E. Angela Murphy's research while affiliated with University of South Carolina and other places

Ulcerative colitis (UC) is an idiopathic inflammatory disease of the large intestine, which impacts millions worldwide. Current interventions aimed at treating UC symptoms can have off-target effects, invoking the need for alternatives that may provide similar benefits with less unintended consequences. This study builds on our initial data, which showed that panaxynol - a novel, potent, bioavailable compound found in American ginseng - can suppress disease severity in murine colitis. Here we explore the underlying mechanisms by which panaxynol improves both chronic and acute murine colitis. 14-week-old C57BL/6 female mice were either given 3 rounds of dextran sulfate sodium (DSS) in drinking water to induce chronic colitis or 1 round to induce acute colitis. Vehicle or panaxynol (2.5 mg/kg) was administered via oral gavage 3x/week for the study duration. Consistent with our previous findings, panaxynol significantly (p<0.05) improved the disease activity index and endoscopic scores in both models. Using the acute model to examine potential mechanisms, we show that panaxynol significantly (p<0.05) reduced DSS-induced crypt distortion, goblet cell loss, and mucus loss in the colon. 16s sequencing revealed panaxynol altered microbial composition to suppress colitis-enriched genera (i.e., Enterococcus, Eubacterium, and Ruminococcus). Additionally, panaxynol significantly (p<0.05) suppressed macrophages and induced regulatory T-cells in the colonic lamina propria. The beneficial effects of panaxynol on mucosal and crypt architecture, combined with its microbial and immune-mediated effects, provide insight into mechanisms by which panaxynol suppresses murine colitis. Overall, this data is promising for the use of panaxynol to improve colitis in the clinic.

Increased production of extracellular matrix is a necessary response to tissue damage and stress. In a normal healing process, the increase in extracellular matrix is transient. In some instances; however, the increase in extracellular matrix can persist as fibrosis, leading to deleterious alterations in organ structure, biomechanical properties, and function. Indeed, fibrosis is now appreciated to be an important cause of mortality and morbidity. Extensive research has illustrated that fibrosis can be slowed, arrested or even reversed; however, few drugs have been approved specifically for anti-fibrotic treatment. This is in part due to the complex pathways responsible for fibrogenesis and the undesirable side effects of drugs targeting these pathways. Natural products have been utilized for thousands of years as a major component of traditional medicine and currently account for almost one-third of drugs used clinically worldwide. A variety of plant-derived compounds have been demonstrated to have preventative or even reversal effects on fibrosis. This review will discuss the effects and the underlying mechanisms of some of the major plant-derived compounds that have been identified to impact fibrosis.

Immune cell driven pathways are linked to cancer cachexia. Tumor presence is associated with immune cell infiltration whereas cytotoxic chemotherapies reduce immune cell counts. Despite these paradoxical effects, both cancer and chemotherapy can cause cachexia; however, our understanding of immune responses in the cachexia condition with cancer and chemotherapy is largely unknown. We sought to advance our understanding of the immunology underlying cancer and cancer with chemotherapy induced cachexia. CD2F1 mice were given 10 ⁶ C26 cells, followed by 5 doses of 5-fluorouracil (5FU; 30mg/kg LM, i.p.) or PBS. Indices of cachexia and tumor (TUM), skeletal muscle (SKM), and adipose tissue (AT) immune cell populations were examined using high-parameter flow cytometry. While 5FU was able to stunt tumor growth, % body weight loss and muscle mass were not different between C26 and C26+5FU. C26 increased CD11b ⁺ Ly6g ⁺ and CD11b ⁺ Ly6c Int inflammatory myeloid cells in SKM and AT, however both populations were reduced with C26+5FU. tSNE analysis revealed 24 SKM macrophage subsets wherein 8 were changed with C26 or C26+5FU. C26+5FU increased SKM CD11b ⁻ CD11c ⁺ dendritic cells, CD11b ⁻ NK1.1 ⁺ NK-cells, and CD11b ⁻ B220 ⁺ B-cells, and reduced Ly6c Hi CX3CR1 ⁺ CD206 ⁺ CD163 Int CD11c ⁻ MHCII ⁻ infiltrated macrophages and other CD11b ⁺ Ly6c Hi myeloid cells compared to C26. Both C26 and C26+5FU had elevated CD11b ⁺ F480 ⁺ CD206 ⁺ MHCII ⁻ or more specifically Ly6c Lo CX3CR1 ⁺ CD206 ⁺ CD163 Int CD11c ⁻ MHCII ⁻ pro-fibrotic macrophages. 5FU suppressed tumor growth and decreased SKM and AT inflammatory immune cells without protecting against cachexia suggesting that these cells are not required for wasting. However, pro-fibrotic cells and muscle inflammatory/atrophic signaling appears consistent with cancer- and cancer with chemotherapy-induced wasting and remain potential therapeutic targets.

Background More than 650 million people are obese (BMI > 30) worldwide, which increases their risk for several metabolic diseases and cancer. While cachexia and obesity are at opposite ends of the weight spectrum, leading many to suggest a protective effect of obesity against cachexia, mechanistic support for obesity's benefit is lacking. Given that obesity and cachexia are both accompanied by metabolic dysregulation, we sought to investigate the impact of obesity on skeletal muscle mass loss and mitochondrial dysfunction in murine cancer cachexia. Methods Male C57BL/6 mice were given a purified high fat or standard diet for 16 weeks before being implanted with 10 ⁶ Lewis lung carcinoma (LLC) cells. Mice were monitored for 25 days, and hindlimb muscles were collected for cachexia indices and mitochondrial assessment via western blotting, high‐resolution respirometry and transmission electron microscopy (TEM). Results Obese LLC mice experienced significant tumour‐free body weight loss similar to lean (−12.8% vs. −11.8%, P = 0.0001) but had reduced survival (33.3% vs. 6.67%, χ ² = 10.04, P = 0.0182). Obese LLC mice had reduced muscle weights (−24%, P < 0.0354) and mCSA (−16%, P = 0.0004) with similar activation of muscle p65 ( P = 0.0337), and p38 ( P = 0.0008). ADP‐dependent coupled respiration was reduced in both Obese and Obese LLC muscle (−30%, P = 0.0072) consistent with reductions in volitional cage activity (−39%, P < 0.0001) and grip strength (−41%, P < 0.0001). TEM revealed stepwise reductions in intermyofibrillar and subsarcolemmal mitochondrial size with Obese (IMF: −37%, P = 0.0009; SS: −21%, P = 0.0101) and LLC (IMF: −40%, P = 0.0019; SS: −27%, P = 0.0383) mice. Obese LLC mice had increased pAMPK (T172; P = 0.0103) and reduced FIS1 ( P = 0.0029) and DRP1 ( P < 0.0001) mitochondrial fission proteins, which were each unchanged in Lean LLC. Further, mitochondrial TEM analysis revealed that Obese LLC mice had an accumulation of damaged and dysfunctional mitochondria (IMF: 357%, P = 0.0395; SS: 138%, P = 0.0174) in concert with an accumulation of p62 ( P = 0.0328) suggesting impaired autophagy and clearance of damaged mitochondria. Moreover, we observed increases in electron lucent vacuoles only in Obese LLC muscle (IMF: 421%, P = 0.0260; SS: 392%, P = 0.0192), further supporting an accumulation of damaged materials that cannot be properly cleared in the obese cachectic muscle. Conclusions Taken together, these results demonstrate that obesity is not protective against cachexia and suggest exacerbated impairments to mitochondrial function and quality control with a particular disruption in the removal of damaged mitochondria. Our findings highlight the need for consideration of the severity of obesity and pre‐existing metabolic conditions when determining the impact of weight status on cancer‐induced cachexia and functional mitochondrial deficits.

It has been suspected that tumor resection surgery itself may accelerate breast cancer (BC) lung metastasis in some patients. Emodin, a natural anthraquinone found in the roots and rhizomes of various plants, exhibits anticancer activity. We examined the perioperative use of emodin in our established surgery wounding murine BC model. Emodin reduced primary BC tumor growth and metastasis in the lungs in both sham and surgical wounded mice, consistent with a reduction in proliferation and enhanced apoptosis (primary tumor and lungs). Further, emodin reduced systemic inflammation, most notably the number of monocytes in the peripheral blood and reduced pro‐tumoral M2 macrophages in the primary tumor and the lungs. Consistently, we show that emodin reduces gene expression of select macrophage markers and associated cytokines in the primary tumor and lungs of wounded mice. Overall, we demonstrate that emodin is beneficial in mitigating surgical wounding accelerated lung metastasis in a model of triple‐negative BC, which appears to be mediated, at least in part, by its actions on macrophages. These data support the development of emodin as a safe, low‐cost, and effective agent to be used perioperatively to alleviate the surgery triggered inflammatory response and consequential metastasis of BC to the lungs.

The incidence of colorectal cancer (CRC) among young people has been on the rise for the past four decades and its underlying causes are only just starting to be uncovered. Recent studies suggest that consuming ultra-processed foods and pro-inflammatory diets may be contributing factors. The increase in the use of synthetic food colors in such foods over the past 40 years, including the common synthetic food dye Allura Red AC (Red 40), coincides with the rise of early-onset colorectal cancer (EOCRC). As these ultra-processed foods are particularly appealing to children, there is a growing concern about the impact of synthetic food dyes on the development of CRC. Our study aimed to investigate the effects of Red 40 on DNA damage, the microbiome, and colonic inflammation. Despite a lack of prior research, high levels of human exposure to pro-inflammatory foods containing Red 40 highlight the urgency of exploring this issue. Our results show that Red 40 damages DNA both in vitro and in vivo and that consumption of Red 40 in the presence of a high-fat diet for 10 months leads to dysbiosis and low-grade colonic inflammation in mice. This evidence supports the hypothesis that Red 40 is a dangerous compound that dysregulates key players involved in the development of EOCRC.

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.