Exploring the therapeutic effect of Xiaoyan d ecoction on lung cancer cachexia skeletal muscle atrophy based on L3-SMI

Background:Lung cancer cachexia has received widespread attention as one of the most common complications in patients with advanced lung cancer.As a multifactorial syndrome,lung cancer cachexia is characterized by a persistent decline in muscle mass that cannot be reversed by conventional nutrition Xiaoyan d ecoction can promote appetite and improve skeletal muscle mass in patients with lung cancer cachexia,while the third lumbar skeletal muscle index(L3-SMI)is able to determine whole-body skeletal muscle mass.To analyze the relationship between L3-SMI and hematological indexes and lung cancer cachexia,and to study the clinical efficacy of Xiaoyan decoction on skeletal muscle atrophy in lung cancer cachexia patients,with the aim of providing a reference basis for the early diagnosis and treatment of lung cancer cachexia patients and skeletal muscle atrophy.Methods:148 patients who were diagnosed with lung cancer in the Department of Oncology of the First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine from January 2020 to December 2022 were included,and were divided into cachexia and non-cachexia groups according to the diagnostic criteria of cachexia,and analyzed the differences of hematological indexes and L3-SMI between cachexia patients and non-cachexia patients.And the patients with cachexia were divided into control group and treatment group,analyzed and compared the changes of body mass index(BMI),L 3-SMI,Karnofsky functional status score,albumin and other hematological indexes of the two groups before and after the treatment,and evaluated the safety of the Xiaoyan decoction in the treatment of cachexia.Results:A total of 148 lung cancer patients were included in this study,including 67 patients in the cachexia group and 81 patients in the non-cachexia group.According to the pre-treatment statistical analysis,the BMI of patients in the cachexia group was lower than that of patients in the non-cachexia group(P<0.05);among the biochemical function indexes,the proportions of creatinine(P<0.05),total protein(P<0.05),The levels of albumin in the cachexia group were significantly lower(P<0.05)compared to the non-cachexia group;in the cachexia group,both males and females had lower L3-SMIs than in the non-cachexia group(P<0.05).A total of 62 cases of lung cancer cachexia were studied,30 cases in the control group and 32 cases in the treatment group,according to statistical analysis,BMI was significantly different before and after treatment(P<0.05);L3-SMI was significantly different in the treatment group before and after treatment(P<0.05);Karnofsky significantly differed in the treatment group before and after treatment(P<0.05);and there was a significant difference in albumin before and after(P<0.05).Conclusion:Cachexia patients had significantly lower third lumbar skeletal muscle mass than non-cachexia patients,according to this study;Xiaoyan decoction was able to improve skeletal muscle mass,nutritional status as well as functional status of patients with cachexia in lung cancer,among others.

Treatment of cancer cachexia with exercise

Cancer cachexia is a multifactorial syndrome characterized by the irreversible loss of body weight,fat,and muscle.Its main characteristics include nutrient intake and absorption disorders,systemic inflammation,mitochondrial dysfunction,immune imbalance,and protein and fat consumption,which ultimately lead to patient death.So far,there has been no effective method identified to combat the malignant progression of cancer cachexia.The effects of a single nutritional supplement or drug intervention strategy are insufficient.Exercise training is considered a potential treatment for cancer cachexia.Both clinical studies and animal experiments suggest that exercise training can help improve the intake and absorption of nutrients,inhibit inflammatory signaling pathways,regulate immunity andmetabolism,alleviate insulin resistance,promote protein synthesis,maintain muscle mass,and so on.The use of multimodal methods that combine nutritional support and/or other treatments with exercise provides a potential prospect for the treatment of cancer cachexia.However,the optimal prescription of exercise for the treatment of cancer cachexia is still unclear.The main purpose of this review is to summarize the growing body of research on the impact of exercise on cancer cachexia and to provide evidence supporting the use of exercise as an intervention for cancer cachexia in the clinical setting.

Study on possible synergistic anticancer cachexia effects of the main active compounds of Radix Sophorae flavescentis

Background:Cancer cachexia is a complex disease secondary to cancer,and no specific therapy for it has been found.The Chinese herb Kushen(Radix Sophorae flavescentis)is the dried root of Sophora flavescens Aiton,which has been widely applied in treating digestive and urinary inflammatory diseases.Matrine,one of the main components of Radix Sophorae flavescentis,can alleviate cancer cachexia.Methods:Compounds from Radix Sophorae flavescentis were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform.The targets related to cancer cachexia were queried from the Therapeutic Target Database(http://db.idrblab.net),DisGeNET database(http://www.disgenet.org),and Search Tool for Interacting Chemicals database,related literature,and constructed cancer cachexia-protein network.Cancer cachexia-protein network was merged with compound-protein networks respectively using Cytoscape software as well as network topology data and key targets counting.Pathway enrichment analysis was conducted via the Database for Functional Annotation Bioinformatics Microarray Analysis.Protein crystal structures and compound structures were queried from RCSB and PubChem databases,respectively.Molecular docking was conducted using Discovery Studio software.Results:The anticancer cachexia compounds of Radix Sophorae flavescentis were screened as oxymatrine,matrine,and kurarinol,and targets such as BIRC2,TNF and STAT3 were found.The mechanisms of oxymatrine,matrine,and kurarinol have the characteristics of synergy and complementarity.Kurarinol has a mechanism similar to that of matrine,which includes the FoxO signaling pathway,insulin resistance and mTOR signaling pathway.TNF signaling pathway is a common signaling pathway of kurarinol,oxymatrine and matrine.Adipocytokine signaling pathway is the other common pathway of kurarinol and oxymatrine except for the TNF signaling pathway.Kurarinol can be successfully docked with CYCS,GPX2,BIRC7,etc.,and kushenol C can be successfully docked with IKBKB and PIK3CD.Conclusion:Kurarinol,matrine,oxymatrine,and kushenol C may be the key compounds of Radix Sophorae flavescentis treating cancer cachexia.Additionally,TNF signaling pathway is the key pathway for the synergistic action of kurarinol,matrine and oxymatrine.

Nutritional support strategies for cancer cachexia

Tumor cachexia is widely seen in patients with various stages of cancer,manifested by inadequate intake or abnormal hypermetabolism resultingin negative nitrogen and energy balance. Early intervention of nutritionaltherapy and penetrate it into other anti-cancer treatment processes cansignificantly benefit cancer patients who receiving palliative treatment.Nutritional therapy for cancer is a process of planning, implementing, evaluatingand nutritional intervention to treat cancer and its complications orphysical condition, to improve the prognosis of cancer patients, includingnutritional diagnosis (screening/evaluation), nutritional intervention, efficacyevaluation (including follow-up) three stages. In practice, we shouldchoose appropriate nutritional risk assessment tools and interventionmethods according to the actual situation of patients, avoid over-treatment,reduce complications, and maximize patients'interests as far as possible.Nutritional support therapy for cancer involves ethics, morality and thewishes of patients and their families, and needs further exploration andimprovement. The best nutritional support strategy often requires the jointparticipation of many disciplines, including clinicians, nurses, nutritionistsand psychosocial workers. Nutritional support group and multidisciplinarycollaboration group on cancer are gradually becoming a trend. With theaccumulation of experience in cancer nutrition therapy, the developmentand application of drugs and nutritional preparations, and the deepening ofmulti-disciplinary collaboration, more cancer patients will benefit in clinicalwork.

Research progress on pathogenesis and related pathways of Cancer cachexia

Cancer cachexia is a complex syndrome of metabolic changes caused by many factors in tumor patients,which characterized by emaciation,weight loss,muscle atrophy,anemia and hypoproteinemia,it's seriously affects the quality of life,cycle and therapeutic effect of patients.At present,there is no curative effect in the treatment of cancer cachexia,because the pathogenesis is still unclear.So it is particularly important to study the pathogenesis,mechanism and related pathway of cancer cachexia.In this paper,the definition,stage and diagnosis of cachexia,traditional Chinese medicine theoretical research,related anorexia mechanism,protein decomposition mechanism,fat decomposition mechanism,sugar metabolism mechanism,inflammatory factor mechanism and other aspects were analyzed and summarized to provide theoretical basis for the study of cachexia pathogenesis and clinical application selection.

Cancer cachexia:Focus on cachexia factors and inter-organ communication

Cancer cachexia is a multi-organ syndrome and closely related to changes in signal communication between organs,which is mediated by cancer cachexia factors.Cancer cachexia factors,being the general name of inflammatory factors,circulating proteins,metabolites,and microRNA secreted by tumor or host cells,play a role in secretory or other organs and mediate complex signal communication between organs during cancer cachexia.Cancer cachexia factors are also a potential target for the diagnosis and treatment.The pathogenesis of cachexia is unclear and no clear effective treatment is available.Thus,the treatment of cancer cachexia from the perspective of the tumor ecosystem rather than from the perspective of a single molecule and a single organ is urgently needed.From the point of signal communication between organs mediated by cancer cachexia factors,finding a deeper understanding of the pathogenesis,diagnosis,and treatment of cancer cachexia is of great significance to improve the level of diagnosis and treatment.This review begins with cancer cachexia factors released during the interaction between tumor and host cells,and provides a comprehensive summary of the pathogenesis,diagnosis,and treatment for cancer cachexia,along with a particular sight on multi-organ signal communication mediated by cancer cachexia factors.This summary aims to deepen medical community’s understanding of cancer cachexia and may conduce to the discovery of new diagnostic and therapeutic targets for cancer cachexia.

Effects of Neuromuscular Electrical Stimulation in Combination with Glutamine Administration on Skeletal Muscle Atrophy in Colon-26 Tumor-Bearing Mice

The depressed protein synthetic response,a phenomenon termed anabolic resistance,has been shown to be involved in muscle wasting induced by cancer cachexia.Moreover,a positive relationship between the protein synthetic rate and intracellular glutamine(GLN)concentration has been found in skeletal muscles.This study investigated the effects of neuromuscular electrical stimulation(ES)and GLN administration on muscle wasting and GLN metabolism in colon-26(C-26)tumor-bearing mice.CD2F1 mice were divided into 8 groups:control(CNT),CNT+ES,CNT+GLN,CNT+ES+GLN,C-26,C-26+ES,C-26+GLN,C-26+ES+GLN.Cancer cachexia was induced by subcutaneous injection of C-26 cells and developed for four weeks.ES was performed on the left plantar flexor muscles every other day,and GLN(1 g/kg)was administered daily intraperitoneally starting one day after the C-26 injection.Tumor-free body mass and fast-twitch gastrocnemius(Gas)muscle weight were lower in the C-26 group than in the CNT group(-19%and-17%,respectively).Neither ES training nor GLN administration,alone or in combination,ameliorated the loss of Gas muscle weight in the C-26 mice.However,ES training in combination with GLN administration inhibited the increased expression of GLN synthetase(GS)in the C-26 muscles.Thus,it is likely that GLN plays a critical role in muscle protein metabolism and,therefore,can be targeted as a tentative treatment of cancer cachexia.

Jianpi Decoction Combined with Medroxyprogesterone Acetate Alleviates Cancer Cachexia and Prevents Muscle Atrophy by Directly Inhibiting E3 Ubiquitin Ligase

ObjectiveTo provide comprehensive evidence for the anti-cancer cachexia effect of Jianpi Decoction(JP)and to explore its mechanism of anti-cancer cachexia.MethodsA mouse model of colon cancer(CT26)-induced cancer cachexia(CC)was used to investigate the anti-CC effect of JP combined with medroxyprogesterone acetate(MPA).Thirty-six mice were equally divided into 6 groups:normal control,CC,MPA(100 mg·kg^(−1)·d^(−1)),MPA+low-dose(20 mg·kg^(−1)·d^(−1))JP(L-JP),MPA+medium-dose(30 mg·kg^(−1)·d^(−1))JP(M-JP),and MPA+high-dose(40 mg·kg^(−1)·d^(−1))JP(H-JP)groups.After successful modeling,the mice were administered by gavage for 11 d.The body weight and tumor volume were measured and recorded every 2 d starting on the 8th day after implantation.The liver,heart,spleen,lung,kidney,tumor and gastrocnemius muscle of mice were collected and weighed.The pathological changes of the tumor was observed,and the cross-sectional area of the gastrocnemius muscle was calculated.The protein expressions of STAT3 and E3 ubiquitinase in the gastrocnemius muscle were measured by Western blot.In addition,an in vitro C2C12 myotube formation model was established to investigate the role of JP in hindering dexamethasone-induced muscle atrophy.In vitro experiments were divided into control,model,and JP serum groups.After 2-d administration,microscopic photographs were taken and myotube diameters were calculated.Western blot was performed to measure the protein expressions of STAT3 and E3 ubiquitinase.ResultsJP combined with MPA restored tumor-induced weight loss(P<0.05,vs.CC)and muscle fiber size(P<0.01,vs.CC).Mechanistically,JP reduced the expression of atrophy-related proteins MuRF1 and MAFbx in tumor-induced muscle atrophy in vivo(P<0.05,vs.CC).In addition,JP reduced the expression of atrophy-related proteins MuRF1 and MAFbx and p-STAT3 phosphorylation(P<0.05 or P<0.01 vs.model group)in C2C12 myotubes treated with dexamethasone in vitro.ConclusionsAdministration of JP combined with MPA restores tumor-induced cachexia conditions.In addition,the profound effect of JP combined with MPA on tumor-induced cachexia may be due to its inhibition of muscle proteolysis(E3 ubiquitinase system).

The effects of resistance training on muscular strength and hypertrophy in elderly cancer patients:A systematic review and meta-analysis

Background:One of the most life-threatening comorbidities in elderly cancer patients is cancer cachexia,which is characterized by the ongoing loss of skeletal muscular strength and mass and is also associated with aging.There is a lack of recommendations for optimal resistance training(RT) for those patients.The purpose of this study was to systematically review and quantify the effects of RT on muscular strength and hypertrophy in elderly cancer patients.Methods: Five electronic databases were searched(until January 2020) for studies that met the following criteria:(i) cancer patients aged>60 years;(ii) structured and supervised RT intervention for>6 weeks;and(iii) measured muscular strength and/or hypertrophy.Results:Thirteen studies(717 participants,average age=66 years) met the inclusion criteria.RT significantly increased muscular strength(mean effect size=0.87,95% confidence interval(95%CI):0.43-1.32,p <0.001) and did not significantly induce muscle hypertrophy(mean effect size=0.09,95%CI:-0.14 to 0.31,p=0.45).In subgroup analyses for muscle strength,higher weekly frequency was significantly associated with larger effect size.Egger’ s test showed no significant publication bias for the 2 outcomes.Conclusion:The results suggest that RT improves muscular strength but does not significantly induce muscle hypertrophy in elderly cancer patients.

Decreased cross-sectional muscle area in male patients with clear cell renal cell carcinoma and peritumoral collateral vessels

BACKGROUND Sarcopenia is the loss of skeletal muscle mass(SMM)and is a sign of cancer cachexia.Patients with advanced renal cell carcinoma(RCC)may show cachexia.AIM To evaluate the amount of SMM in male clear cell RCC(ccRCC)patients with and without collateral vessels.METHODS In this study,we included a total of 124 male Caucasian patients divided into two groups:ccRCCa group without collateral vessels(n=54)and ccRCCp group with collateral vessels(n=70).Total abdominal muscle area(TAMA)was measured in both groups using a computed tomography imaging-based approach.TAMA measures were also corrected for age in order to rule out age-related effects.RESULTS There was a statistically significant difference between the two groups in terms of TAMA(P<0.05)driven by a reduction in patients with peritumoral collateral vessels.The result was confirmed by repeating the analysis with values corrected for age(P<0.05),indicating no age effect on our findings.CONCLUSION This study showed a decreased TAMA in ccRCC patients with peritumoral collateral vessels.The presence of peritumoral collateral vessels adjacent to ccRCC might be a fine diagnostic clue to sarcopenia.

Role of brown adipose tissue in metabolic syndrome, aging, and cancer cachexia

Brown adipose tissue （BAT） plays a fundamental role in maintaining body temperature by producing heat. BAT that had been know to exist only in mammals and the human neonate has received great attention for the treatment of obesity and diabetes due to its important function in energy metabolism, ever since it is recently reported that human adults have functional BAT. In addition, beige adipocytes, brown adipocytes in white adipose tissue （WAT）, have also been shown to take part in whole body metabolism. Multiple lines of evidence demonstrated that transplantation or activation of BAT or/and beige adipocytes reversed obesity and improved insulin sensitivity. Furthermore, many genes involved in BAT activation and/or the recruitment of beige cells have been found, thereby providing new promising strategies for future clinical application of BAT activation to treat obesity and metabolic diseases. This review focuses on recent advances of BAT function in the metabolic aspect and the relationship between BAT and cancer cachexia, a pathological process accompanied with decreased body weight and increased energy expenditure in cancer patients. The underlying possible mechanisms to reduce BAT mass and its activity in the elderly are also discussed.

Preclinical and clinical studies on cancer-associated cachexia

BACKGROUND： Cancer cachexia is the wasting condition that is often seen in advanced stage cancer patients. This wasting is largely attributable to a systemic and progressive loss of skeletal muscle mass that greatly hinders performance of normal daily activities, resulting in reduced quality of life. Moreover, it negatively influences the prognosis of cancer patients. A general consensus in the field is that the loss of muscle mass is due both to an increase in protein degradation and a decrease in protein synthesis. Recent studies using preclinical models for studying cachexia have been useful in identifying the contribution of inflammatory cytokines （e.g. tumor necrosis factor-a and Interleukin-6）, and myostatin receptors （e.g. the type IIB activin receptor） to cachexia development, and have led to several clinical trials. However, many questions remain about the molecular mechanisms thought to play a role in the development of cachexia. METHODS： We conducted a literature search using search engines, such as PubMed and Google Scholar to identify publications within the cancer cachexia field. RESULTS- We summarized our current knowledge of： 1） the driving mechanisms of cancer cachexia, 2） the preclinical models available for studying the condition, and 3） the findings of recent clinical trials. CONCLUSION： Cancer cachexia is a complex and variable condition that currently has no standard effective therapeutic treatment. Further studies are desperately needed to better understand this condition and develop effective combination treatments for patients.

The mechanism by which noncoding RNAs regulate muscle wasting in cancer cachexia

Cancer cachexia(CC)is a complex metabolic syndrome that accelerates muscle wasting and affects up to 80%of patients with cancer;however,timely diagnostic methods and effective cures are lacking.Although a considerable number of studies have focused on the mechanism of CC-induced muscle atrophy,few novel therapies have been applied in the last decade.In recent years,noncoding RNAs(ncRNAs)have attracted great attention as many differentially expressed ncRNAs in cancer cachectic muscles have been reported to participate in the inhibition of myogenesis and activation of proteolysis.In addition,extracellular vesicles(EVs),which function as ncRNA carriers in intercellular communication,are closely involved in changing ncRNA expression profiles in muscle and promoting the development of muscle wasting;thus,EV-related ncRNAs may represent potential therapeutic targets.This review comprehensively describes the process of ncRNA transmission through EVs and summarizes the pathways and targets of ncRNAs that lead to CC-induced muscle atrophy.

Pathological features of tissues and cell populations during cancer cachexia

Cancers remain among the most devastating diseases in the human population in spite of considerable advances in limiting their impact on lifespan and healthspan.The multifactorial nature of cancers,as well as the number of tissues and organs that are affected,have exposed a considerable diversity in mechanistic features that are reflected in the wide array of therapeutic strategies that have been adopted.Cachexia is manifested in a number of diseases ranging from cancers to diabetes and ageing.In the context of cancers,a majority of patients experience cachexia and succumb to death due to the indirect effects of tumorigenesis that drain the energy reserves of different organs.Considerable information is available on the pathophysiological features of cancer cachexia,however limited knowledge has been acquired on the resident stem cell populations,and their function in the context of these diseases.Here we review current knowledge on cancer cachexia and focus on how tissues and their resident stem and progenitor cell populations are individually affected.

The immunological regulation of cancer cachexia and its therapeutic implications

Cachexia affects the majority of patients with advanced cancer. It leads to poor surgical and oncological outcomes, and negatively affects quality of life. It has long been reported that components of the host immune system, including pro-inflammatory cytokines such as IL-1α, IL-6, TNF-α and INF-g, participate in the syndrome of cachexia. Yet therapeutic targeting of these pro-inflammatory factors has not yielded meaningful improvements in cachexia management. More recently, the impact of immune cells in the tumour mass (tumour-associated macrophages) and host circulation (myeloid suppressor cells) has garnered much interest with regards to their role in immune tolerance in cancer. However, their role in the generation of systemic inflammation and cancer cachexia is underexplored and outstanding questions remain. This review summarises the key mediators and targets of immune dysfunction in cancer cachexia. Here we describe the host response including skeletal muscle wasting;highlight the current knowledge gap areas;and report the results of previously trialled immunotherapies. A greater understanding of complex interaction between the tumour, immune system and peripheral tissues in the genesis and maintenance of cancer cachexia is a key step in n identifying future therapeutic targets.