Oral Bacterial Lysate OM-85: Advances in Pharmacology and Therapeutics.

Background: Bacterial lysates are known for having immunomodulatory properties and have been used mainly for the prevention and treatment of respiratory tract infections (RTIs). However, rigorous studies are needed to confirm the clinical efficacy of bacterial lysates with various bacterial antigen components, preparation methods, administration routes and course of treatment. OM-85, an oral standardized lysate prepared by alkaline lysis of 21 strains from 8 species of common respiratory tract pathogens, is indicated as immunotherapy for prevention of recurrent RTIs and acute infectious exacerbations of chronic bronchitis. OM-85 acts on multiple innate and adaptive immune targets and can restore type 1 helper T (Th1)/Th2 balance. Sporadic studies have shown advances in pharmacology and therapeutics of OM-85, and thus an update review is necessary. Methods: Literature was retrieved by searching PubMed, Web of science, Embase, CNKI, and Full Text Database of Chinese Medical Journals. Results: New roles of OM-85 were discovered in prevention and treatment of lung cancer, pulmonary tuberculosis, SARS-CoV-2 infection, allergic rhinitis, pulmonary fibrosis, atopic dermatitis, and nephrotic syndrome. Pharmacoeconomic values of OM-85 were demonstrated in prophylaxis and treatment of RTIs, chronic obstructive pulmonary disease, asthma, chronic bronchitis, rhinosinusitis and allergic rhinitis. Two consecutive courses of OM-85 (6 or 12 months apart) could prevent recurrent RTIs in children. Maternal OM-85 treatment could offer benefits for offspring. Product-specific response was observed. The efficacy of OM-85 may be associated with patient's characteristics (eg, severity of the disease, age, immune response pattern, malignancy risk stratification). Conclusion: OM-85 can improve effectiveness of standard care for some primary diseases, and carry significant pharmacoeconomic implications. The benefits shown by OM-85 in vitro and in vivo, when extrapolated to humans, are exciting but also require caution. Individualized treatment may need to be considered. It is necessary to compare the efficacy and safety of various bacterial lysate preparations.

New Insights into the Role of Mild Hypoxia in Regulating Neural Stem Cell Characteristics.

The proliferation of neural stem cells (NSCs) is precisely regulated by extracellular environmental factors. In situ hypoxia, one of the key factors involved in the regulation of NSC characteristics, has attracted increasing amounts of attention. Numerous studies have demonstrated that hypoxia can significantly promote the formation of neurospheres and the proliferation of NSCs in vitro and that intermittent hypoxia can promote the proliferation of endogenous NSCs in vivo. In this article, the effects of different concentrations of oxygen on NSC proliferation and differentiation both in vivo and in vitro are reviewed, and the potential applications of hypoxia-preconditioned NSCs, as well as research progress and challenges in the treatment of central nervous system diseases, are further summarized. Here, the critical role of oxygen in the neurogenesis of NSCs is emphasized, and insights into the use of hypoxia to regulate NSC characteristics are provided.

Imrecoxib: Advances in Pharmacology and Therapeutics.

Imrecoxib, a cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug (NSAID), was discovered via the balanced inhibition strategy of COX-1/COX-2. It is indicated for the relief of painful symptoms of osteoarthritis. There have been some pharmacological and therapeutic advances since the approval of imrecoxib in 2011. However, an update review in this aspect is not yet available. Relevant literature until January 2024 was identified by search of PubMed, Web of science, Embase and CNKI. From the perspective of efficacy, imrecoxib provides relief of osteoarthritis symptoms, and potential off-label use for treatment of idiopathic pulmonary fibrosis, perioperative pain, hand-foot syndrome, axial spondyloarthritis, COVID-19, cartilage injury, and malignancies such as lung and colon cancer. From a safety point of view, imrecoxib showed adverse effects common to NSAIDs; however, it has lower incidence of new-onset hypertension than other types of selective COX-2 inhibitors, less gastrointestinal toxicities than non-selective NSAIDs, weaker risk of drug interaction than celecoxib, and more suitable for elderly patients due to balanced inhibition of COX-1/COX-2. From a pharmacoeconomic perspective, imrecoxib is more cost-effective than celecoxib and diclofenac for osteoarthritis patients. With the deepening of the disease pathophysiology study of osteoarthritis, new therapeutic schemes and pharmacological mechanisms are constantly discovered. In the field of osteoarthritis treatment, mechanisms other than the analgesic and anti-inflammatory effects of COX-2 inhibitors are also being explored. Taken together, imrecoxib is a moderate selective COX-2 inhibitor with some advantages, and there would be more clinical applications and research opportunities in the future.

Prolyl hydroxylase inhibitor FG-4592 alleviates neuroinflammation via HIF-1/BNIP3 signaling in microglia.

BACKGROUND: Neuroinflammation is responsible for neuropsychiatric dysfunction following acute brain injury and neurodegenerative diseases. This study describes how a hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor FG-4592 prevents the lipopolysaccharide (LPS)-induced acute neuroinflammation in microglia. METHODS: The distribution of FG-4592 in mouse brain tissues was determined by collision-induced dissociation tandem mass spectrometry. Microglial activation in the hippocampus was analyzed by immunofluorescence. Moreover, we determined the activation of HIF-1 and nuclear factor-κB (NF-κB) signaling pathways, proinflammatory responses using molecular biological techniques. Transcriptome sequencing and BNIP3 silencing were conducted to explore signaling pathway and molecular mechanisms underlying FG-4592 anti-inflammatory activity. RESULTS: FG-4592 was transported into the brain tissues and LPS increased its transportation. FG-4592 promoted the expression of HIF-1α and induced the downstream gene transcription in the hippocampus. Administration with FG-4592 significantly inhibited microglial hyperactivation and decreased proinflammatory cytokine levels following LPS treatment in the hippocampus. The LPS-induced inflammatory responses and the NF-κB signaling pathway were also downregulated by FG-4592 pretreatment in microglial cells. Mechanistically, Venn diagram analysis of transcriptomic changes of BV2 cells identified that BNIP3 was a shared and common differentially expressed gene among different treatment groups. FG-4592 markedly upregulated the protein levels of BNIP3 in microglia. Importantly, BNIP3 knockdown aggravated the LPS-stimulated inflammatory responses and partially reversed the protection of FG-4592 against microglial inflammatory signaling and microglial activation in the mouse hippocampus. CONCLUSIONS: FG-4592 alleviates neuroinflammation through facilitating microglial HIF-1/BNIP3 signaling pathway in mice. Targeting HIF-PHD/HIF-1/BNIP3 axis is a promising strategy for the development of anti-neuroinflammation drugs.

Tizanidine: Advances in Pharmacology & Therapeutics and Drug Formulations.

Background: Skeletal muscle relaxants (SMRs) are widely used in treating musculoskeletal conditions. All SMRs, with the exception of baclofen and tizanidine, are on the list of 2023 American Geriatrics Society Beers Criteria® for potentially inappropriate medication use in older adults. In our geriatric practice, off-label use of tizanidine as preemptive analgesia drove us to find recent advances in its pharmacology and therapeutics. An update review of tizanidine was thus presented, aiming to bring the latest knowledge to clinicians and promote further research and practical exploration. Methods: Relevant literature up to December 2023 was identified through searches of PubMed, Web of Science, and Embase. Results: Tizanidine, a centrally acting alpha-2 adrenoceptor agonist with both antispastic and antispasmodic activity, shows efficacy in the common indications for all SMRs. From the perspective of drug safety, tizanidine has lower incidences of adverse events (injury, delirium, encephalopathy, falls, and opioid overdose) compared to baclofen, no association with risk of Alzheimer's disease as with orphenadrine, no risk of serotonin syndrome like metaxalone when comedicated with serotonergic drugs, no significant pharmacokinetic changes in CYP2C19 poor metabolizers unlike diazepam and carisoprodol, and no physically addictive or abuse properties like carisoprodol and diazepam. From the perspective of new and potential therapeutic uses, tizanidine has additional benefits (eg, gastroprotection that can improve patient tolerance to nonsteroidal anti-inflammatory agents, anti-neuropathic pain, a key component of multimodal analgesia strategy to reduce early postoperative pain, and anti-tumor effects). New delivery systems of tizanidine are developing to improve the pharmacokinetics of oral products, including buccal patches, transdermal delivery systems, nasal spray, and in situ rectal gel. Conclusion: Tizanidine is an SMR with unique features and may be an optimal initial choice for older adults. There would be more scientific studies, wider therapeutic applications, and new drug formulations in the future.

Exploring the Roles of Nurses in Medication Reconciliation for Older Adults at Hospital Discharge: A Narrative Approach.

Medication reconciliation (MR) is the process of comparing a patient's medication orders to all of the medications that the patient has been taking in order to identify and resolve medication discrepancies. It is an effective means of risk management to avoid medication errors (eg, omissions, duplication, dosage errors, or drug interactions). Some guidelines explicitly state that MR is a pharmacist-led transition of care; however, there is a shortage of qualified pharmacists to meet the increasing clinical needs, and clinical nurses' roles have not been clearly described. This paper aimed to enable nurses to gain confidence in contributing to MR at discharge and to make the industry aware of the potential risks if nurses do not actively intervene in this area. A narrative approach was used to introduce experiences in identifying discrepancies and medication errors through MR at discharge in a geriatric ward of an academic medical center hospital in China. The nurses' main roles in MR involve chasing, checking, and education. Clinical nurses, an untapped hospital resource, can actively engage in MR at discharge if they receive effective training and motivation. Multidisciplinary collaboration at discharge allowed many discrepancies to be reconciled before harming older patients. It is worth conducting further research in MR when discharging older adults, such as the cost-effectiveness of nurses' efforts, the value of electronic tools and the impact of MR-targeted education and training for nursing students and nursing staff.

Heating tumors with tumor cell-derived nanoparticles to enhance chemoimmunotherapy for colorectal cancer.

Aim: To investigate the mechanism of doxorubicin (DOX)-induced immunogenic cell death (ICD) and to improve immunotherapy efficacy. Materials & methods: In this study, hybrid vesicles containing DOX (HV-DOX) were prepared by thin-film hydration with extrusion, and the formulated nanoparticles were characterized physically. Furthermore, in vitro experiments and animal models were used to investigate the efficacy and new mechanisms of chemotherapy combined with immunotherapy. Results: DOX improved tumor immunogenicity by alkalinizing lysosomes, inhibiting tumor cell autophagy and inducing ICD. HVs could activate dendritic cell maturation, synergistically enhancing chemotherapeutic immunity. Conclusion: The mechanism of DOX-induced ICD was explored, and antitumor immunity was synergistically activated by HV-DOX to improve chemotherapeutic drug loading and provide relevant antigenic information.

The Rate of Infusion Represents an Important Aspect of Administering Anticancer Agents.

Background: Infusion rate is one of the essential elements that should be included in all intravenous orders. Patients may experience adverse consequences or risks associated with inappropriate infusion. Meanwhile, there is growing pressure on the chemotherapy unit to deliver treatment quickly, efficiently, and safely, and thus it is very necessary to improve the chemotherapy process and service to cancer patients. Clinicians should consider how to further standardize infusion therapy, and innovate new infusion strategies to increase efficacy, reduce toxicity, improve patient satisfaction and save health resource costs. Sporadic studies have evaluated the effects of infusion rates of anticancer agents on clinical outcomes, economic benefits, and administration efficiency. However, an update review has not been available. Methods: Relevant literature was identified by search of PubMed until September 2023. Results: Infusion rates may have significant effect on the efficacy of anticancer agents (e.g., methotrexate, fluorouracil, and arsenic trioxide). Slow infusion is safer for platinum compounds, doxorubicin and carmustine, whereas fast infusion is safer than slow infusion of gemcitabine. Optimal flow rates of paclitaxel and fluorouracil are based on the balance between multiple risks of toxicity. Optimal infusion rate may bring economic benefits. If efficacy and safety are not compromised, shortened infusion may result in higher patient satisfaction, improved institutional efficiency and more nursing time available for other activities (e.g., biosimilar products, endostar). Other concerns about infusion rate include clinical indications (eg, paclitaxel and rituximab, methotrexate), severity and type of hypersensitivity reactions (e.g., platinum compounds), formulation features (e.g., paclitaxel, doxorubicin), and genetic polymorphism (e.g., gemcitabine, methotrexate). Conclusion: The latest knowledge of infusion rate concerns will enhance the appropriateness and accuracy in intravenous administration. Interdisciplinary teams should collaborate and implement relevant risk management and healthcare policy. It is worthwhile to conduct comparative studies of intravenous therapy with different infusion speeds.

Effects of folic acid and folic acid plus zinc supplements on the sperm characteristics and pregnancy outcomes of infertile men: A systematic review and meta-analysis.

Background: Folic acid and zinc supplements have been used to treat male infertility, but their efficacy is still debated. Objective: To systematically evaluate the effects of folic acid and folic acid plus zinc supplements on sperm characteristics and pregnancy outcomes of infertile men. Methods: An online systematic search was performed using PubMed, Cochrane Library, and EMBASE databases from inception to August 1, 2022. The goal was to identify randomized controlled trials (RCTs) that used folic acid or folic acid plus zinc to improve sperm characteristics of infertile men. Data were extracted by two investigators who independently screened the literature and assessed for quality according to the criteria. The meta-analysis was performed using RevMan 5.4 software. Results: A total of 8 RCT studies involving 2168 patients were included. The results showed that compared with the controls, folic acid significantly increased sperm motility (MD, 3.63; 95% CI, -1.22 to 6.05; P = 0.003), but did not affect the sperm concentration (MD, 2.53; 95% CI, -1.68 to 6.73; P = 0.24) and sperm morphology (MD, -0.02; 95% CI, -0.29 to 0.24; P = 0.86) in infertile men. Folic acid plus zinc did not affect sperm concentration (MD, 1.87; 95% CI, -1.39 to 5.13; P = 0.26), motility (MD, 1.67; 95% CI, -1.29 to 4.63; P = 0.27), and morphology (MD, -0.05; 95% CI, -0.27 to 0.18; P = 0.69) in infertile men. Secondary results showed that compared with a placebo, folic acid alone had a higher rate of pregnancy in transferred embryos (35.6% vs. 20.4%, P = 0.082), but the difference was not significant. Folic acid plus zinc did not affect pregnancy outcomes. Conclusions: Based on the meta-analysis, no significant improvements in sperm characteristics with folic acid plus zinc supplements were seen. However, folic acid alone has demonstrated the potential to improve sperm motility and in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) outcomes. This indicates that folic acid supplements alone may be a viable treatment option for male infertility.

[Hypoxia promotes lipopolysaccharide-induced CXCL10 expression in microglia].

This study was aimed to investigate the effect of hypoxia on lipopolysaccharide (LPS)-induced CXC-chemokine ligand-10 (CXCL10) expression and the underlying mechanism. C57BL/6J mice were randomly divided into control, hypoxia, LPS, and hypoxia combined with LPS groups. The LPS group was intraperitoneally injected with 0.5 mg/kg LPS, and the hypoxia group was placed in a hypobaric hypoxia chamber (simulated altitude of 6 000 m). The serum and hippocampal tissue samples were collected after 6 h of the treatment. The levels of CXCL10 in the serum and hippocampal tissue of mice were detected by ELISA. The microglia cell line BV2 and primary microglia were stimulated with hypoxia (1% O2) and/or LPS (100 ng/mL) for 6 h. The mRNA expression level of CXCL10 and its content in culture supernatant were detected by real-time quantitative PCR and ELISA, respectively. The phosphorylation levels of nuclear factor κB (NF-κB) signaling pathway-related proteins, p65 and IκBα, were detected by Western blot. Moreover, after NF-κB signaling pathway being blocked with a small molecular compound, PDTC, CXCL10 mRNA expression level was detected in the BV2 cells. The results showed that in the LPS-induced mouse inflammatory model, hypoxia treatment could promote LPS-induced up-regulation of CXCL10 in both serum and hippocampus. Compared with the cells treated with LPS alone, the expression of CXCL10 mRNA and the content of CXCL10 in the culture supernatant of BV2 cells treated with hypoxia combined with LPS were significantly increased. The CXCL10 mRNA level of primary microglial cells treated with hypoxia combined with LPS was significantly up-regulated. Compared with the cells treated with hypoxia or LPS alone, the phosphorylation levels of p65 and IκBα in the BV2 cells treated with hypoxia combined with LPS were significantly increased. PDTC blocked the induction of CXCL10 gene expression by LPS in the BV2 cells. These results suggest that hypoxia promotes LPS-induced expression of CXCL10 in both animal and cell models, and NF-κB signaling pathway plays an important role in this process.

Autophagy Is Essential for Neural Stem Cell Proliferation Promoted by Hypoxia.

Hypoxia as a microenvironment or niche stimulates proliferation of neural stem cells (NSCs). However, the underlying mechanisms remain elusive. Autophagy is a protective mechanism by which recycled cellular components and energy are rapidly supplied to the cell under stress. Whether autophagy mediates the proliferation of NSCs under hypoxia and how hypoxia induces autophagy remain unclear. Here, we report that hypoxia facilitates embryonic NSC proliferation through HIF-1/mTORC1 signaling pathway-mediated autophagy. Initially, we found that hypoxia greatly induced autophagy in NSCs, while inhibition of autophagy severely impeded the proliferation of NSCs in hypoxia conditions. Next, we demonstrated that the hypoxia core regulator HIF-1 was necessary and sufficient for autophagy induction in NSCs. Considering that mTORC1 is a key switch that suppresses autophagy, we subsequently analyzed the effect of HIF-1 on mTORC1 activity. Our results showed that the mTORC1 activity was negatively regulated by HIF-1. Finally, we provided evidence that HIF-1 regulated mTORC1 activity via its downstream target gene BNIP3. The increased expression of BNIP3 under hypoxia enhanced autophagy activity and proliferation of NSCs, which was mediated by repressing the activity of mTORC1. We further illustrated that BNIP3 can interact with Rheb, a canonical activator of mTORC1. Thus, we suppose that the interaction of BNIP3 with Rheb reduces the regulation of Rheb toward mTORC1 activity, which relieves the suppression of mTORC1 on autophagy, thereby promoting the rapid proliferation of NSCs. Altogether, this study identified a new HIF-1/BNIP3-Rheb/mTORC1 signaling axis, which regulates the NSC proliferation under hypoxia through induction of autophagy.

Progress in Research on the Mechanisms and Interventions of Phlebitis from the Perspective of Vascular Endothelial Cell and Signaling Pathway.

Background: Phlebitis is a common complication of intravenous administration and greatly affects clinical outcomes, patient satisfaction, and health-care expenditure. Numerous studies have revealed venous injuries only through visual and histopathological examination. Although sporadic studies have explored the cellular and molecular biological mechanisms of phlebitis and the outcomes of pharmacological interventions, an updated review over the last decade is not available. Methods: Progress in research on the mechanisms and interventions of phlebitis was summarized from the perspective of endothelial cells and signaling pathways by retrieving the PubMed, Web of Science Core Collection, MEDLINE, Embase, and CNKI. Results: Phlebitis involves multiple signaling pathways (eg, nuclear factor kappa B, Wnt/ß-catenin, focal adhesion kinase/protein kinase B, Toll-like receptor, protein kinase C beta/NADPH oxidase, PI3K/AKT/TNF, and JAK2/STAT3), upregulation of E-selectin, GBP5/NLRP3 inflammasome axis, cell apoptosis, intracellular ROS generation, SOD reduction, stimulation of angiogenesis, and induction of autophagy-associated cell death. Preventive and curative interventions included α-solanine, baicalein, escin, intermedin, Y15, micro-ribonucleic acid-223, sotrastaurin, cimetidine, aescin, resveratrol, α-chaconine, Chahuang ointment, QingLuoTongMai, Mailuo Shutong, and N-acetylcysteine. Laboratory models included vascular endothelial cells, real-time cell-monitoring analysis, network pharmacology analysis and experimental verification in vivo, animal models of phlebitis (rat, rabbit, and mouse), rabbit models with peripherally inserted central catheters (PICC) catheterization, models of PICC/central venous catheter indwelling with combined drugs in human umbilical vein endothelial cells, and compatibility with endothelial cells. Factors affecting vascular endothelial cell injury include difference in the same class of drugs, concentration and exposure time of precipitant, and infusion strategy. Conclusion: Phlebitis is accompanied by endothelial dysfunction and may involve multiple molecular and cellular mechanisms. These findings improve our understanding of the molecular targets of interventions and help identify effective candidates for the prophylaxis and treatment of phlebitis. Vascular health and risk management should be considered when initiating intravenous administration.

BNIP3 phosphorylation by JNK1/2 promotes mitophagy via enhancing its stability under hypoxia.

Mitophagy is an important metabolic mechanism that modulates mitochondrial quality and quantity by selectively removing damaged or unwanted mitochondria. BNIP3 (BCL2/adenovirus e1B 19 kDa protein interacting protein 3), a mitochondrial outer membrane protein, is a mitophagy receptor that mediates mitophagy under various stresses, particularly hypoxia, since BNIP3 is a hypoxia-responsive protein. However, the underlying mechanisms that regulate BNIP3 and thus mediate mitophagy under hypoxic conditions remain elusive. Here, we demonstrate that in hypoxia JNK1/2 (c-Jun N-terminal kinase 1/2) phosphorylates BNIP3 at Ser 60/Thr 66, which hampers proteasomal degradation of BNIP3 and drives mitophagy by facilitating the direct binding of BNIP3 to LC3 (microtubule-associated protein 1 light chain 3), while PP1/2A (protein phosphatase 1/2A) represses mitophagy by dephosphorylating BNIP3 and triggering its proteasomal degradation. These findings reveal the intrinsic mechanisms cells use to regulate mitophagy via the JNK1/2-BNIP3 pathway in response to hypoxia. Thus, the JNK1/2-BNIP3 signaling pathway strongly links mitophagy to hypoxia and may be a promising therapeutic target for hypoxia-related diseases.

Dietary meat mutagens intake and cancer risk: A systematic review and meta-analysis.

Background: Clinical and preclinical studies suggested that certain mutagens occurring as a reaction of creatine, amino acids, and sugar during the high temperature of cooking meat are involved in the pathogenesis of human cancer. Here we conducted a systematic review and meta-analysis to examine whether meat mutagens [PhIP, MeIQx, DiMeIQx, total HCA, and B(a)P] present a risk factor for human cancer. Methods: We searched the following databases for relevant articles published from inception to 10 Oct 2021 with no language restrictions: Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Baidu Academic, Zhejiang Digital Library. Two independent researchers screened all titles and obtained eligible texts for further screening. Independent data extraction was conducted, and meta-analysis was carried out using random-effects models to calculate the risk ratio of the meat mutagens exposure. Results: A total of 1,786,410 participants and 70,653 cancer cases were identified. Among these, there were 12 different types of cancer at various sites, i.e., breast, bladder, colorectal, colon, rectum, prostate, lung, Non-Hodgkin lymphoma, kidney, gastric, esophagus, pancreatic, hepatocellular carcinoma. Cancer risk was significantly increased by intake of PhIP (OR = 1.13;95% CI 1.07-1.21; p < 0.001), MeIQx (OR = 1.14; 95% CI: 1.07-1.21; p < 0.001), DiMeIQx (OR = 1.07; 95% CI: 1.01-1.13; p = 0.013), total HCA (OR = 1.20; 95% CI: 1.03-1.38; p = 0.016), and cancer risk was not significantly increased by intake of B(a)P (OR = 1.04; 95% CI: 0.98-1.10; p = 0.206). Conclusion: Meat mutagens of PhIP, MeIQx, DiMeIQx, and total HCA have a positive association with the risk of cancer. Systematic review registration: [www.crd.york.ac.uk/prospero], identifier [CRD42022148856].

Gypenosides (GPs) alleviates hypoxia-induced injury in PC12 cells and enhances tolerance to anoxia in C57BL/6 mice.

Oxygen is a necessary substance for life activities, but reduced oxygen utilization due to high altitude exposure and respiratory dysfunction diseases could lead to pathological changes in the organisms. Herein gypenosides, the active ingredients in the food and medicine resource plant Gynostemma pentaphyllum (Thunb.) Makino were found to alleviate hypoxia-induced injury in PC12 cells. Moreover, hypoxia induced an increase in Ca2+ and reactive oxygen species content, and such patterns were both significantly reduced by gypenosides treatment. At the same time, gypenosides significantly blocked the decrease of both NO content and mitochondrial membrane potential caused by hypoxia. Furthermore, gypenosides gavage treatment significantly prolonged the survival time of C57BL/6 mice in confinement up to 24.3% and enhanced the locomotor ability of mice. Therefore, gypenosides have good neuroprotective effects and hypoxia tolerance activity and have the prospect of being developed as a preventive and therapeutic drug for hypoxia-related diseases. PRACTICAL APPLICATIONS: Gypenosides can enhance tolerance of cells and mice to hypoxia and have the potential to be developed into hypoxia-resistant health food and drugs.