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Zhang, J.; Chen, X.; Han, L.; Ma, B.; Tian, M.; Bai, C.; Zhang, Y. Pharmacology of Cynomorium songaricum. Encyclopedia. Available online: https://encyclopedia.pub/entry/55875 (accessed on 20 April 2024).
Zhang J, Chen X, Han L, Ma B, Tian M, Bai C, et al. Pharmacology of Cynomorium songaricum. Encyclopedia. Available at: https://encyclopedia.pub/entry/55875. Accessed April 20, 2024.
Zhang, Jin, Xingyi Chen, Lu Han, Biao Ma, Mengting Tian, Changcai Bai, Ye Zhang. "Pharmacology of Cynomorium songaricum" Encyclopedia, https://encyclopedia.pub/entry/55875 (accessed April 20, 2024).
Zhang, J., Chen, X., Han, L., Ma, B., Tian, M., Bai, C., & Zhang, Y. (2024, March 05). Pharmacology of Cynomorium songaricum. In Encyclopedia. https://encyclopedia.pub/entry/55875
Zhang, Jin, et al. "Pharmacology of Cynomorium songaricum." Encyclopedia. Web. 05 March, 2024.
Pharmacology of Cynomorium songaricum
Edit

Cynomorium songaricum Rupr. (CSR) belongs to the family Cynomoriaceae. It is a perennial succulent parasitic herb with a reddish-brown coloration, predominantly submerged in sand and lacking chlorophyll. 

Cynomorium songaricum Rupr. traditional uses pharmacology

1. Anti-Tumor Effects

Inducing apoptosis serves as a method for preventing and treating tumors as it plays an essential role in tumor progression [1]. Cancer stem cells are inhibited from proliferating and dying when exposed to CSR. It can be used to treat malignant tumors such as breast cancer, leukemia, colon cancer, and others.

1.1. Anti-Cancer

There are four breast cancer cell lines inhibited by CSR extracts and its ethyl acetate extraction site, including MDA-MB-231 [2][3], MCF-7 [2][3], MB468 [2], and 4T1 [2]. Furthermore, CSR extract induces Foxo3 expression in apoptosis and prevents the transition from G1 to S phases [2]. It has been found that chloroform and ethyl acetate extraction sites from the CSR ethanol extract are capable of inhibiting the proliferation of the colon adenocarcinoma cell line Caco-2 [4]. In cell research for cervical cancer treatment, Cynomrium songaricum polysaccharides (CSP) inhibit proliferative activity in HeLa cells [5]. A further study showed that both methanol extract and anthocyanin 3-O-glucoside from CSR inhibited KBWT cell proliferation in a dose-dependent manner [6]. By inhibiting telomerase reverse transcriptase (TERT) mRNA, CSP induced apoptosis in A549 cells [7]. Methanol extract and aqueous extract from CSR inhibited the growth of B16 cells, which are used for studying skin cancer in humans [2]. Further, CSR ethyl acetate extract inhibited both LNCaP and HepG2 cells, showing that it may have therapeutic effects on prostate cancer and liver cancer [3]. Research has shown that the anticancer ingredients in CSR are concentrated in the ethyl acetate extraction site, and it may be related to activating and enhancing autophagy processes in cells to trigger. In autophagy and apoptotic cell death, mitochondrial-related proteins Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) and Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L) play a critical role [3].

1.2. Leukemia

CCRF-CEM and CCRF-SB cells were inhibited by methanol extract and anthocyanin 3-O-glucoside from CSR [6]. Similarly, mitochondrial pathways modulate caspase-3 activity. Therefore, CSR ethanol extract causes apoptosis in leukemia cells by causing apoptosis in HL-60 cells [8].
The above studies indicate that CSR has a certain inhibitory effect on two types of tumor cells, cancer, and leukemia. In cancer, it inhibits the growth of cancer cells by inducing the expression of Foxo3 and inhibiting telomerase reverse transcriptase mRNA to activate mitochondrial-related proteins BNIP3 and BNIP3L. Regulating caspase-3 activity through the mitochondrial pathway in leukemia induces cell apoptosis. In contrast, there is more research data on adenocarcinoma and less research on leukemia. However, it cannot be concluded with certainty that CSR has a better therapeutic effect on cancer than on leukemia.

2. Anti-Oxidation Function

Different parts of CSR have different antioxidant activities when extracted from methanol. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radicals are best scavenged in the central part, hydroxyl radicals are best inhibited in the lower part, and superoxide anions are highly resisted in the upper part [9]. Multiple solvent extracts of CSR exhibit antioxidant activity. A methanol extract of the CSR and an ethyl acetate extraction site strongly inhibit superoxide anions [10][11]. DPPH radicals, 2,2′-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radicals, and hydroxyl radicals are also scavenged by the aqueous extract and ethyl acetate extraction site [12]. Additionally, the aqueous extract was able to scavenge DPPH free radicals and inhibit superoxide anion formation [13].
Different extracts exhibit significantly different antioxidant and radical scavenging properties. CSR aqueous extract scavenges DPPH free radicals and nitrates more effectively than ethanol extract. In contrast, ethanol extract inhibits xanthine oxidase (XO) and superoxide dismutase (SOD) more effectively than aqueous extract [14].
To examine the categories of substances with superior antioxidant effects, compounds of the same type extracted from CSR were compared to their antioxidant activity. This was performed to clarify the strong antioxidant activity of CSR extract. Within a certain concentration range, CSP exhibits effective scavenging ability against superoxide anion radicals, DPPH radicals, and hydroxyl radicals [15]. CSR flavonoids also scavenge DPPH and hydroxyl radicals [16].
Crude polyphenols exhibited significantly higher antioxidant activity than crude polysaccharides when measured against DPPH radicals, ABTS free radicals, and crude polysaccharides in CSR [17]. According to another study, microwave-extracted procyanidins exhibited superior scavenging activity against DPPH and hydroxyl free radicals [18].
The main antioxidant component in the CSR ethyl acetate extraction site is catechin, which was isolated from protocatechuic acid, gallic acid, and catechins [19]. The aqueous extract of CSR was separated into catechin, epicatechin, and olive saponin to determine the DPPH free radical scavenging capacity [20].
In vivo experiments were used to verify the CSR extract’s significant antioxidant activity. CSR extracts (0.22 g/kg, 0.44 g/kg, 0.88 g/kg) can enhance the serum DPPH free radical scavenging ability of KM mice, and reduce oxidative damage caused by free radicals and lipid peroxides [21].
Some in vivo and in vitro experiments have shown that the antioxidant components in CSR exert antioxidant effects by clearing free radicals, as well as inhibiting XO and SOD, etc. The antioxidant activity of CSR is one of its main functions, which can slow down the oxidative state of the body and fight against diseases.

3. Anti-Aging Effects

Several studies have demonstrated the anti-aging effects of CSR through a variety of mechanisms. According to reports, adding CSR to the diet can extend the average and maximum lifespans of adult female flies. Ethanol extract of CSR suppresses age-related learning disabilities in elderly flies by reducing hydrogen peroxide levels and increasing antioxidants, extending their lifespan, improving mating readiness, increasing fertility, and inhibiting age-related learning disabilities [22]. A transcriptome sequencing study found that CSR extract impacted wild-type Caenorhabditis elegans aging. The lifespan of Caenorhabditis elegans was extended and motor abilities were enhanced by ethyl acetate extract (0.4 mg/mL). Multiple pathways and genes collaborate to produce the effects of the ethyl acetate extract [23]. Various research results have shown that extracts, CSP, and preparations from CSR can delay aging by inhibiting telomere length shortening [24], enhancing telomerase activity [25], improving immune function [26][27][28], inhibiting neuronal apoptosis [25][29], improving hippocampal CA1 neurons [30], enhancing antioxidant capacity [26][28][29][31][32].
The aqueous extract of CSR can also improve the energy metabolism of liver mitochondria in aging model KM mice. It can also alleviate free radical damage to mitochondrial membrane structure and function and play a role in delaying aging [33].
These findings not only reveal the potential of the polysaccharide and extract in combating aging but also lay the groundwork for future clinical research. It would be beneficial to further investigate the chemical composition of CSR and the mechanism underlying anti-aging as well as their safety and effectiveness to offer novel insights and possibilities for delaying the aging process in the future.

4. Anti-Fatigue and Anti-Hypoxia Activities

The aqueous extract and ethanol extract of CSR are responsible for its anti-fatigue properties. By lowering the lactate index [34], inhibiting amino acid protein breakdown, and increasing glycogen reserves [35][36][37], they can improve energy metabolism. It also possesses the ability to increase the level of cyclic adenosine monophosphate (cAMP), reduce cyclic adenosine monophosphate/cyclic guanosine monophosphate (cAMP/cGMP) ratio [38], improve free radical metabolism [37][39]. In addition, CSR flavonoids (CSF) reduce MAO activity and reactive oxygen species (ROS) levels by improving free radical metabolism [40][41][42].
Oxygen deficiency can cause abnormal tissue metabolism, function, and morphology. The main cause of death is hypoxia of the brain and heart. CSR aqueous extract has positive atmospheric pressure anti-hypoxia and anti-acute cerebral ischemia and hypoxia effects [43], which increases blood hemoglobin content and enhances oxygen-carrying function [44]. As well as reducing brain edema, it increases myocardial protein content [45].
CSR exhibits remarkable anti-fatigue and anti-hypoxia properties. Research on anti-fatigue effects focuses on its active ingredients, such as water extract, ethanol extract, and flavonoids. Currently, hypoxic resistance studies are primarily focused on CSR water extract. Developing highly potent and pharmaceutically viable compounds from CSR for anti-fatigue and anti-hypoxia purposes will require further investigation.

5. Effects on Nervous System

Ethyl acetate extract and methanol extract are both effective against Aβ25–35, hypoxanthine/xanthine oxidase (HPX/XO) [46], Xanthine dehydrogenase/xanthine oxidase (XDH/XO) [10] induced SK-N-SH cells have protective effects. Among them, ethyl acetate extract is more effective against Amyloidβ-Protein 25–35 (Aβ25–35) and has an anti-Starosporin-induced injury effect [11]. CSP and ethyl acetate extraction sites of CSR can protect PC12 cells against damage by H2O2 [47] and Aβ25–35 [48]. Ethyl acetate extract has cytotoxicity to Neuro2A cells (EC50 = 116 mg/L) and increases the expression of synaptophysin through the mitogen-activated protein kinases (MAPK) pathway [49]. In another study, the methanol extract of CSR inhibits Aβ25–35 induced phosphorylation of dynamin-related protein 1 (Drp1) at Ser637 in HT22 cells and reduced the expression of Fission 1 Protein (Fis1) in H2O2 induced model for the treatment of Alzheimer’s disease (AD) [50].
Based on neuroprotective effects at the cellular level, scholars have further explored them through animal models. The ethyl acetate fraction of CSR improves the behavior of C57BL/6 male mice by reducing mitochondrial dynamics imbalance. It also downregulated the expression of the Drp1 protein and upregulated the expression of Optic Atrophy 1 (OPA1) and Mito Fusin 1 (MFN1) proteins [51]. It also improves the spatial memory and learning ability of AD model mice by regulating fecal microbiota disorder [52]. In the ovariectomized Sprague–Dawley (SD) rat model, it increased the expression of Growth-Associated Protein 43 (GAP-43) protein in the hippocampus [53], regulated the MAPK pathway, increased the expression of phosphorylation-cAMP response element-binding protein (p-CREB), and decreased the expression of p38, thereby promoting the survival and repair of hippocampal neurons.
Other studies have shown that CSR ethyl acetate extract increases the expression levels of synaptic plasticity-related proteins Syn and postsynaptic density protein-95 (PSD-95) [54] while upregulating the protein expression levels of phosphor-extracellular regulated protein kinases 1/2 (P-Erk1/2) and P-CREB in the MAPK/ERK1/2 signaling pathway [55]. It increases the effect of Long-term Potential (LTP) in Morris water maze and neuroelectrophysiology, further improving cognitive dysfunction in chronic stress Institute of Cancer Research (ICR) mice after ovariectomy [56].
The ethanol extract of CSR increased cAMP response element-binding protein /Brain-Derived Neurotrophic Factor (CREB/BDNF) expression in ovariectomized SD rats by inhibiting the p38MAPK/ERK pathway [57]. It also reduced serum corticosterone levels, increased the expression of BDNF mRNA in this region, promoted the proliferation of mouse dentate gyrus cells and differentiation of neuroblasts, enhanced the potential for hippocampal plasticity in male C57BL/6J mice [58], and thus achieved neuroprotective effects on the nerves.
The aqueous extract of CSR has a significant improvement effect on the learning and memory of scopolamine-induced KM male mice. Its mechanism may be related to reducing oxidative stress in brain tissue [59].
In Wistar male rats, through upregulating the Brain-Derived Neurotrophic Factor/Tyrosine Kinase receptor B (BDNF/TrkB) signaling pathway, enhancing cognitive function, increasing acetylcholine (ACH) content in the central cholinergic system, inhibiting cell apoptosis, and enhancing synaptic plasticity, CSF improves the AD model induced by Aβ1–42 [60]. In addition, CSF inhibits oxidative stress and inflammatory reactions. It can also downregulate the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, ROS, and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) in the hippocampus, exerting neuroprotective effects [61].
The main component of CSR, ursolic acid, at a concentration of 5–15 µM, can effectively protect SD rat hippocampal neurons from damage induced by kainic acid by regulating α-amino-3-hydroxy-5-methy1-4-isoxazole propionic acid (AMPA) receptors, protecting mitochondria, and reducing free radical generation [62][63].
In summary, the neuroprotective active ingredients are mainly concentrated in the methanol, ethanol, and ethyl acetate extracts of CSR. However, the main components that play a key neuroprotective role are not yet clear because of the complex components in CSR extract. Therefore, future studies should explore compounds that play a major role in protecting the nervous system.

6. Effects on Reproductive System

In geriatrics, benign prostatic hyperplasia (BPH) is a common genitourinary disorder characterized by prostate gland enlargement and urinary dysfunction [64]. There is an inhibitory effect of ethanol extract of CSR (2.5 mg/mL) on testosterone 5α-reductase [65]. Moreover, it interferes with estrogen/androgen signals to inhibit prostate hyperplasia in Wistar rats [66] and improves the disorder of prostate epithelial cells and abnormal proliferation of connective tissue in Wistar rats with BPH model, inhibiting Proliferating Cell Nuclear Antigen (PCNA), Androgen Receptor (AR), and estrogen receptor α (Erα) Protein expression while promoting estrogen receptor β (ERβ) Protein expression while promoting ERβ Protein expression [67]. Meanwhile, Wistar male rat protein expression of prostate AR, ERα/β, and 3-oxo-5-alpha-steroid 4-dehydrogenase 1/2 (SRD5A1/2) were regulated to inhibit BPH [68]. Additionally, CSR aqueous extract inhibits prostate hyperplasia, increases SOD and glutathione (GSH) activities, decreases malondialdehyde (MDA) content, and significantly reduces prostate wet weight and prostate index by improving testosterone propionate-induced oxidative stress levels [69].
In vitro experiments, Luteolin, Gallic acid, Ferulic acid, Protocatechualdehyde from CSR suppressed BPH by downregulating the expression of AR and ERα in BPH-1 cells and upregulation ERβ expression [68]. CSRs containing luteolin, epicatechin, and epicatechin gallate all improve the contractility of Wistar male rats’ bladder detrusors [70].
Infertility in men is complex and multifactorial, with idiopathic infertility accounting for approximately 30% of cases [71]. It has been shown that CSR improves sexual hormone levels as a kidney tonifying traditional Chinese medicine [57]. Under the intervention of CSR aqueous extract, serum testosterone and Follicle-stimulating Hormone (FSH) levels are reduced, and interstitial cell-stimulating hormone (ICSH) levels are increased to directly affect the spermatogenic effect of immature seminiferous tubules of Wistar rats [72]. It can also promote the secretion of testosterone in SD rats and inhibit abnormal secretion of FSH and Luteinizing hormone (LH) by regulating gonadal hormone levels [73]. Glial Cell Line-derived Neurotrophic Factor (GDNF) production in testes of SD rats and undifferentiated spermatogonia proliferation stimulates, increases testosterone levels, and improves sperm motility [74]. Relieving sperm damage and serum testosterone levels are increased through the MAPK-3-mediated GDNF signaling pathway, thereby enhancing sperm motility [75].
In addition, enhancing sperm production in Wistar rats and upregulating the expression pathway of GDNF in the testes to improve male fertility [76], enhancing sperm production in golden hamsters, and blocking the impact of short photoperiod on reproductive function [77] by CSR aqueous extract.
In summary, active compounds from CSR that inhibit BPH mainly exist in its ethanol extract, while the active ingredients that promote spermatogenesis are mainly concentrated in the aqueous extract, which has been proven to have good therapeutic effects in treating male infertility.

7. Anti-Virus

Despite a significant increase in the number of approved antiviral drugs, these existing drugs are not always effective or well tolerated. It is becoming increasingly common for viruses to develop drug resistance. As of now, many polysaccharides have been approved as drugs as independent or major bioactive components [78]. The methyl thiazolyl tetrazolium (MTT) method was used to detect the toxicity of CSP on MT-4 cells, which showed that only sulfated polysaccharides (SCSP-M, SCSP-1, SCSP-2) are anti-HIV. Due to the interaction between sulfated polysaccharides and poly L-lysine, sulfated polysaccharides have antiviral properties [79].
In addition to the CSP, the triterpenoids contained in CSR also have antiviral activity. Ursolic acid, half ursolic malonate, malonyl oleanolic acid hemiester [80], acetyl ursolic acid, and condensed tannin extracted from CSR all have the function of inhibiting human immunodeficiency virus (HIV) protease [81]. Furthermore, triterpenoids in CSR also have inhibitory activity against hepatitis C virus (HCV) protease, with malonyl ursolic acid hemiester having the maximum inhibitory effect [82].
The main components of CSR are polysaccharides and triterpenoids, which are potentially useful for developing antiviral drugs. Additionally, it is worth noting that the antiviral efficacy of CSR has predominantly been tested in vitro with limited reports on its in vivo effects. Consequently, the precise mechanism by which CSR is antiviral remains unclear. Future studies should explore this aspect further to uncover the antiviral mechanism of CSR and establish solid foundations for its application.

8. Anti-Diabetic Properties

CSP as one of the pivotal active constituents in CSR, exhibits significant therapeutic effects on several diseases. Consequently, CSR is being considered a potential candidate for the development of novel anti-diabetic drugs [83]. Oral administration of CSR water-soluble polysaccharide (CSPA) significantly reduced the blood glucose level, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, blood urea nitrogen, creatinine activity in streptozotocin (STZ) induced diabetes model rats, effectively increased the serum insulin level and liver glycogen content and promoted the recovery of pancreatic islet cells in the pancreas to near normal levels [84]. CSP (300 mg/kg) can upregulate the expression of protein kinase B (AKT) and endothelial nitric oxide synthase (eNOS), and downregulate tumor necrosis factor α (TNF-α) expression [85]. It can also regulate phospholipid metabolism, including phosphatidylcholine, Lys phosphatidylcholine, phosphatidylethanolamine, and sphingomyelin to play a role in the treatment of diabetes [86].
In addition to polysaccharides, the flavonoids and their amino acid derivatives contained in CSR can also exert hypoglycemic effects. Flavan-3-ol derivatives prepared from CSR and other reagents, including 3 cysteine conjugates and 3 acetylcysteine conjugates, were found to have significant effects on α-glucosidase, sucrase, and maltase have inhibitory effects [87]. Furthermore, the flavane-3-ol oligomer and compound Pentamers (pentamer) in the stem have inhibitory effects on α-Glucosidase has inhibitory effects [88].
The investigation of CSR’s anti-diabetic activity is limited to in vitro and in vivo experiments. It plays an anti-diabetes role by regulating blood sugar levels, improving insulin sensitivity, protecting islet cells, controlling the risk of complications, etc. While these studies have demonstrated some anti-diabetic effects of CSR, further clinical trials are necessary to confirm its efficacy and safety for human use.

9. Anti-Osteoporosis Effect

A few studies have demonstrated the favorable anti-osteoporotic effects of CSR. After screening the methanol and water extracts of 60 natural medicinal herbs, it was found that the methanol extract of CSR has a stimulating effect on the proliferation ability of osteoblast UMR106 and an inhibitory activity on osteoclast formation [89]. CSP (100 μg/mL) induces osteogenic differentiation in MC3T3-E1 cells by activating Phosphatidylinositide 3-kinases/AKT/glycogen synthase kinase-3β/β-Catenin (PI3K/AKT/GSK3 β/β-Catenin) pathway and upregulates mRNA, PI3K, phos-pho-phosphatidylinositide 3-kinases (p⁃PI3K), AKT, phospho-protein kinase B (p⁃AKT), GSK3β, phosphor-glycogen synthase kinase-3β (p⁃GSK3β), β⁃catenin protein expression [90]. Ethanol extract of CSR can promote the differentiation of osteoblasts from MC3T3-E1 while inhibiting osteoblast apoptosis, upregulating the expression of Bax and caspase-3, and downregulating the expression of B-cell lymphoma-2 (Bcl-2) [91]. CSR aqueous extract containing serum can promote the proliferation and differentiation of MC3T3-E1 osteoblasts, increase alkaline phosphatase (ALP) activity, and increase the number of calcified nodules [92].
In in vitro experiments, CSP was administered to ovariectomized SD rats. The results express that CSP can increase the osteoclastogenesis inhibitory fac-tor/Receptor Activator for Nuclear Factor-κB Ligand (OPG/RANKL) ratio, inhibit osteoclast activity by activating the OPG/Receptor Activator for Nuclear Factor-κB (RANK)/RANKL signaling pathway, regulate osteocalcin levels to reduce bone turnover rate, restore the balance between bone formation and bone resorption, reduce bone loss, increase bone density, improve tibial biomechanical properties, reduce bone fragility and fracture risk, and promote osteoblast differentiation [93].
The ethanol extract of CSR can accelerate bone formation, inhibit bone resorption, and alleviate oxidative stress. It can also increase ALP levels in ovariectomized SD rats and reduce the levels of bone resorption-related biomarkers tartrate-resistant acid phosphatase (TRAP), Cathepsin K, and DPD [94]. At the same time, it can also mediate PI3K/AKT and Nuclear Factor-κB (NF-κB) through RANKL/RANK/ TNF receptor-associated factor 6 (TRAF6) pathway to play an anti-osteoporosis role [95].
To summarize, the anti-osteoporotic effect of CSR is primarily attributed to its extract and polysaccharide constituents. By increasing bone density, slowing down the process of osteoporosis, enhancing the resistance to fractures, reducing the risk of fractures, improving blood circulation, and increasing the nutrient supply of bones, it plays its role. However, there are currently no mechanisms of action for specific components. Further investigations are still required to clarify the underlying anti-osteoporosis mechanisms associated with the active constituents of CSR.

10. Liver Protection

Among its many functions, the liver plays a crucial role in immunity, metabolism, detoxification, and digestion. Fibrosis of the liver is an injury-repair response, which can be partially reversed. However, persistent damage can lead to chronic inflammation, which triggers the formation of liver fibers [96].
In order to effectively treat patients with chronic liver disease, liver fibrosis must be halted or slowed down [97]. Blood levels of glutamic oxalate transaminase (GOT) and glutamic pyruvate transaminase (GPT) increase when the liver is damaged. In liver injury induced by Streptozocin (STZ) in Wistar rats, CSPA (200 mg/kg, 150 mg/kg) reduces levels of GOT and GPT [84]. By increasing white blood cell (WBC) levels, hematocrit (HCT) levels, red blood cells (RBCs), mean corpuscular volumes (MCVs), and red blood cell distribution width (RDW) levels in the blood cells of SD male rats induced by carbon tetrachloride. CSR extract regulates the transforming growth factor β1 (TGF-β1) expression [98] and increases levels of WBC, HCT, RBC, MCV, and RDW in the blood cells of SD male rats induced by carbon tetrachloride, to impact blood cell typing and alleviate symptoms of liver fibrosis [99]. Furthermore, it can also reduce the liver’s exposure to the inflammatory factors TGF-β1, TNF-α, and interleukin 1 (IL-1) stimulation, thereby reducing liver fibrosis [100]. CSR aqueous extract (3.5 g/kg) alleviates the lipid peroxidation damage caused by free radicals attacking the liver cell membrane of male Wister rats and protects the liver tissue from normal physiological operation [35].
The use of 60% ethanol extract from CSR has been found to reduce serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydro-genase (LDH), and laminin (LN) in KM male mice induced by carbon tetrachloride. Additionally, the extract of CSR reduced the content of Hyp and MDA in liver tissue, while increasing SOD and GSH. By increasing the body’s antioxidant level and scavenging free radicals, reducing collagen fiber production, and reducing extracellular matrix deposition, the extract of CSR protects the liver [101].
HCY2 and ursolic acid isolated from the ethanol extract of CSR can enhance mitochondrial function and glutathione antioxidant status in liver tissue, inhibit plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, and protect SD female rats from carbon tetrachloride damage [102]. CSF enhances the activity of SOD and Glutathione peroxidase (GSH-Px) in formaldehyde-induced T6 cells [103], reduces the protein concentration and MDA content of H2O2-induced damage to T6 cells, increases the expression level of nitric oxide synthase (NOS) protein [104], and has a protective effect on oxidative damage to T6 cells.
Along with the current increasing demand for hepatoprotective drugs, CSR has demonstrated promising potential in the field of drug development for liver protection. However, due to the intricate physiological functions of the liver, further investigations are required to elucidate more specific mechanisms underlying hepatoprotection. Additionally, it is also imperative to conduct comparative analyses of CSR constituents to assess their respective hepatoprotective abilities.

11. Other Pharmacological Effects

11.1. Intestinal Effects

A specific effect of CSR is to promote intestinal peristalsis, facilitate bowel movement, and maintain intestinal moisture. CSP (14.28 mg/kg, 28.57 mg/kg, 57.14 mg/kg) counteracted atropine’s inhibitory effect on intestinal peristalsis in KM mice by modulating parasympathetic nervous system function, reducing phenol red residue, and increasing intestinal propulsion rates [105]. Comparing the effects of aqueous extract with ethyl acetate, methanol, and the aqueous extraction site of CSR on intestinal defecation in KM mice, it was observed that the aqueous extract (3.9 g/kg) showed significant activity [106]. As demonstrated by the aqueous extracts of CSR (0.01 g/mL, 0.015 g/mL, 0.02 g/mL), the CSR augments smooth muscle contraction frequency while attenuating smooth muscle contraction amplitude in New Zealand white rabbits, resulting in mild “intestinal moistening and purging” effects [107].

11.2. Mitigate Obesity

Ursolic acid (UA), an active component of CSR, HCY2 significantly reduced both body weight gain and fat pad weight in ICR mice [108]. Furthermore, the expression of mitochondrial uncoupling protein 3 in skeletal muscle can be increased by ursolic acid through the regulation of the Adenosine phosphate-activated protein kinase/peroxisome proliferator-activated receptor γ coactivator-1 (AMPK/PGC1) pathway, thereby potentially contributing to the treatment of obesity [109].

11.3. Renal Protective Effects

With the aggravation of diabetes and the side effects of hypoglycemic drugs, kidney damage is gradually caused. Serum levels of blood urea nitrogen (BUN) and creatinine (Cr) are significantly increased, which is considered to be an important indicator of renal dysfunction. HCY2 (0.5 mg/kg, 1.0 mg/kg) and ursolic acid (0.35 mg/kg, 0.70 mg/kg), derived from the CSR, resulted in a reduction in BUN and Cr levels and provided protection against gentamicin-induced nephrotoxicity in female SD rats [102]. CSPA (200 mg/kg, 150 mg/kg) in vivo significantly reduces the levels of BUN and Cr, thereby ameliorating renal dysfunction in streptozotocin-induced Wistar rats [84]. The CSP concentrations (0.25 mg/mL, 0.5 mg/mL, 1.0 mg/mL) indirectly attenuated H2O2-induced apoptosis of VERO cells by suppressing caspase-3 activity in vitro, indicating the potential of CSR for the prevention and treatment of kidney-related diseases [110].
In summary, CSR protects kidney function from further damage by improving renal blood circulation, anti-fibrotic, antioxidant, and anti-inflammatory effects. For acute kidney injury, renal protection can promote the repair and regeneration of kidney tissue, reduce oxidative damage and inflammatory reactions, and help alleviate the degree of kidney injury and restore kidney function. For chronic renal failure, renal protection can delay the progression of the disease and reduce the loss of renal function.

11.4. Immune System Modulation

Studies have demonstrated that CSR exine levels effectively inhibit the autoimmune antibodies and enhance humoral immune function, thereby improving overall immune competence in the body.
The 75% alcohol extract (0.1 g/kg, 0.2 g/kg, 0.4 g/kg) and aqueous extract (0.18 g/kg, 0.36 g/kg, 0.72 g/kg) of CSR significantly augmented the thymus index and spleen index in immunosuppressed KM mice while also enhancing phagocytic function within the immune system. They promoted hemolysin antibody production and increased serum levels, interferon-γ (IFN-γ), and TNF-α secretion, thereby bolstering both humoral and cellular immunity responses; notably, aqueous extract to the ethanol extract [111]. The aqueous extract of CSR part Ⅲ (300 mg/kg) demonstrated a protective effect on BALB/C mice immunosuppressed by cyclophosphamide (CTX). It enhanced the phagocytic capacity of macrophages towards foreign bodies and resulted in an elevation in serum, effectively improving the humoral immune function of mice [112]. In addition to the immunomodulatory effects observed with CSR aqueous extract and ethanol extract, CSP exhibits significant immunomodulatory effects in vitro experiments. Specifically, CSP polysaccharide demonstrates remarkable potential as it promotes the proliferation and enhances the phagocytic activity of RAW264.7 macrophages at concentrations ranging from 25 to 400 μg/mL. Moreover, CSP also induces an increase in the secretion levels of IL-6, TNF-α, and NO [113].

11.5. Anti-Ulcer Effect

In recent years, despite the efficacy of antiplatelet drugs such as aspirin and clopidogrel in managing arterial circulation disorders caused by excessive platelet aggregation, it is crucial to consider potential gastrointestinal complications like gastric bleeding and ulceration when administering these medications.
CSR has also demonstrated positive outcomes in the restoration and optimization of digestive functionality. The following examples are provided. The administration of CSP (100 mg/kg, 200 mg/kg, 400 mg/kg) effectively inhibits the development of water immersion restraint stress-induced gastric ulcers and pyloric ligation-induced gastric ulcer index in Wister rats. It also enhances the microcirculation of the gastric mucosa and improves its defensive capabilities, thereby exerting an anti-ulcer effect [114]. Additionally, CSR can stimulate the synthesis and release of endogenous prostaglandin E2 (PGE2) and epidermal growth factor (EGF), enhance mucosal blood defense and repair functions of gastric mucosa, suppress the inflammatory mediator platelet-activating factor (PAF), mitigate its damage to mucosa, and restore the balance and defense factors for achieving an anti-gastric ulcer effect [115].

11.6. Anti-Depressant Effect

The therapeutic potential of CSF has garnered significant attention in research studies. The administration of CSF at doses of 0.2 g/kg, 0.1 g/kg, and 0.05 g/kg has mitigated perimenopausal depression in female SD rats by modulating the hypothalamic-pituitary-gonadal axis through an increase in E2 levels [116]. Not singly but in pairs, CSF (400 mg/kg, 200 mg/kg, 100 mg/kg) also effectively demonstrates significant therapeutic efficacy in perimenopausal depression KM female mice, ameliorating the pathological alterations in the uterus, thymus, spleen, and hypothalamus [117].

11.7. Anti-Epileptic

The maximum electroconvulsive seizure (MES) model is widely regarded as a robust experimental model for grand mal epilepsy. The clinical efficacy of drugs with potent anti-MES effects extends to grand mal seizures. Based on this, CSR aqueous extract (1 g/mL), which exhibits a potent anti-MES effect in KM mice, holds promising potential for the treatment of grand mal epilepsy [43].

11.8. Anti-Bacterial

For good measure, the polyphenolic compounds and polymeric procyanidins present in CSR exhibit antibacterial properties. Cynomoriitannin (MIC = 64 μg/mL) demonstrates higher efficacy against methicillin-resistant staphylococcus aureus (MRSA) than other compounds separated from CSR [118].

References

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