Cancer-associated cachexia is a disorder characterized by loss of body weight with specific losses of skeletal muscle and adipose tissue. Cachexia is driven by a variable combination of reduced food intake and metabolic changes, including elevated energy expenditure, excess catabolism and inflammation. Cachexia is highly associated with cancers of the pancreas, oesophagus, stomach, lung, liver and bowel; this group of malignancies is responsible for half of all cancer deaths worldwide. Cachexia involves diverse mediators derived from the cancer cells and cells within the tumour microenvironment, including inflammatory and immune cells. In addition, endocrine, metabolic and central nervous system perturbations combine with these mediators to elicit catabolic changes in skeletal and cardiac muscle and adipose tissue. At the tissue level, mechanisms include activation of inflammation, proteolysis, autophagy and lipolysis. Cachexia associates with a multitude of morbidities encompassing functional, metabolic and immune disorders as well as aggravated toxicity and complications of cancer therapy. Patients experience impaired quality of life, reduced physical, emotional and social well-being and increased use of healthcare resources. To date, no effective medical intervention completely reverses cachexia and there are no approved drug therapies. Adequate nutritional support remains a mainstay of cachexia therapy, whereas drugs that target overactivation of catabolic processes, cell injury and inflammation are currently under investigation.

Cancer-associated cachexia

Background Cancer Anorexia Cachexia Syndrome (CACS) is a distinct atrophy disease negatively influencing multiple aspects of clinical care and patient quality of life. Although it directly causes 20% of all cancer-related deaths, there are currently no model systems that encompass the entire multifaceted syndrome, nor are there any effective therapeutic treatments. Methods A novel model of systemic metastasis was evaluated for the comprehensive CACS (metastasis, skeletal muscle and adipose tissue wasting, inflammation, anorexia, anemia, elevated protein breakdown, hypoalbuminemia, and metabolic derangement) in both males and females. Ex vivo skeletal muscle analysis was utilized to determine ubiquitin proteasome degradation pathway activation. A novel ketone diester (R/S 1,3-Butanediol Acetoacetate Diester) was assessed in multifaceted catabolic environments to determine anti-atrophy efficacy. Results Here, we show that the VM-M3 mouse model of systemic metastasis demonstrates a novel, immunocompetent, logistically feasible, repeatable phenotype with progressive tumor growth, spontaneous metastatic spread, and the full multifaceted CACS with sex dimorphisms across tissue wasting. We also demonstrate that the ubiquitin proteasome degradation pathway was significantly upregulated in association with reduced insulin-like growth factor-1/insulin and increased FOXO3a activation, but not tumor necrosis factor-α-induced nuclear factor-kappa B activation, driving skeletal muscle atrophy. Additionally, we show that R/S 1,3-Butanediol Acetoacetate Diester administration shifted systemic metabolism, attenuated tumor burden indices, reduced atrophy/catabolism and mitigated comorbid symptoms in both CACS and cancer-independent atrophy environments. Conclusions Our findings suggest the ketone diester attenuates multifactorial CACS skeletal muscle atrophy and inflammation-induced catabolism, demonstrating anti-catabolic effects of ketone bodies in multifactorial atrophy.

Ketone Bodies Attenuate Wasting in Models of Atrophy.

Mitochondrial dynamics in cancer-induced cachexia.

Hidden pharmacological activities of valproic acid: A new insight.

Adipose tissue browning in cancer-associated cachexia can be attenuated by inhibition of exosome generation.

Muscle wasting is the hallmark of cancer cachexia and is associated with poor quality of life and increased mortality. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has important biological effects in the treatment of muscular dystrophy. To verify whether VPA could ameliorate muscle wasting induced by cancer cachexia, we explored the role of VPA in two cancer cachectic mouse models [induced by colon-26 (C26) adenocarcinoma or Lewis lung carcinoma (LLC)] and atrophied C2C12 myotubes [induced by C26 cell conditioned medium (CCM) or LLC cell conditioned medium (LCM)]. Our data demonstrated that treatment with VPA increased the mass and cross-sectional area of skeletal muscles in tumor-bearing mice. Furthermore, treatment with VPA also increased the diameter of myotubes cultured in conditioned medium. The skeletal muscles in cachectic mice or atrophied myotubes treated with VPA exhibited reduced levels of CCAAT/enhancer binding protein beta (C/EBPβ), resulting in atrogin1 downregulation and the eventual alleviation of muscle wasting and myotube atrophy. Moreover, atrogin1 promoter activity in myotubes was stimulated by CCM via activating the C/EBPβ-responsive cis-element and subsequently inhibited by VPA. In contrast to the effect of VPA on the levels of C/EBPβ, the levels of inactivating forkhead box O3 (FoxO3a) were unaffected. In summary, VPA attenuated muscle wasting and myotube atrophy and reduced C/EBPβ binding to atrogin1 promoter locus in the myotubes. Our discoveries indicate that HDAC inhibition by VPA might be a promising new approach for the preservation of skeletal muscle in cancer cachexia.

Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPβ-regulated atrogin1 expression in cancer cachexia.

Abstract Background Endoclita signifer causes severe damage to eucalyptus plantations, and the larvae transfer to and damage eucalyptus accurately in mixed forests, suggesting that the larval olfactory system contributes to host selection. The olfactory proteins in the head and tegument of E. signifer larvae were previously identified. To identify the relationship between olfactory protein expression in the larval head the larvae head and the developmental expression dynamics, and its functions in further recognition of plant volatiles, the head transcriptomes of two instar larvae and the expression profiles of olfactory proteins in the instars after exposure to volatiles were studied. Results Eight odorant-binding proteins, six chemosensory proteins, three odorant receptors, three gustatory receptors, and 18 ionotropic receptors were identified. Half of the olfactory proteins were the most highly expressed in the young (5th) larval head, and EsigGOBP2, EsigGOBP4, EsigGOBP5, EsigCSP1, EsigCSP3, EsigGR1 and EsigGR3 were highly expressed and showed a specific expression pattern. In addition, after exposure to o-cymene, α-phellandrene, n-butyl ether, and 4-ethylacetophenone, EsigGR3 was downregulated significantly, and exposure to n-butyl ether caused EsigGR1 to be downregulated significantly. Conclusions Seven specific olfactory proteins may be important genes in larval olfactory recognition. Furthermore, based on the receptors that were downregulated after exposure to volatiles and the previous electrophysiological activity in the third larvae, we speculated that the ligand of EsigGR1 was n-butyl ether, and the ligands of the newly identified EsigGR3 are all electrophysiologically active compounds, which demonstrated host recognition in the third larvae of E . signifer . These results provide a way to find key plant volatiles recognized by the key olfactory proteins as new targets for pest control. Graphical Abstract 

/pdf/olfactory-proteins-of-endoclita-signifer-larvae-and-their-1ypju2ij.pdf

Olfactory proteins of Endoclita signifer larvae and their roles in host recognition

/pdf/olfactory-proteins-of-endoclita-signifer-larvae-and-their-172oe65z.pdf

Simple Summary In gene expression investigations, the first crucial step is choosing appropriate housekeeping genes. However, the choice of reference genes is not absolute but relative and varies with different experimental conditions. It is vital to note that using unvalidated or unscreened internal reference genes can lead to erroneous inferences. This study was conducted on Leptocybe invasa to calculate the stability of eight housekeeping genes across various test conditions, such as sexes, somites, temperatures, diets, and pesticides. The relative expression of HSP90 at different temperature settings was evaluated to validate the results. This study aims to assist future gene expression research on this invasive species and lay the groundwork for further investigations into the gene function of this pest. Abstract Leptocybe invasa (Hymenoptera: Eulophidae) is a globally intrusive pest. Despite extensive research into the physiological responses of this pest, our understanding of the molecular mechanisms still needs to be improved. We want to accurately investigate the expression of L. invasa’s target genes, so it is imperative to select fitting reference genes. In this study, eight housekeeping genes’ stability (RPS30, ACTR, 18S rRNA, ACT, RPL18, GAPDH, 28S rRNA, and TUB) was tested under five different experimental conditions, including male or female adults, somites (head, thorax, and abdomen), temperatures (0 °C, 25 °C, and 40 °C), diets (starvation, clear water, 10% honey water, Eucalyptus sap), and pesticides (acetone was used as a control, imidacloprid, monosultap). Gene stability was calculated using RefFinder, which integrates four algorithms (the ∆Ct method, geNorm, NormFinder, and BestKeeper). The findings implied that ACT and ACTR were the most accurate when comparing sexes. For analyzing different somites, 28S rRNA and RPL18 were ideal; the 28S rRNA and RRS30 were perfect for analyzing at different temperatures. The combination of ACT and GAPDH helped to analyze gene expression in different diets, and GAPDH and 28S rRNA were suitable for various pesticide conditions. Overall, this research offers a complete list of reference genes from L. invasa for precise analysis of target gene expression, which can improve the trustworthiness of RT-qPCR and lay the foundation for further investigations into the gene function of this pest.

/pdf/identification-and-validation-of-reference-genes-for-sp3wyzgk.pdf

Identification and Validation of Reference Genes for Expression Analysis Using RT-qPCR in Leptocybe invasa Fisher and La Salle (Hymenoptera: Eulophidae)

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Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPβ-regulated atrogin1 expression in cancer cachexia.

Olfactory proteins of Endoclita signifer larvae and their roles in host recognition

Olfactory proteins of Endoclita signifer larvae and their roles in host recognition

Identification and Validation of Reference Genes for Expression Analysis Using RT-qPCR in Leptocybe invasa Fisher and La Salle (Hymenoptera: Eulophidae)