Structural Characters and Pharmacological Activity of Protopanaxadiol-Type Saponins and Protopanaxatriol-Type Saponins from Ginseng.

Ginseng has a long history of drug application in China, which can treat various diseases and achieve significant efficacy. Ginsenosides have always been deemed important ingredients for pharmacological activities. Based on the structural characteristics of steroidal saponins, ginsenosides are mainly divided into protopanaxadiol-type saponins (PDS, mainly including Rb1, Rb2, Rd, Rc, Rh2, CK, and PPD) and protopanaxatriol-type saponins (PTS, mainly including Re, R1, Rg1, Rh1, Rf, and PPT). The structure differences between PDS and PTS result in the differences of pharmacological activities. This paper provides an overview of PDS and PTS, mainly focusing on their chemical profile, pharmacokinetics, hydrolytic metabolism, and pharmacological activities including antioxidant, antifatigue, antiaging, immunodulation, antitumor, cardiovascular protection, neuroprotection, and antidiabetes. It is intended to contribute to an in-depth study of the relationship between PDS and PTS.

Swallowing rehabilitation of patients undergoing T-tube implantation for the treatment of laryngotracheal stenosis.

OBJECTIVE: Patients with laryngotracheal stenosis (LTS) often have dysphagia after laryngotracheal reconstruction with T-tube insertion, which affects the quality of life. The purpose of this study is to observe the effect of swallowing rehabilitation therapy on the improvement of quality of life in patients of otolaryngology-head and neck surgery with dysphagia undergoing T-tube implantation treatment through longitudinal study. METHODS: Thirty-eight patients with LTS who experienced dysphagia after laryngotracheal reconstruction and T-tube implantation were recruited. All patients received swallowing rehabilitation therapy. The assessment of swallowing function was performed using the 10-item Eating Assessment Tool (EAT-10), the 30 mL water swallow test (WST), and flexible endoscopic evaluation of swallow (FEES). RESULTS: After swallowing rehabilitation therapy, timing of swallowing, grade of dysphagia, performance on FEES and 30 mL WST, and EAT-10 score all improved. Thirty-eight patients successfully transitioned to oral feeding and were able to remove their nasogastric tubes without experiencing any complications, including aspiration pneumonia. CONCLUSION: For patients with LTS who experienced dysphagia after laryngotracheal reconstruction and T-tube implantation, swallowing rehabilitation therapy could improve swallowing function of the patients, so as to reduce the potential harm caused by the pain and complications of surgery experienced by patients.

α-Ketoglutarate alleviates osteoarthritis by inhibiting ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway.

Osteoarthritis (OA) is the most common degenerative joint disorder that causes disability in aged individuals, caused by functional and structural alterations of the knee joint. To investigate whether metabolic drivers might be harnessed to promote cartilage repair, a liquid chromatography-mass spectrometry (LC-MS) untargeted metabolomics approach was carried out to screen serum biomarkers in osteoarthritic rats. Based on the correlation analyses, α-ketoglutarate (α-KG) has been demonstrated to have antioxidant and anti-inflammatory properties in various diseases. These properties make α-KG a prime candidate for further investigation of OA. Experimental results indicate that α-KG significantly inhibited H2O2-induced cartilage cell matrix degradation and apoptosis, reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) and glutathione (GSH)/glutathione disulfide (GSSG) levels, and upregulated the expression of ETV4, SLC7A11 and GPX4. Further mechanistic studies observed that α-KG, like Ferrostatin-1 (Fer-1), effectively alleviated Erastin-induced apoptosis and ECM degradation. α-KG and Fer-1 upregulated ETV4, SLC7A11, and GPX4 at the mRNA and protein levels, decreased ferrous ion (Fe2+) accumulation, and preserved mitochondrial membrane potential (MMP) in ATDC5 cells. In vivo, α-KG treatment inhibited ferroptosis in OA rats by activating the ETV4/SLC7A11/GPX4 pathway. Thus, these findings indicate that α-KG inhibits ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway, thereby alleviating OA. These observations suggest that α-KG exhibits potential therapeutic properties for the treatment and prevention of OA, thereby having potential clinical applications in the future.

Ginseng total saponin improves red blood cell oxidative stress injury by regulating tyrosine phosphorylation and glycolysis in red blood cells.

BACKGROUND: Oxidative stress is the main cause of many diseases, but because of its complex pathogenic factors, there is no clear method for treating it. Ginseng total saponin (GTS) an important active ingredients in Panax ginseng C.A. Mey (PG) and has potential therapeutic ability for oxidative stress due to various causes. However, the molecular mechanism of GTS in the treating oxidative stress damage in red blood cells (RBCs) is still unclear. PURPOSE: This study aimed to examine the protective effect of GTS on RBCs under oxidative stress damage and to determine its potential mechanism. METHODS: The oxidative stress models of rat RBCs induced by hydrogen peroxide (H2O2) and exhaustive swimming in vivo and in vitro was used. We determined the cell morphology, oxygen carrying capacity, apoptosis, antioxidant capacity, and energy metabolism of RBCs. The effect of tyrosine phosphorylation (pTyr) of Band 3 protein on RBCs glycolysis was also examined. RESULTS: GTS reduced the hemolysis of RBCs induced by H2O2 at the lowest concentration. Moreover, GTS effectively improved the morphology, enhanced the oxygen carrying capacity, and increased antioxidant enzyme activity, adenosine triphosphate (ATP) levels, and adenosine triphosphatase (ATPase) activity in RBCs. GTS also promoted the expression of membrane proteins in RBCs, inhibited pTyr of Band 3 protein, and further improved glycolysis, restoring the morphological structure and physiological function of RBCs. CONCLUSIONS: This study shows, that GTS can protect RBCs from oxidative stress damage by improving RBCs morphology and physiological function. Changes in pTyr expression and its related pTyr regulatory enzymes before and after GTS treatment suggest that Band 3 protein is the main target of GTS in the treating endogenous and exogenous oxidative stress. Moreover, GTS can enhance the glycolytic ability of RBCs by inhibiting pTyr of Band 3 protein, thereby restoring the function of RBCs.

Inhibitory effect of phellodendrine on C48/80-induced allergic reaction in vitro and in vivo.

The incidence of allergic reactions has risen steadily in recent years, prompting growing interest in the identification of efficacious and safe natural compounds that can prevent or treat allergic diseases. Phellodendron amurense Rupr. has long been applied as a treatment for allergic diseases, whose primary component is phellodendrine. However, the efficacy of phellodendrine as a treatment for allergic diseases remains to be assessed. Mast cells are the primary effectors of allergic reactions, which are not only activated by IgE-dependent pathway, but also by IgE-independent pathways via human MRGPRX2, rat counterpart MRGPRB3. As such, this study explored the effect and mechanism of phellodendrine through this family receptors in treating allergic diseases in vitro and in vivo. These analyses revealed that phellodendrine administration was sufficient to protect against C48/80-induced foot swelling and Evans blue exudation in mice, and suppressed C48/80-induced RBL-2H3 rat basophilic leukemia cells degranulation, and ß-HEX, HIS, IL-4, and TNF-α release. Moreover, phellodendrine could reduce the mRNA expression of MRGPRB3 and responsiveness of MRGPRX2 by altering its structure. It was able to decrease Ca2+ levels, phosphorylation levels of CaMK, PLCß1, PKC, ERK, JNK, p38, and p65, and inhibit the degradation of IκB-α. These analyses indicate that berberine inhibits the activation of PLC and downregulates the release of Ca2+ in the endoplasmic reticulum by altering the conformation of MRGPRB3/MRGPRX2 protein, thereby inhibiting the activation of PKC and subsequently inhibiting downstream MAPK and NF-κB signaling, ultimately suppressing allergic reactions. There may thus be further value in studies focused on developing phellodendrine as a novel anti-allergic drug.

Ginseng-derived nanoparticles alleviate alcohol-induced liver injury by activating the Nrf2/HO-1 signalling pathway and inhibiting the NF-κB signalling pathway in vitro and in vivo.

BACKGROUND: Previous studies have confirmed the antioxidant and anti-inflammatory effects of active ginseng components that protect against liver injury. However, ginseng-derived nanoparticles (GDNPs), low-immunogenicity nanovesicles derived from ginseng, have not been reported to be hepatoprotective. PURPOSE: In this study, we investigated whether GDNPs could attenuate alcohol-induced liver injury in LO2 cells and mice by modulating oxidative stress and inflammatory pathways, thereby advancing the theoretical basis for the development of novel pharmacological treatments. STUDY DESIGN: Alcohol was used to construct in vitro and in vivo models of alcoholic liver injury. To explore the mechanisms by which GDNPs exert their protective effects against alcoholic liver injury, we examined the expression of oxidative stress-related genes and analysed inflammatory responses in vitro and in vivo. The experimental findings were verified using network pharmacology. METHODS: The composition of the GDNPs was analysed using liquid chromatography-mass spectrometry. GDNPs were extracted and purified using differential ultracentrifugation and sucrose density gradient centrifugation. In vitro models of alcoholic liver injury were established using LO2 cells, whereas C57BL/6 J mice were used as in vivo models. Oxidative stress, inflammation, and liver injury indicators were measured using appropriate kits. Levels of proteins associated with oxidative stress and inflammation were measured via western blot, while nuclear factor erythroid2-related factor 2 (Nrf2) and NF-κB protein expression was tested using immunofluorescence, immunohistochemistry, and flow cytometry. The levels of relevant transcription factors were determined using qPCR. Experimental haematoxylin and eosin staining was used to characterise the liver histological appearance and damage in mice. Network pharmacological analysis of GDNP mRNA sequencing of GDNPs was used to predict drug targets and disease associations using TCMSP. RESULTS: GDNPs primarily included 77 compounds, including organic acids and their derivatives, amino acids and their derivatives, sugars, terpenoids, and flavonoids. GDNPs have features that allow them to be taken up by LO2 cells and promote their proliferation. In vitro data indicated that GDNPs reduced the levels of alcohol-induced reactive oxygen species by activating the Nrf2/HO-1 signalling pathway, whilst inhibiting the NF-κB pathway and thereby reducing NO, tumour necrosis factor-α, and interleukin-1ß levels to alleviate inflammation. An in vivo model showed that GDNPs improved the liver parameters and pathology in mice with alcoholic liver injury. GDNPs activate the Nrf2/HO-1/Keap1 signalling pathway in a p62-dependent manner to exert antioxidant effects. Furthermore, the TLR4/NF-κB signalling pathway was involved in the in vivo anti-inflammatory effect. Network pharmacology also confirmed that the effects of GDNPs on liver disease were associated with oxidative stress and inflammation-related targets and pathways. CONCLUSION: This study showed for the first time that GDNPs can alleviate alcohol-induced liver damage by activating the Nrf2/HO1 signalling pathway and blocking the NF-κB signalling pathway, thus lowering oxidative stress and inflammatory responses. Hereby, we present the Nrf2/HO1 and NF-κB signalling pathways as potential targets and GDNPs as a novel therapeutic approach for the management of alcohol-induced liver damage.

Ginsenoside Rf in wild ginseng adventitious roots extract inhibits melanogenesis via cAMP/PKA and NO/cGMP signalling pathways in α-melanocyte-stimulating hormone-stimulated B16F10 mouse melanoma cells and zebrafish.

The scarcity of more effective wild ginseng has severely limited its use, culturing of adventitious roots from wild ginseng were its good substitute. In this study, we found ginsenoside Rf as the special component in adventitious roots extract significantly decreased melanin levels and tyrosinase activity in B16F10 cells and zebrafish, and suppressed the expression of microphthalmia-associated transcription factor and melanogenic enzymes in B16F10 cells. Notably, Rf treatment of B16F10 cells led to reduced cell levels of adenosine cyclic 3', 5'-monophosphate (cAMP), nitric oxide (NO), and guanoside cyclic 3', 5'-monophosphate (cGMP), and reduced activities of adenylate cyclase (AC), protein kinase A (PKA), guanylate cyclase (GC), and protein kinase G (PKG), which suggest Rf anti-melanogenic activity potentially involved inhibition of AC/cAMP/PKA and NO/GC/cGMP/PKG signalling pathway. This work provides experimental basis for skin-lightening effect of wild ginseng adventitious roots and their functional part.

[Transoral robotic surgery in the management of solitary fibrous tumor at the entrance of the hypolaryngeal esophagus: a case report and literature review].

To explore the clinical diagnosis and treatment experience of isolated fibrotic tumor （SFT） occurring in the larynx, hypopharynx and esophageal inlet with a wide range.The patient, admitted to the Department of Otolaryngology-Head and Neck Surgery of Tangdu Hospital of Air Force Medical University was a female aged at 78 years, who was diagnosed with SFT primarily occured at laryngeal, hypopharynx and esophageal entrance. The clinical data, surgical methods, histopathology characteristics of the patient were analyzed respectively. It's proved that a tumor sized about 3.8 cm×2.8 cm×2.0 cm with slippy surface was found at the entrance of the laryngeal, hypopharynx and esophageal entrance, covering the laryngeal vestibule, glottis and right piriform fossa, which was completely resected by transoral robotic surgery. The postoperative pathological diagnosis was SFT. The patient recovered well after surgery and showed no recurrence within 16-month follow-up. SFT occurring in the larynx, hypopharynx, and esophageal inlet is very rare, and transoral da Vinci robotic surgical resection of the tumor in this area is feasible, and has the advantages of clear field of vision, less bleeding, less trauma, fewer complications, and quicker postoperative recovery.

De-Epithelialized Viable Tracheal Allotransplantation Without Immunosuppressants: 5-Year Follow-Up.

OBJECTIVE: Tracheal transplantation could be a better option for patients with long segmental laryngotracheal stenosis or defects, but the need for immunosuppressants limits its widespread use due to the antigenicity of the tracheal epithelium. Chemically treated or cryopreserved nonviable tracheal allografts have no immunogenicity but lead to necrosis and stenosis in long-term outcomes. The present report describes the 5-year outcomes of de-epithelialized viable tracheal allotransplantation without immunosuppressants in a patient with severe laryngotracheal stenosis. METHODS: The recipient was a 47-year-old female with relapsing polychondritis affecting the larynx and cervical trachea and producing a 5 cm long stenosis that could not be repaired using resection and anastomosis. A tracheal allograft was obtained from a 45-year-old male donor and treated with a combination of 3% sodium dodecyl sulfate (SDS) and organ preservation solution for 138 hours. The allograft was revascularized by heterotopical implantation in the infrahyoid muscles of the recipient for 3 months and then transplantation to the laryngotracheal defect with a split-thickness skin graft sutured to the lumen and a silicon T-tube. No immunosuppressants were used postoperatively. RESULTS: The allograft was de-epithelialized, and most of the cartilage rings remained viable after the treatment. The allograft was revascularized, viable, and mechanically stable after 3 months of heterotopic implantation. No apparent signs of rejection or destruction were observed. The T-tube was removed, and the internal lining of the allograft was repopulated 4 months after orthotopic transplantation, despite the skin graft necrotizing at 2 weeks. Endoscopy and computed tomography showed a patent airway 5 years after orthotopic transplantation. The patient was able to resume her usual quality of life. CONCLUSION: The present study demonstrates that transplantation of the de-epithelialized viable tracheal allograft without immunosuppressants is safe and promising for patients with long laryngotracheal stenosis or defects, especially for those with malignant tumor resections.

Immunomodulatory activity of semen Ziziphi Spinosae protein: a potential plant protein functional food raw material.

Semen Ziziphi Spinosae protein (SZSP) is a new plant protein resource with good food functional properties and health care function. However, the biological activity of SZSP has not been further studied, which greatly limits the development and utilization of SZSP in the food industry. The aim of this study was to investigate the protective effect of SZSP on immunosuppressed mice and its inhibitory effect on immune-stimulated RAW264.7 cells. The results demonstrated that SZSP remarkably improved the immunomodulatory secretion in serum (interleukin-2, tumor necrosis factor-α [TNF-α], interferon-γ, immunoglobulin-A, immunoglobulin-G, immunoglobulin-M) and primary macrophages (nitric oxide, interleukin-1ß, TNF-α) and promoted the NK-cell killing activity of primary splenocytes in CTX-induced immunosuppression mice. Immunohistochemical analysis results indicated that the secretion of CD4+ and CD8+ in the spleen and thymus can be regulated by SZSP, leading to inhibition of the damage induced by cyclophosphamide in mice. Meanwhile, in order to clarify the immunomodulatory mechanism of SZSP, we showed that SZSP significantly inhibited the secretion of NO, interleukin-6, and TNF-α and reduced the phosphorylation expression of p-ERK, p-JNK, and p-IκBα in lipopolysaccharide-stimulated RAW264.7 cells. Therefore, the immunomodulatory effect of SZSP may be related to the activation of MAPKs and NF-κB signaling pathways. Based on the above studies, the preliminary purification of SZSP was continued, and S1F2G1 with immunomodulatory activity was obtained. Taken together, SZSP has an immunoregulatory effect in vivo and in vitro and may be a favorable candidate of functional food raw material for regulating immune responses.

Herbal/Natural Compounds Resist Hallmarks of Brain Aging: From Molecular Mechanisms to Therapeutic Strategies.

Aging is a complex process of impaired physiological integrity and function, and is associated with increased risk of cardiovascular disease, diabetes, neurodegeneration, and cancer. The cellular environment of the aging brain exhibits perturbed bioenergetics, impaired adaptive neuroplasticity and flexibility, abnormal neuronal network activity, dysregulated neuronal Ca2+ homeostasis, accumulation of oxidatively modified molecules and organelles, and clear signs of inflammation. These changes make the aging brain susceptible to age-related diseases, such as Alzheimer's and Parkinson's diseases. In recent years, unprecedented advances have been made in the study of aging, especially the effects of herbal/natural compounds on evolutionarily conserved genetic pathways and biological processes. Here, we provide a comprehensive review of the aging process and age-related diseases, and we discuss the molecular mechanisms underlying the therapeutic properties of herbal/natural compounds against the hallmarks of brain aging.

Prevention effect of total ginsenosides and ginseng extract from Panax ginseng on cyclophosphamide-induced immunosuppression in mice.

Oral decoction is widely applied in traditional Chinese medicines. The polysaccharides of decoction promote the exposure of small molecules and increase their bioavailability. This study mainly compared the component and activities of total ginsenosides (TGS) and ginseng extract (GE) on immunosuppressed mice induced by cyclophosphamide. Thirty-two mice were randomly divided into control, model, TGS, and GE groups. The mice were orally administered for 28 days and then injected with cyclophosphamide on the last four days. The results of component analysis showed the total content of 12 ginsenosides in TGS (67.21%) was higher than GE (2.04%); the total content of 17 amino acids in TGS (1.41%) was lower than GE (5.36%); the total content of 10 monosaccharides was similar in TGS (74.12%) and GE (76.36%). The animal results showed that both TGS and GE protected the hematopoietic function of bone marrow by inhibiting cell apoptosis, and recovering the normal cell cycle of BM; maintained the dynamic balance between the Th1 and Th2 cells; also protected the spleen, thymus, and liver. Meanwhile, TGS and GE protected the intestinal bacteria of immunosuppressed mice by increasing the abundance of lactobacillus and decreasing the abundance of the odoribacter and clostridia_UCG-014. The prevention effect of GE was superior to TGS in some parameters. In conclusion, TGS and GE protected the immune function of immunosuppressed mice induced by cyclophosphamide. Meanwhile, GE showed higher bioavailability and bioactivity compared with TGS, because the synergistic effect of polysaccharides and ginsenosides plays an important role in protecting the immune function.

Therapeutic application of natural products: NAD+ metabolism as potential target.

BACKGROUND: Nicotinamide adenine dinucleotide (NAD+) metabolism is involved in the entire physiopathological process and is critical to human health. Long-term imbalance in NAD+ homeostasis is associated with various diseases, including non-alcoholic fatty liver disease, diabetes mellitus, cardiovascular diseases, neurodegenerative disorders, aging, and cancer, making it a potential target for effective therapeutic strategies. Currently, several natural products that target NAD+ metabolism have been widely reported to have significant therapeutic effects, but systematic summaries are lacking. PURPOSE: To summarize the latest findings on the prevention and treatment of various diseases through the regulation of NAD+ metabolism by various natural products in vivo and in vitro models, and evaluate the toxicities of the natural products. METHODS: PubMed, Web of Science, and ScienceDirect were searched using the keywords "natural products sources," "toxicology," "NAD+ clinical trials," and "NAD+," and/or paired with "natural products" and "diseases" for studies published within the last decade until January 2023. RESULTS: We found that the natural products mainly include phenols (curcumin, cyclocurcumin, 4-hydroxybenzyl alcohol, salvianolic acid B, pterostilbene, EGCG), flavonoids (pinostrobin, apigenin, acacetin, tilianin, kaempferol, quercetin, isoliquiritigenin, luteolin, silybin, hydroxysafflor yellow A, scutellarin), glycosides (salidroside), quinones (emodin, embelin, ß-LAPachone, shikonin), terpenoids (notoginsenoside R1, ginsenoside F2, ginsenoside Rd, ginsenoside Rb1, ginsenoside Rg3, thymoquinone, genipin), pyrazines (tetramethylpyrazine), alkaloids (evodiamine, berberine), and phenylpropanoids (ferulic acid). These natural products have antioxidant, energy-producing, anti-inflammatory, anti-apoptotic and anti-aging effects, which mainly influence the NAMPT/NAD+/SIRT, AMPK/SIRT1/PGC-1α, Nrf2/HO-1, PKCs/PARPs/NF-κB, and AMPK/Nrf2/mTOR signaling pathways, thereby regulating NAD+ metabolism to prevent and treat various diseases. These natural products have been shown to be safe, tolerable and have fewer adverse effects in various in vivo and in vitro studies and clinical trials. CONCLUSION: We evaluated the toxic effects of natural products and summarized the available clinical trials on NAD+ metabolism, as well as the recent advances in the therapeutic application of natural products targeting NAD+ metabolism, with the aim to provide new insights into the treatment of multiple disorders.

Panax ginseng Meyer cv. Silvatica phenolic acids protect DNA from oxidative damage by activating Nrf2 to protect HFF-1 cells from UVA-induced photoaging.

ETHNOPHARMACOLOGICAL RELEVANCE: Long-wave ultraviolet A (UVA) causes skin aging by damaging the fine structures of the skin, such as elastic fibers and collagen fibers, through oxidation. Currently, the use of plant extracts to protect skin from photoaging is a popular method. Panax ginseng C.A. Meyer exerts commendable anti-photoaging and antioxidant effects. P. ginseng Meyer cv. Silvatica, also known as forest ginseng (FG), is a type of ginseng cultivated by artificially simulating the growth environment of wild ginseng aged >15 years. However, there are only a few reports on its anti-photoaging effect on the skin caused by UVA stimulation. AIM OF THE STUDY: To investigate whether isolated and extracted FG can inhibit skin photoaging as well as to explore its action mechanism. METHODS: The FG extract (FGE) was obtained from the supernatant of FG after water extraction and alcohol precipitation with the D101 resin. The composition and content of phenolic acids in FGE were determined by high-performance liquid chromatography (HPLC). The MTT assay was performed to detect cell viability. The ratio of SA-ß-GAL-positive cells, CoL-I level, 8-OHdG concentration, MDA, GSH, GPx, SOD, and CAT activity were measured using relevant kits. Furthermore, cell cycle alterations and ROS accumulation were assessed by flow cytometry. The expressions of p53, p21, p16, and Keap1 protein were detected by Western blotting. The Nrf2 translocation was monitored by immunofluorescence staining. RESULTS: The findings revealed that FGE significantly restored UVA injury-induced cell viability, reduced the proportion of SA-ß-GAL-positive cells, and increased the level of CoL-I secretion in a dose-dependent manner, where the main ingredients were chlorogenic acid, protocatechuic acid, salicylic acid, p-hydroxybenzoic acid, vanillic acid, ferulic acid, and caffeic acid. Further studies indicated that this phenolic acid mixture (PAM) could alleviate UVA-induced HFF-1 cell cycle arrest and protect the DNA from oxidative damage caused by UVA stimulation. Moreover, the expressions of cell cycle regulatory proteins p53, p21, and p16 and the accumulation of ROS were inhibited, the translocation of Nrf2 into the nucleus was promoted, the expression of Keap1 protein was inhibited, the activity of intracellular antioxidant indicators GSH, GPx, SOD, and CAT was enhanced, and the expression of malondialdehyde (MDA) was inhibited. CONCLUSIONS: Collectively, our results demonstrated that FG phenolic acids protect DNA from oxidative damage by activating Nrf2 to safeguard the skin from photoaging induced by UVA stimulation.

Ginseng polysaccharide attenuates red blood cells oxidative stress injury by regulating red blood cells glycolysis and liver gluconeogenesis.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C.A. Mey (PG) is famous for "Qi-tonifying" effect, which has a medicinal history of more than 2 millennia. Modern pharmacology has confirmed that the "Qi-tonifying" effect of PG may be closely related to its pharmacological properties such as anti-oxidation, antineoplastic and treatment of cardiovascular disease. As one of the earliest cells affected by oxidative stress, RBCs are widely used in the diagnosis of diseases. Ginseng polysaccharide (GPS), is one of the major active components of PG, which plays an important role in resisting oxidative stress, affecting energy metabolism and other effects. However, the molecular mechanism explaining the "Qi-tonifying" effect of GPS from the perspective of RBCs oxidative damage has not been reported. AIM OF THE STUDY: This study aimed to investigate the protective effect of GPS on oxidatively damaged RBCs using in vitro and in vivo models and explore the molecular mechanisms from the perspective of glycolysis and gluconeogenesis pathways. To provides a theoretical basis for the future research of antioxidant drugs. MATERIALS AND METHODS: Established three different in vitro and in vivo research models: an in vitro model of RBCs exposed to hydrogen peroxide (H2O2) (40 mM), an in vivo model of RBCs from rats subjected to exhaustive swimming, and an in vitro model of BRL-3A cells exposed to H2O2 (25 µM). All three models were also tested in the presence of different concentrations of GPS. RESULTS: The findings showed that GPS was the most potent antagonist of H2O2-induced hemolysis and redox inbalance in RBCs. In exhaustive exercise rats, GPS ameliorated RBVs hemolysis, including reducing whole-blood viscosity (WBV), improving deformability, oxygen-carrying and -releasing capacities, which was related to the enhancing of antioxidant capacity. Moreover, GPS promoted RBCs glycolysis in rats with exhaustive exercise by recovering the activities of glycolysis-related enzymes and increasing band 3 protein expression, thereby regulating the imbalance of energy metabolism caused by oxidative stress. Furthermore, we demonstrated that GPS improved antioxidant defense system, enhanced energy metabolism, and regulated gluconeogenesis via activating PPAR gamma co-activator 1 alpha (PGC-1α) pathway in H2O2-exposed BRL-3A cells. Mechanistically, GPS promoted glycolysis and protected RBCs from oxidative injury was partly dependent on the regulation of gluconeogenesis, as inhibition of gluconeogenesis by metformin (Met) attenuates the regulation of antioxidant enzymes and key enzymes of glycolytic by GPS in exhaustive exercise rats. CONCLUSION: This study demonstrates that GPS protects RBCs from oxidative stress damage by promoting RBCs glycolysis and liver gluconeogenesis pathways. These results may contribute to the study of new RBCs treatments to boost antioxidant capacity and protect RBCs against oxidative stress.

Panax ginseng against myocardial ischemia/reperfusion injury: A review of preclinical evidence and potential mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C. A. Meyer (P. ginseng) is effective in the prevention and treatment of myocardial ischemia-reperfusion (I/R) injury. The mechanism by which P. ginseng exerts cardioprotective effects is complex. P. ginseng contains many pharmacologically active ingredients, such as molecular glycosides, polyphenols, and polysaccharides. P. ginseng and each of its active components can potentially act against myocardial I/R injury. Myocardial I/R was originally a treatment for myocardial ischemia, but it also induced irreversible damage, including oxygen-containing free radicals, calcium overload, energy metabolism disorder, mitochondrial dysfunction, inflammation, microvascular injury, autophagy, and apoptosis. AIM OF THE STUDY: This study aimed to clarify the protective effects of P. ginseng and its active ingredients against myocardial I/R injury, so as to provide experimental evidence and new insights for the research and application of P. ginseng in the field of myocardial I/R injury. MATERIALS AND METHODS: This review was based on a search of PubMed, NCBI, Embase, and Web of Science databases from their inception to February 21, 2022, using terms such as "ginseng," "ginsenosides," and "myocardial reperfusion injury." In this review, we first summarized the active ingredients of P. ginseng, including ginsenosides, ginseng polysaccharides, and phytosterols, as well as the pathophysiological mechanisms of myocardial I/R injury. Importantly, preclinical models with myocardial I/R injury and potential mechanisms of these active ingredients of P. ginseng for the prevention and treatment of myocardial disorders were generally summarized. RESULTS: P. ginseng and its active components can regulate oxidative stress related proteins, inflammatory cytokines, and apoptosis factors, while protecting the myocardium and preventing myocardial I/R injury. Therefore, P. ginseng can play a role in the prevention and treatment of myocardial I/R injury. CONCLUSIONS: P. ginseng has a certain curative effect on myocardial I/R injury. It can prevent and treat myocardial I/R injury in several ways. When ginseng exerts its effects, should be based on the theory of traditional Chinese medicine and with the help of modern medicine; the clinical efficacy of P. ginseng in preventing and treating myocardial I/R injury can be improved.

Recent advances in ginsenosides against respiratory diseases: Therapeutic targets and potential mechanisms.

BACKGROUND: Respiratory diseases mainly include asthma, influenza, pneumonia, chronic obstructive pulmonary disease, pulmonary hypertension, lung fibrosis, and lung cancer. Given their high prevalence and poor prognosis, the prevention and treatment of respiratory diseases are increasingly essential. In particular, the development for the novel strategies of drug treatment has been a hot topic in the research field. Ginsenosides are the major component of Panax ginseng C. A. Meyer (ginseng), a food homology and well-known medicinal herb. In this review, we summarize the current therapeutic effects and molecular mechanisms of ginsenosides in respiratory diseases. METHODS: The reviewed studies were retrieved via a thorough analysis of numerous articles using electronic search tools including Sci-Finder, ScienceDirect, PubMed, and Web of Science. The following keywords were used for the online search: ginsenosides, asthma, influenza, pneumonia, chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH), lung fibrosis, lung cancer, and clinical trials. We summarized the findings and the conclusions from 176 manuscripts on ginsenosides, including research articles and reviews. RESULTS: Ginsenosides Rb1, Rg1, Rg3, Rh2, and CK, which are the most commonly reported ginsenosides for treating of respiratory diseases, and other ginsenosides such as Rh1, Rk1, Rg5, Rd and Re, all primarily reduce pneumonia, fibrosis, and inhibit tumor progression by targeting NF-κB, TGF-ß/Smad, PI3K/AKT/mTOR, and JNK pathways, thereby ameliorating respiratory diseases. CONCLUSION: This review provides novel ideas and important aspects for the future research of ginsenosides for treating respiratory diseases.

Ginsenoside Rh2 Induces HeLa Apoptosis through Upregulating Endoplasmic Reticulum Stress-Related and Downstream Apoptotic Gene Expression.

Cervical cancer is a common gynecological malignancy afflicting women all over the world. Ginsenoside Rh2 (GRh2), especially 20(S)-GRh2, is a biologically active component in the natural plant ginseng, which can exhibit anticancer effects. Here, we aimed to investigate the effect of 20(S)-GRh2 on cervical cancer and elucidate the underlying mechanism through RNA-seq. In this study, the CCK-8 assay showed that 20(S)-GRh2 inhibited HeLa cell viability in a time- and dose-dependent manner. Caspase 3 activity and Annexin V staining results showed that 20(S)-GRh2 induced apoptosis of HeLa cells. Gene function enrichment analysis revealed that the biological process gene ontology (GO) terms were associated with the apoptotic signaling pathway. Biological process GO terms' similarity network indicated that apoptosis might be from endoplasmic reticulum stress (ERs). Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that 20(S)-GRh2 primarily modulates apoptosis pathway genes. Combined protein-protein interaction network, hub gene screening, and qPCR validation data showed that ERs-related genes (ATF4 and DDIT3) and the downstream apoptotic genes (JUN, FOS, BBC3, and PMAIP1) were potential novel targets of 20(S)-GRh2-inducing cervical cancer cell apoptosis. Differential transcript usage analysis indicated that DDIT3 is also a differential transcript and its usage of the isoform (ENST00000552740.5) was reduced by 20(S)-GRh2. Molecular docking suggested that 20(S)-GRh2 binds to the targets (ATF4, DDIT3, JUN, FOS, BBC3, and PMAIP1) with high affinity. In conclusion, our findings indicated that 20(S)-GRh2 might promote ERs-related apoptosis of cervical cancer cells by regulating the DDIT3-based targets' signal pathway. The role of 20(S)-GRh2 at the transcriptome level provides novel targets and evidence for the treatment of cervical cancer.

Rosmarinic Acid and Related Dietary Supplements: Potential Applications in the Prevention and Treatment of Cancer.

Cancer constitutes a severe threat to human health and quality of life and is one of the most significant causes of morbidity and mortality worldwide. Natural dietary products have drawn substantial attention in cancer treatment and prevention due to their availability and absence of toxicity. Rosmarinic acid (RA) is known for its excellent antioxidant properties and is safe and effective in preventing and inhibiting tumors. This review summarizes recent publications on culture techniques, extraction processes, and anti-tumor applications of RA-enriched dietary supplements. We discuss techniques to improve RA bioavailability and provide a mechanistic discussion of RA regarding tumor prevention, treatment, and adjuvant therapy. RA exhibits anticancer activity by regulating oxidative stress, chronic inflammation, cell cycle, apoptosis, and metastasis. These data suggest that daily use of RA-enriched dietary supplements can contribute to tumor prevention and treatment. RA has the potential for application in anti-tumor drug development.

Major ginsenosides from Panax ginseng promote aerobic cellular respiration and SIRT1-mediated mitochondrial biosynthesis in cardiomyocytes and neurons.

Background: Aerobic cellular respiration provides chemical energy, adenosine triphosphate (ATP), to maintain multiple cellular functions. Sirtuin 1 (SIRT1) can deacetylate peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) to promote mitochondrial biosynthesis. Targeting energy metabolism is a potential strategy for the prevention and treatment of various diseases, such as cardiac and neurological disorders. Ginsenosides, one of the major bioactive constituents of Panax ginseng, have been extensively used due to their diverse beneficial effects on healthy subjects and patients with different diseases. However, the underlying molecular mechanisms of total ginsenosides (GS) on energy metabolism remain unclear. Methods: In this study, oxygen consumption rate, ATP production, mitochondrial biosynthesis, glucose metabolism, and SIRT1-PGC-1α pathways in untreated and GS-treated different cells, fly, and mouse models were investigated. Results: GS pretreatment enhanced mitochondrial respiration capacity and ATP production in aerobic respiration-dominated cardiomyocytes and neurons, and promoted tricarboxylic acid metabolism in cardiomyocytes. Moreover, GS clearly enhanced NAD+-dependent SIRT1 activation to increase mitochondrial biosynthesis in cardiomyocytes and neurons, which was completely abrogated by nicotinamide. Importantly, ginsenoside monomers, such as Rg1, Re, Rf, Rb1, Rc, Rh1, Rb2, and Rb3, were found to activate SIRT1 and promote energy metabolism. Conclusion: This study may provide new insights into the extensive application of ginseng for cardiac and neurological protection in healthy subjects and patients.