3) Methods: Multiple animal models of IBD were used to determine if OJS can reduce visceral nociception. TNFα-macrophage deficient mice were used to investigate the mechanism of action by which OJS reduces nociceptive behavior. Mechanical sensitivity and operant conditioning tests were used to determine the analgesic and rewarding effects of OJS. Body weight, colon length/weight, blood in stool, colonic inflammation, and complete blood count were assessed to determine disease progression. (4) Results: OJS reduced the evoked mechanical nociception in the dextran sulphate sodium model of colitis and IL-10 knockout (KO) mice and delayed aversion to colorectal distension in C57BL/6 mice. No rewarding behavior was observed in OJS-treated IL-10 KO and mdr1a KO mice. The analgesic effects of OJS are independent of macrophage TNFα levels and IBD progression. (5) Conclusions: OJS ameliorated elicited mechanical and visceral nociception without producing rewarding effects. The analgesic effects of OJS are not mediated by macrophage TNFα.

Cancer patients can develop visceral, somatic, and neuropathic pain, largely due to the malignancy itself and its treatments. Often cancer patients and survivors turn to the use of complementary and alternative medicine (CAM) to alleviate pain and fatigue. Thus, it is necessary to investigate how CAM therapies work as novel analgesics to treat cancer pain. Ojeok-san (OJS) is an herbal formula consisting of seventeen herbs. This herbal formula has been shown to possess anti-inflammatory, immunoregulatory, and analgesic properties. In this study, we examined the potential beneficial effects and mechanism of action of OJS in a preclinical model of colitis-associated colorectal cancer. Male and female C57BL/6J mice were exposed to the carcinogen, azoxymethane (AOM, 10 mg/kg) and a chemical inflammatory driver, dextran sulfate sodium (DSS1-2%), to promote tumorigenesis in the colorectum. OJS was given orally (500, 1000, and 2000 mg/kg) to determine its influence on disease activity, tumor burden, nociception, sedation, Erk signaling, and behavioral and metabolic outcomes. In addition, in vitro studies were performed to assess CT-26 cell viability, dorsal root ganglia (DRG) activation, and bone-marrow-derived macrophage (BMDM) inflammatory response to lipopolysaccharide stimulation after OJS treatment. We found that administration of 2000 mg/kg of OJS was able to mitigate mechanical somatic and visceral nociception via Erk signaling without affecting symptom score and polyp number. Moreover, we discovered that OJS has sedative properties and elicits prolonged total sleeping time in AOM/DSS mice. Our in vitro experiments showed that OJS has the capacity to reduce TNFα gene expression in LPS-stimulated BMDM, but no changes were observed in DRG spike number and CT-26 cell proliferation. Taken together, these data suggest that OJS ameliorates nociception in mice and warrants further examination as a potential CAM therapy to promote analgesia.

A cachexia diagnosis is associated with a doubling in hospital stay and increased healthcare cost for cancer patients and most cachectic patients do not survive treatment. Unfortunately, complexity in treating cachexia is amplified by both the underlying malignancy and the anti-cancer therapy which can independently promote cachexia. Quercetin, an organic polyphenolic flavonoid, has demonstrated anti-inflammatory and antioxidant properties with promise in protecting against cancer and chemotherapy-induced dysfunction; however, whether quercetin is efficacious in maintaining muscle mass in tumor-bearing animals receiving chemotherapy has not been investigated. C26 tumor-bearing mice were given 5-fluorouracil (5FU; 30 mg/kg of lean mass i.p.) concomitant with quercetin (Quer; 50 mg/kg of body weight via oral gavage) or vehicle. Both C26 + 5FU and C26 + 5FU + Quer had similar body weight loss; however, muscle mass and cross-sectional area was greater in C26 + 5FU + Quer compared to C26 + 5FU. Additionally, C26 + 5FU + Quer had a greater number and larger intermyofibrillar mitochondria with increased relative protein expression of mitochondrial complexes V, III, and II as well as cytochrome c expression. C26 + 5FU + Quer also had increased MFN1 and reduced FIS1 relative protein expression without apparent benefits to muscle inflammatory signaling. Our data suggest that quercetin protected against cancer and chemotherapy-induced muscle mass loss through improving mitochondrial homeostatic balance.