Traditional Chinese medicine-based formulations for the prevention and treatment of cachexia

Abstract

The present invention discloses a traditional Chinese medicine, Moutanpi (Moutan radicis cort), which has potential use in preventing or treating cachexia and muscle loss in cancer patients. The composition is a novel treatment for cachexia.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 255,963, filed October 15, 2021, which is incorporated by reference herein in its entirety.

[0002] The present invention discloses a traditional Chinese medicine (TCM)-based agent, Mudanpi (Moutan radicis cort; Mudanpi), which can be used to prevent or treat tumor-induced muscle wasting and cachexia in cancer patients. This agent has been developed through an integrated multi-layered strategy involving both in vitro and in vivo muscle wasting platforms from an in-house TCM library. [Background technology]

[0003] A major challenge in the treatment of certain cancer types, such as pancreatic, gastric, lung, and colon cancer, is cancer-induced weight loss, which, in terms of cachexia, is characterized by anorexia and loss of adipose tissue and skeletal muscle mass. Because there is no clear consensus on the definition of cancer cachexia, cachexia was considered to be present if at least three of the following five characteristics were present: muscle weakness, fatigue, anorexia or restricted food intake, low fat mass index, abnormal biochemistry (e.g., elevated C-reactive protein, anemia, or decreased serum albumin), and a 5% weight loss without edema (or a BMI <20.0 kg / m at 12 months). 2 As a result, weight loss due to cancer cachexia cannot be restored by nutritional support and has a profound impact on the morbidity, mortality, and quality of life of cancer patients. Although significant progress has been made in understanding the multifactorial pathophysiology of cachexia, prevention and / or treatment of this debilitating disease remains an unmet medical need.

[0004] Currently, there are no approved targeted therapies available for the treatment of cachexia. Megestrol, a semisynthetic progestational steroid, is used to improve cachexia-related symptoms.

[0005] Furthermore, in Japan, several herbal medicines (i.e., multi-ingredient herbal extracts) that act on the immune system and improve inflammation and nutritional status are commonly prescribed to alleviate fatigue and chronic weakness in cachexia patients. More recently, the hunger hormone ghrelin and ghrelin mimetics have attracted much attention given their potential to increase appetite and quality of life, but clinical evidence supporting their use in the treatment of cachexia is lacking.

[0006] The advantages of TCM over small molecule targeted agents in the prevention and / or treatment of cachexia are manifold. First, the therapeutic utility of TCM's polypharmacology (or network pharmacology) has been demonstrated by its long history in the treatment of various chronic and complex diseases. Second, many TCM products may be consumed routinely as dietary supplements for disease suppression and prevention. Third, in Eastern societies, TCM is generally considered to have fewer side effects, potentially improving compliance among cancer patients with muscle wasting. Summary of the Invention

[0007] In view of the above technical situation, the present invention provides a TCM composition for the treatment and / or prevention of cachexia, its preparation, and a method for preparing the same, which has obvious clinical benefits.

[0008] The present invention discloses a TCM, Moutan Peel (MDP), which has the potential to be used for the prevention or treatment of cachexia in cancer patients. MDP extract is prepared by soaking TCM in 50%-100% methanol or 50%-100% ethanol.

[0009] The present invention also provides a method for treating or preventing cancer-induced cachexia, comprising administering to a subject with tumor-associated cachexia an effective amount of a composition comprising Moutan Cortex or an extract thereof. The MDP extract is prepared by soaking TCM in 50% to 100% methanol or 50% to 100% ethanol.

[0010] The present invention further provides a composition for preventing or treating skeletal muscle atrophy in cancer patients, which may be due to its ability to reverse tumor-induced reprogramming of muscle homeostasis-related gene expression in skeletal muscle, thereby rescuing skeletal muscle from wasting. MDP extract is prepared by soaking TCM in 50%-100% methanol or 50%-100% ethanol.

[0011] The present invention also provides a method for treating or preventing cancer-induced skeletal muscle mass loss, comprising administering to a subject with tumor-associated skeletal muscle atrophy an effective amount of a composition comprising Moutan Peony or Moutan Peony extract, which can reverse tumor-induced reprogramming of muscle homeostasis-related gene expression in skeletal muscle, thereby relieving skeletal muscle wasting. Moutan Peony Extract (MDP) is prepared by soaking TCM in 50%-100% methanol or 50%-100% ethanol. [Brief explanation of the drawings]

[0012] [Figure 1] Figure 1 shows the effects of different TCMs on C26CM-induced atrophy of C2C12 myotubes. [Figure 2] These results show that 24 TCM extracts have no protective effect on C26CM-induced atrophy of C2C12 myotubes. [Figure 3] Figure 1 shows the time-dependent effects of MDP versus DR on age-associated motility and / or whole-body contractions in C. elegans. [Figure 4] The effects of oral gavage of three doses of MDP (MDP-L, MDP-H, and MDP-H) and vehicle on body weight (A and B) and tumor volume (C), on the protection of hindlimb muscles in C-26 tumor-bearing mice (D), and on the alertness and active phenotype of C-26 tumor-bearing mice (D). [Figure 5] The effect of 100 mg / kg DR and vehicle by oral gavage on body weight (tumor-free) is shown. [Figure 6] Duplicate experiments are shown showing the effects of oral gavage of 1000 mg / kg MDP (MDP-H) versus vehicle on body weight (A and B), tumor volume (C), the ability to attenuate cachexia-associated loss of skeletal muscle weight (D), the ability to rescue the shift in fiber size distribution toward smaller cross-sectional area (E), and the recovery of forelimb grip strength at day 17 in C-26 tumor-bearing mice (F). [Figure 7] 1 shows the effect of MDP on serum IL-6 and cell viability on C26 cells in C26-tumor-bearing mice treated with Veh and C26-tumor-bearing mice treated with MDP-H. [Figure 8] Bioinformatics analysis of shotgun sequencing is shown. [Figure 9] 1 shows the effect of MDP on the expression of skeletal muscle-related genes and proteins. DETAILED DESCRIPTION OF THE INVENTION

[0013] As used herein, "a," "an," "the," "at least one," and "one or more" are used interchangeably.

[0014] In one embodiment, DR and MDP demonstrated the ability to suppress the effects of inflammatory cytokine-induced atrophy of C2C12 myotubes.

[0015] In one embodiment, MDP ameliorates age-associated motor performance decline in C. elegans.

[0016] In one embodiment, MDP prevents tumor-induced muscle wasting in C26 tumor-bearing mice.

[0017] In one embodiment, MDP is effective in protecting hind limb muscles, such as the quadriceps and tibialis anterior, from cancer-induced wasting.

[0018] In one embodiment, MDPs demonstrate in vivo efficacy in protecting mice from C-26 tumor-induced weight loss.

[0019] In another embodiment, MDP attenuates cachexia-associated loss of skeletal muscle mass.

[0020] In one embodiment, MDP can rescue the shift in fiber size distribution towards smaller cross-sectional area in cachectic muscle (P<0.05).

[0021] In one embodiment, the MDP reduces serum IL-6 levels.

[0022] In one embodiment, MDP exerts its anti-cachectic effect by reversing tumor-induced reprogramming of muscle homeostasis-related gene expression in skeletal muscle.

[0023] The present invention also provides a method for treating or preventing cancer-induced cachexia, the method comprising administering to a subject having cancer-induced cachexia an effective amount of a composition, wherein the composition comprises Moutan Cortex or an extract of Moutan Cortex.

[0024] The present invention also provides a method for treating or preventing cancer-induced loss of skeletal muscle mass, the method comprising administering an effective amount of a composition to a subject with cancer-induced muscle atrophy, wherein the composition comprises Moutan Cortex or an extract of Moutan Cortex.

[0025] In one embodiment, the peony bark extract is prepared by soaking the peony bark in 50% to 100% methanol or 50% to 100% ethanol.

[0026] In a preferred embodiment, the peony bark extract is prepared by soaking the peony bark in 70% methanol or 70% ethanol.

[0027] Example The following examples are non-limiting and merely representative of various aspects and features of the present invention. [Example]

[0028] Example 1 C26CM-induced myotube atrophy model The experimental design is shown in Figure 1A. C2C12 myoblasts were exposed to 2% horse serum-containing differentiation medium (DM) for 4 days to facilitate differentiation into myotubes, followed by treatment with C26CM for 4 days. At the end of this 8-day treatment, the diameters of C2C12 myotubes treated with C26CM and those of control cells (treated with DM only) were analyzed under a light microscope, and the difference was quantified as a readout of C26CM-induced atrophy. To replicate the use of TCM to delay the onset of muscle wasting, individual TCMs and DMSO were added to the culture medium from the beginning and replaced daily (H3–H14 as additional controls) throughout the course of the experiment, each replicated four times. As shown, C26CM caused significant constriction of C2C12 myotubes (Figure 1B and Figure 1C).

[0029] As shown in Figure 1, the effects of different TCMs on C26CM-induced atrophy of C2C12 myotubes were demonstrated. A schematic diagram of the experimental design is shown in Figure 1A. Figure 1B shows the corresponding images. Figure 1C shows two quantitative analyses of the images in Figure 1B regarding the protective effects of Dioscorea Root (DR), MDP, and three other representative TCMs on C26CM-induced atrophy of C2C12 myotubes in a representative experiment. Bars represent the mean ± SD (data from two independent experiments, Expt#1 and Expt#2).

[0030] The anti-atrophic activities of the extracts of different TCMs (25 and / or 50 μg / ml, respectively) were evaluated. These extracts include Dioscoreae rhizome (DR), MDP, Sambuci chinensis radix et caulis (SCRC), Helminthostachydis radix et rhizome (HRR), Condonopsis radix (CR), Polygonati odorati rhizome (Jade bamboo), and Glycyrrhizae. radix et rhizome, Lilii bulbus, Citri sarcodactylis fructus, Euryales semen, Hordei fructus germinates, Siraitiae fructus, Pruni semen, Lycii fructus, Poria, Platycodonis radix, Bombycis chrysallidem, Alpiniae oxyphyllae Fructus, Nelumbinis semen, Polygonati rhizome, Sesami nigrum semen, Ziziphi spinosae semen, Coicis semen, Rubi fructus, Ginseng radix et rhizome, Amynthas et metaphire, Arctii radix, Portulacae herba, and Trionycis. Carapax (tortoiseshell) is an example. Among these TCM extracts, we found that two widely used TCMs, DR and MDP, shared H3-14's ability to completely protect C2C12 myotubes from C26CM-induced atrophy (all P = 0.0002 compared to C26CM controls in the myotube atrophy platform, Figure 1C). However, the others were either cytotoxic or did not confer protection. Representative data are shown in Figure 1C.

[0031] Data for other TCMs are shown in Figure 2. Bars represent mean ± SD (N=4). #1 was Polygonati odorati rhizoma; #2 was Glycyrrhizae radix et rhizome; #3 was White laurel (Lilii bulbus); #4 was Citri sarcodactylis fructus; #5 was Euryales semen; #6 was Hordei fructus germination; #7 was Siraitiae fructus; #8 was Pruni semen; #9 was Lycium fructus; #10 was Poria japonica (Poria columbine); #11 was Platycodonis radix (Bonion flower); #12 was Bombycis chrysallidem; #13 was Yakuchi (Alpiniae oxyphyllae fructus); #14 was lotus fruit (Nelumbinis semen); #15 was king laurel (Polygonati rhizoma); #16 was black laurel (Sesami nigrum semen); #17 was Sansonin (Ziziphi spinosae semen); #18 was Job's tears (Coicis semen); #19 was Fukubonshi (Rubi fructus); #20 was red ginseng (Ginseng radix and rhizoma); #21 was Amynthas and metaphire; #22 was Arctii radix; #23 was purslane (Portulacae herba); and #24 was tortoiseshell (Trionycis carapax). [Example]

[0032] Example 2: Motility test of DR and MDP in C. elegans For this C. elegans phenotypic assay, MDP and DR were dissolved in 1% DMSO-containing water as 10 mg / ml stock solutions. 100 μl of each solution (compared to the vehicle control) was evenly spread onto nematode growth medium (NGM) agar plates (total agar volume: 10 ml) containing OP50 bacterial lawns. After the solution was fully absorbed into the agar, these OP50 plates were irradiated with UV light for 40 minutes and then seeded with approximately 50 synchronized eggs of CF512 worms. These plates were incubated at 25°C, and worm motility was measured every other day from post-adult day 1 to day 7. Data are mean ± SEM (n = 170–420). *P < 0.05; **P < 0.01; ***P < 0.0001 (t-test). C. elegans of different ages (1-, 5-, 9-, and 13-day-old adults) were first incubated in a drug-free solution and then in a solution containing levamisole for 10 minutes. Body length of the nematodes was quantified using ImageJ digital imaging. Data are mean ± SEM (n > 50). *P < 0.05; **P < 0.01; ***P < 0.0001 (t-test).

[0033] As shown in Figure 3A, the time-dependent effects of Dioscorea root (DR) on age-associated motility and / or whole-body contraction in C. elegans were not different compared to the control (vehicle).

[0034] As shown in Figure 3B, MDP can ameliorate the age-related decline in motility in C. elegans compared with the control group.

[0035] As shown in Figure 3C , the time-dependent effect of MDP showed a parallel protective effect on motility (body bending / sec on days 1, 3, 5, 7, and 9) with a longer life expectancy in a separate experiment.

[0036] As shown in Figure 3D, MDP significantly delayed the age-related decline in % whole body contraction in muscle function (relative whole body contraction on days 1, 5, 9, and 13).

[0037] In summary, MDP, but not DR, exhibited a unique ability to ameliorate the age-related decline in worm motility compared to controls. [Example]

[0038] Example 3: Efficacy of MDP in the C26 model of cancer cachexia The C-26 model was designed to confirm the in vivo anti-muscle wasting efficacy of MDP and DR in protecting CD2F1 mice from C-26 tumor-induced weight loss, which has been reported to be associated with excessive IL-6 secretion by tumors.

[0039] In the first series of experiments, three different doses (low dose: MDP-L, 100 mg / kg; medium dose: MDP-M, 500 mg / kg; high dose: MDP-H, 1,000 mg / kg) were orally administered to CD2F1 mice once daily by gavage starting 7 days before C-26 tumor cell implantation and continued until the mice were sacrificed on day 17. Individual mouse body weight, tumor size, and food and water intake were measured every other day. At the time of sacrifice, hindlimb skeletal muscles were dissected, weighed, and stored at -80 °C for further analysis. The first set of experiments is shown in Figure 4.

[0040] Figure 4 shows the effects of three doses of MDP (MDP-L, MDP-H, and MDP-H), vehicle, and control (H3-14) administered by oral gavage on the body weight (Figure 4A and Figure 4B) and tumor volume (Figure 4C) of C-26 tumor-bearing mice. NC, tumor-free mice. Tumor weight was 1,000 mm 3The weights were estimated based on the assumption that 1 g corresponds to 1 gram of body weight. SD bars are not shown to avoid overcrowding the graph. Statistical analysis used a generalized linear mixed-effects model with a random intercept for each individual subject and fixed effects for treatment and treatment day, with Tukey-Kramer correction for multiple comparisons to test for differences between groups. (a) Significant differences from the control group were p<0.05. (b) Significant differences from the vehicle group were p<0.05. Figure 4D shows the effects of three doses of MDP, vehicle, and H3-14 administered orally by gavage to three different sites in the skeletal muscle of the hind limbs of C-26 tumor-bearing mice. NC, tumor-free mice. (a) and (b) indicate significant differences from the NC and vehicle groups, respectively (Kruskal-Wallis test, Dunn's multiple comparison test with Bonferroni adjustment, p<0.05). Figure 4E shows a photograph of one representative mouse from these five groups at the end of the study, demonstrating the therapeutic effect of MDP-H and MDP-M in tumor-bearing mice, as indicated by their alertness, normal posture, smooth coat, and improved physical condition despite the large tumor burden.

[0041] As shown in Figure 4A, MDP-H was effective in ameliorating weight loss in C-26 tumor-bearing mice.

[0042] As shown in Figure 4B, MDP-H was effective in ameliorating weight loss (tumor-free) in C-26 tumor-bearing mice.

[0043] As shown in Figure 4C, MDP-H exhibited very little tumor-suppressive effect on tumor growth.

[0044] As shown in Figure 4D, MDP-M was effective in protecting the hindlimb muscles of C-26 tumor-bearing mice.

[0045] As shown in Figure 4E, C-26 tumor-bearing mice treated with MDP-M and MDP-H exhibited an alert and aggressive phenotype.

[0046] In a second set of experiments, the in vivo efficacy of 100 mg / kg DR and vehicle by oral gavage was evaluated, and the results are shown in FIG.

[0047] Figure 5 shows the effects of oral gavage of 100 mg / kg DR and vehicle on body weight (tumor-free) (Figure 5A) and tumor volume (Figure 5C) of C-26 tumor-bearing mice (*P<0.05; n=3-6). Control, tumor-free mice. (Figure 5B) Photographs of representative mice from each group at the end of the study, demonstrating the lack of therapeutic effect of DR. (a) and (b) show significant differences between the control and vehicle groups, respectively (generalized linear mixed-effects model with Tukey-Kramer correction for multiple comparisons).

[0048] As shown in Figure 5A, 100 mg / kg DR exacerbated weight loss.

[0049] As shown in Figure 5B, 100 mg / kg DR caused a deterioration in physical appearance compared to the vehicle control.

[0050] As shown in Figure 5C, 100 mg / kg DR had no effect on tumor growth.

[0051] Figure 6 shows a replicate experiment demonstrating the effect of oral gavage of 1000 mg / kg MDP (MDP-H) compared with vehicle on body weight (Figures 6A and 6B) and tumor volume (Figure 6C) in C-26 tumor-bearing mice. NC, tumor-free mice. Tumor weight was 1,000 mm 3The weights were estimated based on the assumption that 1 g corresponds to 1 gram of body weight. SD bars are not shown to avoid overcrowding the graph. Statistical analysis used a generalized linear mixed-effects model with a random intercept for each individual subject and fixed effects for treatment and treatment day, with Tukey-Kramer correction for multiple comparisons to test for differences between groups. (b) Significant difference from the control group at p<0.05. (c) Significant difference from the vehicle group at p<0.05. Figure 6D shows the effects of MDP-H and vehicle on three different sections of skeletal muscle in the hind limbs of C-26 tumor-bearing mice. Control group, tumor-free mice. (a) and (b) show significant differences from the control group and vehicle group, respectively (Kruskal-Wallis test, Dunn's multiple comparison test with Bonferroni adjustment, p<0.05). Figure 6E shows the effect of MDP-H on muscle fiber size in C-26 tumor-bearing mice. The cross-sectional area of ​​gastrocnemius muscle fibers was presented as a frequency histogram. Five sections of gastrocnemius muscle from each of five mice per treatment group were analyzed as described in the Methods section. Using the log-rank multiple comparison test, comparisons of muscles between tumor-bearing / vehicle mice and tumor-bearing / MDP mice showed statistical significance (P<0.001). Data are presented as mean + / - SEM. Figure 6F shows the effect of MDP on grip strength.

[0052] As shown in Figure 6A, MDP-H was shown to protect mice from C-26 tumor-induced weight loss at day 17 of tumor burden.

[0053] As shown in Figure 6B, MDP-H was shown to protect mice from C-26 tumor-induced weight loss (tumor-free) at day 17 of tumor challenge.

[0054] As shown in Figure 6C, MDP-H did not have a significant inhibitory effect on tumor burden at day 17.

[0055] As shown in Figure 6D, MDP-H demonstrated the ability to attenuate the loss of skeletal muscle mass associated with cachexia.

[0056] As shown in Figure 6E, MDP-H was able to rescue the shift in fiber size distribution toward smaller cross-sectional area in cachectic muscle, as determined by immunostaining of GC myofibers with anti-dystrophin and subsequent quantification of myofiber diameter ( P < 0.0001).

[0057] As shown in Figure 6F, MDP-H was able to restore forelimb grip strength on day 17 (P<0.001).

[0058] Figure 7 shows the effect of MDP on serum IL-6 levels in C26 tumor-bearing mice treated with Veh and MDP-H. Statistical analysis was performed using the Wilcoxon rank-sum test (n = 5). Figure 7B shows the effect of 25 μg / mL and 50 μg / mL MDP on IL-6 production in C26 cell culture medium, and Figure 7C shows the viability of C26 cells. Bars indicate mean ± SD (for data from three independent experiments in (B) and (C)). ****, P < 0.0001).

[0059] As shown in Figure 7A, the mean serum IL-6 (the main cause of cachexia in the C-26 tumor model) levels in C-26 tumor-bearing mice treated with MDP-H were lower compared with the vehicle control group, but the difference was not statistically significant (P = 0.06).

[0060] As shown in Figure 7B, the reduction in serum IL-6 levels was associated with the unique ability of 25 μg / mL and 50 μg / mL MDP to suppress the secretion of IL-6 into the culture medium by C26 cells (P<0.001).

[0061] As shown in Figure 7C, 25 μg / mL and 50 μg / mL of MDP were not cytotoxic to C26 cells. [Example]

[0062] Example 4: Whole-transcriptome shotgun sequencing (RNA-seq) analysis Whole-transcriptome shotgun sequencing (RNA-seq) analysis was performed by a commercial vendor (Welgene Biotech; Taiwan). Subsequently, principal component analysis (PCA) of these RNA-seq data was performed to examine transcriptome changes between these groups. This clustering of expression profiles suggests that MDP was able to shift the gene expression profile of cachectic skeletal muscle (T / Veh) to a state similar to that of non-cachectic muscle (TF / Veh). Furthermore, pairwise comparisons of RNA-seq data were performed to analyze differences in gene expression profiles between individual groups. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) Knowledgebase were used to describe related biological signaling pathways.

[0063] As shown in Figure 8A, a two-dimensional projection of the RNA-seq data of the three test groups. Principal component analysis axes (Dim1, x-axis; Dim2, y-axis) highlight the overall changes in the RNA-seq data. As shown in Figure 8B, each black dot represents a transformed gene expression value. Venn diagram of differentially expressed genes in each of the two pairwise comparisons: T / Veh vs. TF / Veh and T / Veh vs. T / MDP.

[0064] As shown in Figure 8A, the principal component analysis (PCA) plot indicates that the two-dimensional projection of the changes in the T / MDP group is closer to those in the TF / Veh group than to those in the T / Veh group.

[0065] As shown in Figure 8B , Venn diagram analysis revealed a total of 1849 differentially expressed genes shared by two pairwise comparisons whose expression changed in the same direction (middle section).

[0066] The bioinformatics analysis described above demonstrated the ability of MDP to reprogram the expression of genes related to muscle homeostasis in cachectic skeletal muscle, as reflected in the top 20 most up-regulated and down-regulated genes in Tables 1-3 and 4-6 below.

[0067] Table 1

[0068] Table 2

[0069] Table 3

[0070] Table 4

[0071] Table 5

[0072] Table 6

[0073] As shown in Figure 9, the effect of MDP on skeletal muscle-related gene and protein expression was demonstrated. As shown in Figure 9A, qPCR analysis revealed five up-regulated genes (left) and five down-regulated genes (right) in the skeletal muscle of vehicle-treated and MDP-H-treated mice (n = 3 per group). The fold increase and expression rate of the up-regulated and down-regulated genes, respectively, are shown as the relative expression levels of selected skeletal muscle-related genes in MDP-H-treated mice compared to their vehicle counterparts. Bars, mean + SD (n = 3). As shown in Figure 9B, Western blot analysis of MuRF1 and Atrogin-1 protein expression levels in the skeletal muscle of vehicle- and MDP-H-treated C26 tumor-bearing mice (T / Veh and T / MDP-H, respectively) compared to vehicle-treated tumor-free mice (TF / Veh) is shown. The forward and reverse primers for quantitative RT-PCR are listed in Table 7 below.

[0074] [Table 7]

[0075] As shown in Figure 9A, the changes in the expression levels of up- and down-regulated genes by qPCR analysis were consistent with those by RNA-seq analysis.

[0076] As shown in Figure 9B, MDP-H was effective in suppressing the protein expression of Atrogin-1 and MuRF1 in C26 tumor-bearing mice to the basal levels observed in the control group by Western blotting analysis.

[0077] Although the invention has been described and illustrated in sufficient detail to enable those skilled in the art to make and use it, it will be apparent that various substitutions, modifications, and improvements will become apparent without departing from the spirit and scope of the invention.

[0078] Those skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The processes and methods for producing them are representative of preferred embodiments and are exemplary and are not intended to limit the scope of the invention. Modifications therein and other uses will occur to those skilled in the art. These modifications are encompassed within the spirit of the invention and defined by the scope of the claims.

Claims

1. Use of a composition in the manufacture of a medicament for treating or preventing cancer-induced cachexia in a subject, wherein the composition comprises an effective amount of peony bark or peony bark extract.

2. 2. The use according to claim 1, wherein the extract of peony bark is prepared by soaking the peony bark in 50% to 100% methanol or 50% to 100% ethanol.

3. The use according to claim 2, wherein the extract of peony bark is prepared by soaking the peony bark in 70% methanol or 70% ethanol.

4. Use of a composition in the manufacture of a medicament for treating or preventing cancer-induced skeletal muscle mass loss in a subject, wherein the composition comprises an effective amount of peony bark or peony bark extract.

5. The use according to claim 4, wherein the extract of peony bark is prepared by soaking the peony bark in 50% to 100% methanol or 50% to 100% ethanol.

6. The use according to claim 5, wherein the extract of peony bark is prepared by soaking the peony bark in 70% methanol or 70% ethanol.

7. 5. The use of claim 4, wherein the composition upregulates muscle homeostasis-related genes, including Ccl21a, Ccl12, Lep, Kera, Tmem233, Chad, Ky, Clip, Mettl21e, Mylk4, Kcng4, Plcd4, Vwa3b, Plin1, Casq1, Itgb6, Tnmd, Sypl2, Mss51, Mettl21c27, or a combination thereof, to alleviate cancer-induced muscle atrophy.

8. 5. The use of claim 4, wherein the composition downregulates muscle homeostasis-related genes, including Aldh8a1, Lcn2, Mt2, Dnase1, Mt1, Slc39a14, Nyx, Krt80, Serpina3m, Kcnk5, Cxcl13, Adamts2, Ampd3, Fah, Doc2b, Acox2, Myo1a, Itpkc, Acss1, Igfbp3, or a combination thereof, to alleviate cancer-induced muscle atrophy.

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