Loss of SP-A in the Lung Exacerbates Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating and common chronic lung disease that is pathologically characterized by the destruction of lung architecture and the accumulation of extracellular matrix in the lung. Previous studies have shown an association between lung surfactant protein (SP) and the pathogenesis of IPF, as demonstrated by mutations and the altered expression of SP in patients with IPF. However, the role of SP in the development of lung fibrosis is poorly understood. In this study, the role of surfactant protein A (SP-A) was explored in experimental lung fibrosis induced with a low or high dose of bleomycin (BLM) and CRISPR/Cas9-mediated genetic deletion of SP-A. Our results showed that lung SP-A deficiency in mice promoted the development of fibrotic damage and exacerbated inflammatory responses to the BLM challenge. In vitro experiments with murine lung epithelial LA-4 cells demonstrated that in response to transforming growth factor-ß1 (TGF-ß1), LA-4 cells had a decreased protein expression of SP-A. Furthermore, exogenous SP administration to LA-4 cells inhibited the TGF-ß1-induced upregulation of fibrotic markers. Overall, these findings suggest a novel antifibrotic mechanism of SP-A in the development of lung fibrosis, which indicates the therapeutic potential of the lung SP-A in preventing the development of IPF.

Cyclase-associated protein 1 is a binding partner of proprotein convertase subtilisin/kexin type-9 and is required for the degradation of low-density lipoprotein receptors by proprotein convertase subtilisin/kexin type-9.

AIMS: Proprotein convertase subtilisin/kexin type-9 (PCSK9), a molecular determinant of low-density lipoprotein (LDL) receptor (LDLR) fate, has emerged as a promising therapeutic target for atherosclerotic cardiovascular diseases. However, the precise mechanism by which PCSK9 regulates the internalization and lysosomal degradation of LDLR is unknown. Recently, we identified adenylyl cyclase-associated protein 1 (CAP1) as a receptor for human resistin whose globular C-terminus is structurally similar to the C-terminal cysteine-rich domain (CRD) of PCSK9. Herein, we investigated the role of CAP1 in PCSK9-mediated lysosomal degradation of LDLR and plasma LDL cholesterol (LDL-C) levels. METHODS AND RESULTS: The direct binding between PCSK9 and CAP1 was confirmed by immunoprecipitation assay, far-western blot, biomolecular fluorescence complementation, and surface plasmon resonance assay. Fine mapping revealed that the CRD of PCSK9 binds with the Src homology 3 binding domain (SH3BD) of CAP1. Two loss-of-function polymorphisms found in human PCSK9 (S668R and G670E in CRD) were attributed to a defective interaction with CAP1. siRNA against CAP1 reduced the PCSK9-mediated degradation of LDLR in vitro. We generated CAP1 knock-out mice and found that the viable heterozygous CAP1 knock-out mice had higher protein levels of LDLR and lower LDL-C levels in the liver and plasma, respectively, than the control mice. Mechanistic analysis revealed that PCSK9-induced endocytosis and lysosomal degradation of LDLR were mediated by caveolin but not by clathrin, and they were dependent on binding between CAP1 and caveolin-1. CONCLUSION: We identified CAP1 as a new binding partner of PCSK9 and a key mediator of caveolae-dependent endocytosis and lysosomal degradation of LDLR.

Multi-Class Determination of 64 Illicit Compounds in Dietary Supplements Using Liquid Chromatography-Tandem Mass Spectrometry.

In this work, liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for screening and confirmation of 64 illicit compounds in dietary supplements. The target compounds were illegally used pharmaceutical drugs, prohibited compounds, and not authorized ingredients for different therapeutics (sexual enhancement, weight loss, muscular strengthening, and relaxing products). The validation procedure was performed to evaluate selectivity, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, and precision according to the Association of Official Analytical Chemists guidelines. The linearity was >0.98 in the range of 0.5-200 µg L-1. The LOQs were in the range 1-10 µg kg-1 for all target compounds. The accuracy (expressed as recovery) was 78.5-114%. The precision (expressed as the relative standard deviation) was below 9.15%. The developed method was applied for the determination of illicit compounds in dietary supplements collected from websites. As a result, the total detection rate was 13.5% (27 samples detected in 200 samples). The concentrations of detected samples ranged from 0.51 to 226 mg g-1. The proposed methodology is suitable for monitoring the adulteration of illicit compounds in dietary supplements.

Body contouring effects of at-home beauty device equipped with suction, radiofrequency, and electrical muscle stimulation functions.

BACKGROUND: With the rise in interest and demand for body contouring, beauty devices have continuously developed. Suction can aid in increasing the rate of fat breakdown by inducing a massage-like effect, thereby increasing blood flow. Moreover, radiofrequency (RF) can boost fibroblast activity and help reduce cellulite. In addition, electrical muscle stimulation (EMS) can use electrical stimulation to induce muscle contraction, leading to an athletic, and skin elasticity-increasing effect. AIMS: This study aimed to assess the effects of body contouring, such as cellulite and swelling, in healthy Korean women to objectively prove the efficacy of an at-home beauty device equipped with suction, RF, and EMS functions. METHODS: For 8 weeks, 21 participants used the at-home beauty device 3 days a week on their abdomen, thighs, and left calf. Validity assessments and subjective surveys were conducted at 4 and 8 weeks, including the first visit. RESULTS: The results of the validity assessments revealed that cellulite, swelling, elasticity, femoral skin texture, and dermal density were significantly (p < 0.05) improved in the experimental group compared with those at the baseline. CONCLUSIONS: The results of this study demonstrate that the combination of suction, RF, and EMS function is effective for body skin, fat, and body shape management. For better body-contouring effects, combining the beauty device with regular exercise and healthy eating habits is recommended.

Arc-poration improves transdermal delivery of biomolecules.

BACKGROUND: To increase skin permeability, various transdermal delivery techniques have been developed. However, due to the stratum corneum as a skin barrier, transdermal delivery remains limited. AIMS: In this study, we evaluated efficacy and safety of arc-poration as a novel technique disrupting the stratum corneum. RESULTS: Optical images and histological analysis using reconstituted human skin and porcine skin showed that the treatment of arc-poration created micropores with an average diameter of approximately 100 µm only to the depth of the stratum corneum, but not viable epidermis. In addition, the Franz diffusion cell experiment using reconstituted human skin showed a remarkable increase in permeability following pretreatment with arc-poration. Clinical results clearly demonstrated the enhancement of the skin-improving effect of cosmetics by pretreatment of arc-poration in terms of gloss, hydration, flakiness, texture, tone, tone evenness, and pigmentation of skin, without causing abnormal skin responses. The concentration of ozone and nitrogen oxides generated by arc-poration was below the permissible value for the human body. CONCLUSIONS: Arc-poration can increase skin permeability by creating stratum corneum-specific micropores, which can enhance the skin-improving effect of cosmetics without adverse responses.

PCSK9 stimulates Syk, PKCδ, and NF-κB, leading to atherosclerosis progression independently of LDL receptor.

Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to and degrades low-density lipoprotein (LDL) receptor, leading to increase of LDL cholesterol in blood. Its blockers have emerged as promising therapeutics for cardiovascular diseases. Here we show that PCSK9 itself directly induces inflammation and aggravates atherosclerosis independently of the LDL receptor. PCSK9 exacerbates atherosclerosis in LDL receptor knockout mice. Adenylyl cyclase-associated protein 1 (CAP1) is the main binding partner of PCSK9 and indispensable for the inflammatory action of PCSK9, including induction of cytokines, Toll like receptor 4, and scavenger receptors, enhancing the uptake of oxidized LDL. We find spleen tyrosine kinase (Syk) and protein kinase C delta (PKCδ) to be the key mediators of inflammation after PCSK9-CAP1 binding. In human peripheral blood mononuclear cells, serum PCSK9 levels are positively correlated with Syk, PKCδ, and p65 phosphorylation. The CAP1-fragment crystallizable region (CAP1-Fc) mitigates PCSK9-mediated inflammatory signal transduction more than the PCSK9 blocking antibody evolocumab does.

Resistin impairs mitochondrial homeostasis via cyclase-associated protein 1-mediated fission, leading to obesity-induced metabolic diseases.

OBJECTIVE: One of the suggested mechanisms of obesity-induced insulin resistance is mitochondrial dysfunction in target tissues such as skeletal muscle. In our study, we examined whether resistin, an adipokine associated with obesity-mediated insulin resistance, induced metabolic disorders by impairing mitochondrial homeostasis. METHODS: The morphology and function of mitochondria of skeletal muscle were examined in resistin-knockout and humanized resistin mice that were subjected to high-fat diet for 3 months. Morphology was examined by transmission electron microscopy. Mitochondria bioenergetics of skeletal muscle were evaluated using a Seahorse XF96 analyzer. Human skeletal myoblasts were used for in vitro studies on signaling mechanisms in responses to resistin. RESULTS: A high-fat diet in humanized resistin mice increased fragmented and shorter mitochondria in the skeletal muscle, whereas resistin-knockout mice had healthy normal mitochondria. In vitro studies showed that human resistin treatment impaired mitochondrial homeostasis by inducing mitochondrial fission, leading to a decrease in ATP production and mitochondrial dysfunction. Induction of mitochondrial fission by resistin was accompanied by increased formation of mitochondria-associated ER membranes (MAM). At the same time, resistin induced up-regulation of the protein kinase A (PKA) pathway. This activation of PKA induced phosphorylation of Drp1 at serine 616, leading to Drp1 activation and subsequent induction of mitochondrial fission. The key molecule that mediated human resistin-induced mitochondrial fission was adenylyl cyclase-associated protein 1 (CAP1), which was reported as a bona fide receptor for human resistin. Moreover, our newly developed biomimetic selective blocking peptide could repress human resistin-mediated mitochondrial dysfunction. High-fat diet-fed mice showed lower exercise capacity and higher insulin resistance, which was prevented by a novel peptide to block the binding of resistin to CAP1 or in the CAP1-knockdown mice. CONCLUSIONS: Our study demonstrated that human resistin induces mitochondrial dysfunction by inducing abnormal mitochondrial fission. This result suggests that the resistin-CAP1 complex could be a potential therapeutic target for the treatment of obesity-related metabolic diseases such as diabetes and cardiometabolic diseases.

Association between Low-Dose Computed Tomography Results and 1-Year Smoking Cessation in a Residential Smoking Cessation Program.

The COVID-19 pandemic is a global health threat. Smoking and smoking-related lung diseases are risk factors for severe COVID-19 infection. This study investigated whether low-dose computed tomography (LDCT) scan results affected the success of 1-year smoking cessation. The Gyeonggi Southern Smoking Support Center performed the residential smoking cessation program from January to December 2018. During the program, LDCT was performed on 292 participants; 6 months later, follow-up via telephone or visit was conducted. Among the 179 participants who succeeded in smoking cessation for 6 months, telephone follow-up was conducted to determine whether there was a 12-month continuous smoking cessation. In order to evaluate the association between LDCT results and 12-month continuous abstinence rate (CAR), logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI). The CARs at 6 and 12 months were 61.3% and 31.5%, respectively. Indeterminate or suspicious malignant lung nodules were associated with a higher 12-month CAR (OR, 3.02; 95% CI, 1.15-7.98), whereas psychiatric history was associated with a lower 12-month CAR (OR, 0.06; 95% CI, 0.03-0.15). These results suggest that abnormal lung screening results may encourage smokers to quit smoking.

Authentication of tejocote (Crataegus mexicana) dietary supplements based on DNA barcoding and chemical profiling.

Tejocote (Crataegus mexicana, Mexican hawthorn), known as a weight-loss supplement, has been marketed online and is easily available for overseas direct purchase. Alipotec (brand name) is known as one of the most popular products containing tejocote in Mexico and other countries. However, adverse effects have been reported by users of these supplements. Therefore it is necessary to find the reason for the side effect. Dietary supplement samples labelled as containing tejocote were analysed using mass spectrometry and DNA barcoding analysis. Our results demonstrate that Alipotec samples contained ingredients from different species, yellow oleander instead of tejocote. The rpoB barcode region was able to differentiate between tejocote and yellow oleander species. Moreover, it was also observed that three compounds, including thevetin B, neriifolin, and digitoxigenin, clearly distinguish between tejocote and yellow oleander samples. This is the first and preliminary investigation to use an integrated approach of both chemical and genomic profiling for the authentication of dietary supplement containing tejocote.

Direct conversion of adult human fibroblasts into functional endothelial cells using defined factors.

We aimed to directly convert adult human dermal fibroblasts (aHDFs) into functional endothelial cells (ECs). Lentiviral vectors encoding endothelial transcription factors (TFs) were constructed. We examined whether five TFs (FOXO1, ER71, KLF2, TAL1, and LMO2) used for the generation of mouse induced ECs (iECs) could convert the aHDFs into human iECs. Twenty-eight days after transduction with lentiviral constructs, 32.1 ± 5.1% cells expressed vascular endothelial (VE)-cadherin. Factor screening revealed that only three factors (3F: ER71, KLF2, and TAL1) were necessary to induce VE-cadherin (+) cells (49.4 ± 3.5%). However, whole transcriptome sequencing showed that VE-cadherin (+) cells were not completely reprogrammed. Mature iECs double-positive for VE-cadherin/Pecam1 (DP cells) with a cobblestone appearance were obtained at a frequency of only 5.1 ± 0.6%. Using whole transcriptome analysis, the potential factors that could block the conversion were screened. Among candidates TWIST1-knockdown enhanced efficiency of conversion. Rosiglitazone, an inhibitor of epithelial-mesenchymal transition (EMT), also improved the conversion efficiency. Moreover, a 2nd second-stage conversion process, in which VE-cadherin (+) cells were incubated for additional two weeks, further enhanced the efficiency. The final protocol for 6 weeks yielded a conversion rate of 19.6 ± 3.0% iECs, defined by DP cells depicting the nature of mature ECs in various analyses. Further analyses revealed that the genetic and epigenetic profiles of iECs resembled those of functional ECs. Collectively, aHDFs can be converted into functional ECs through the transduction of ER71, KLF2, and TAL1, combined with two EMT inhibitors (siTWIST1 and rosiglitazone), followed by 2nd stage conversion.

Bee Venom Phospholipase A2 Ameliorates Atherosclerosis by Modulating Regulatory T Cells.

Atherosclerosis is a chronic inflammatory disease caused by lipids and calcareous accumulations in the vascular wall due to an inflammatory reaction. Recent reports have demonstrated that regulatory T (Treg) cells have an important role as a new treatment for atherosclerosis. This study suggests that bee venom phospholipase A2 (bvPLA2) may be a potential therapeutic agent in atherosclerosis by inducing Treg cells. We examined the effects of bvPLA2 on atherosclerosis using ApoE-/- and ApoE-/-/Foxp3DTR mice. In this study, bvPLA2 increased Treg cells, followed by a decrease in lipid accumulation in the aorta and aortic valve and the formation of foam cells. Importantly, the effect of bvPLA2 was found to depend on Treg cells. This study suggests that bvPLA2 can be a potential therapeutic agent for atherosclerosis.

Intratracheal Ovalbumin Administration Induces Colitis Through the IFN-γ Pathway in Mice.

Recent studies have reported an increased incidence of inflammatory bowel disease (IBD) in patients with pulmonary diseases. Despite clinical and epidemiological studies of the interplay between colitis and asthma, the diseases' related underlying mechanisms remain unclear. In this study, we evaluated the development of colitis in a model of allergic airway inflammation. We revealed that intratracheal chronic ovalbumin (OVA) exposure induces colitis and allergic airway inflammation. Interestingly, induction of colitis was largely regulated by Th1, rather than Th2 responses, whereas allergic airway inflammation was primarily mediated by Th2 responses. Experiments in Tbx21 (T-bet) and Ifng (IFN-γ) deficient mice have confirmed that IFN-γ is a major mediator involved in OVA-induced colitis. These findings broaden current understanding of allergen induced colitis pathology and could play a role in the development of novel clinical treatment strategies for asthmatic patients who are at risk of developing colitis.

Bee Venom Phospholipase A2 Alleviate House Dust Mite-Induced Atopic Dermatitis-Like Skin Lesions by the CD206 Mannose Receptor.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by highly pruritic, erythematous, and eczematous skin plaques. We previously reported that phospholipase A2 (PLA2) derived from bee venom alleviates AD-like skin lesions induced by 2,4-dinitrochlorobenzene (DNCB) and house dust mite extract (Dermatophagoides farinae extract, DFE) in a murine model. However, the underlying mechanisms of PLA2 action in actopic dermatitis remain unclear. In this study, we showed that PLA2 treatment inhibited epidermal thickness, serum immunoglobulin E (IgE) and cytokine levels, macrophage and mast cell infiltration in the ear of an AD model induced by DFE and DNCB. In contrast, these effects were abrogated in CD206 mannose receptor-deficient mice exposed to DFE and DNCB in the ear. These data suggest that bvPLA2 alleviates atopic skin inflammation via interaction with CD206.

Prevalence of Antibiotic Residues and Antibiotic Resistance in Isolates of Chicken Meat in Korea.

The aim of study was to investigate the correlation between the level of 17 antibiotic residues and 6 antibiotic resistances of Escherichia coli isolates in chicken meats. A total of 58 chicken meats were collected from retail grocery stores in five provinces in Korea. The total detection rate of antibiotic residues was 45% (26 out of 58). Ten out of 17 antibiotics were detected in chicken meats. None of the antibiotics exceeded the maximum residue level (MRLs) in chicken established by the Ministry of Food and Drug Safety (MFDS). The most detected antibiotics were amoxicillin (15.5%), followed by enrofloxacin (12.1%) and sulfamethoxazole (10.3%). In a total of 58 chicken meats, 51 E. coli strains were isolated. E. coli isolates showed the highest resistance to ampicillin (75%), followed by tetracycline (69%), ciprofloxacin (65%), trimethoprim/ sulfamethoxazole (41%), ceftiofur (22%), and amoxicillin/clavulanic acid (12%). The results of study showed basic information on relationship between antibiotic residue and resistance for 6 compounds in 13 chicken samples. Further investigation on the antibiotic resistance patterns of various bacteria species is needed to improve food safety.

A standardized herbal extract PM014 ameliorates pulmonary fibrosis by suppressing the TGF-ß1 pathway.

Idiopathic pulmonary fibrosis (IPF) is a devastating and common chronic lung disease pathologically characterized by loss of epithelial cells and activation of fibroblasts and myofibroblasts. The etiology of IPF remains unclear and the disease pathology is poorly understood with no known efficacious therapy. PM014 is an herbal extract that has been shown to have beneficial effects in pulmonary diseases, which are likely to exert anti-inflammatory bioactions. In the present study, we observed that bleomycin (BLM) caused increased inflammatory infiltration as well as collagen deposition in lungs of mice on day 14 after treatment. Administration of PM014 suppressed BLM-induced inflammatory responses and fibrotic changes in dose-dependent manner in mice. Additionally, we provided in vitro evidence suggesting that PM014 inhibited TGF-ß1-induced epithelial-mesenchymal transition (EMT) and fibroblast activation in alveolar epithelial cells and human lung fibroblasts from healthy donor and IPF patients. PM014 appeared to target TGF-ß1 signaling via Smad-dependent pathways and p38 mitogen-activated protein kinases (MAPKs) pathways. Taken together, our data suggest that PM014 administration exerts a protective effect against lung fibrosis and highlight PM014 as a viable treatment option that may bring benefits to patient with IPF.

Cigarette Smoking Triggers Colitis by IFN-γ+ CD4+ T Cells.

The increased incidence of Crohn's disease in smokers has been recently reported, suggesting a strong association of cigarette smoke (CS) with colitis. However, the mechanism of the action of CS on colitis has not yet been explored. Here, we demonstrate that CS exposure is sufficient to induce colitis in mice. Interestingly, the colitis is mainly mediated by Th1, but not Th17, responses. CD4+ T-cell depletion or T-bet/IFN-γ deficiency protects against the development of colitis induced by CS. Additionally, IFN-γ-producing CD4+ T cells play a substantial role in CS-induced colitis. The adoptive transfer (AT) of effector T cells from CS-exposed WT mice into colitis-prone mice caused these mice to develop colitis, while the AT of effector T cells from IFN-γ knock-out mice did not. These findings have implications for broadening our understanding of CS-induced pathology and for the development of novel therapeutic strategies to treat Crohn's disease.

Schisandrae Fructus Reduces Symptoms of 4-Vinylcyclohexene Diepoxide-Induced Ovarian Failure in Mice.

Menopause is associated with a decrease in the level of sex hormones such as ovarian estradiol and progesterone and can cause various symptoms such as depression, hot flash, fatigue, heart palpitations, and headache. Furthermore, there is a risk of developing complications such as osteoporosis, cardiovascular diseases, Alzheimer's disease, and ovarian cancer. Schisandrae Fructus (SF) is widely used in Korean medicine as a cure for such complications. This study was conducted to evaluate the therapeutic effects of SF against menopause symptoms associated with follicle depletion caused by the industrial chemical 4-vinylcyclohexene diepoxide (VCD) in mice. VCD directly targets the preantral follicles. Mice were injected with VCD (160 mg/kg intraperitoneally) daily for 15 days and then with SF dosage 3 times/week for six weeks. To evaluate the effects of SF, body weight, tail skin temperature, uterine weight, lipid profile, and osteocalcin levels were measured. A decrease in body weight and tail skin temperature and an increase in uterine weight were observed upon SF treatment. Moreover, SF treatment significantly decreased total cholesterol, triglyceride, osteocalcin, and low-density lipoprotein levels and low-density/high-density lipoprotein ratio. These results suggest the potential use of SF in the treatment of menopausal symptoms in women.

Standardized Herbal Formula PM014 Inhibits Radiation-Induced Pulmonary Inflammation in Mice.

Radiation therapy is widely used for thoracic cancers. However, it occasionally causes radiation-induced lung injuries, including pneumonitis and fibrosis. Chung-Sang-Bo-Ha-Tang (CSBHT) has been traditionally used to treat chronic pulmonary disease in Korea. PM014, a modified herbal formula derived from CSBHT, contains medicinal herbs of seven species. In our previous studies, PM014 exhibited anti-inflammatory effects in a chronic obstructive pulmonary disease model. In this study, we have evaluated the effects of PM014 on radiation-induced lung inflammation. Mice in the treatment group were orally administered PM014 six times for 2 weeks. Effects of PM014 on radiation pneumonitis were evaluated based on histological findings and differential cell count in bronchoalveolar lavage fluid. PM014 treatment significantly inhibited immune cell recruitment and collagen deposition in lung tissue. Normal lung volume, evaluated by radiological analysis, in PM014-treated mice was higher compared to that in irradiated control mice. PM014-treated mice exhibited significant changes in inspiratory capacity, compliance and tissue damping and elastance. Additionally, PM014 treatment resulted in the downregulation of inflammatory cytokines, chemokines, and fibrosis-related genes and a reduction in the transforming growth factor-ß1-positive cell population in lung tissue. Thus, PM014 is a potent therapeutic agent for radiation-induced lung fibrosis and inflammation.

The therapeutic effects of tuberostemonine against cigarette smoke-induced acute lung inflammation in mice.

Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking and is characterized by the destruction of lung parenchyma, structural alterations of the small airways, and systemic inflammation. Tuberostemonine (TS) is an alkaloid-type phytochemical from Stemona tuberosa. In the present study, we evaluated the anti-inflammatory effect of TS in a cigarette smoke (CS)-induced mouse model of acute lung inflammation. The mice were whole-body exposed to CS or fresh air for 7 days. TS was administered by an intraperitoneal (i.p.) injection 1h before exposure to CS. To test the effects of TS, the numbers of total cells, neutrophils, macrophages and lymphocytes in the bronchoalveolar lavage (BAL) fluid were counted. Furthermore, we measured the levels of several chemokines, such as GCP-2, MIP-3α, MCP-1 and KC, in the lung tissue. The cellular profiles and histopathological analysis demonstrated that the infiltration of peribronchial and perivascular inflammatory cells significantly decreased in the TS-treated groups compared with the CS-exposure group. The TS treatment significantly ameliorated the airway epithelial thickness induced by CS exposure and caused a significant decrement in the production of chemokines in the lung. These results suggest that TS has anti-inflammatory effects against CS-induced acute lung inflammation.

Preventive Effects of Bee Venom Derived Phospholipase A2 on Oxaliplatin-Induced Neuropathic Pain in Mice.

Oxaliplatin, a chemotherapy drug used to treat colorectal cancer, induces specific sensory neurotoxicity signs that are aggravated by cold and mechanical stimuli. Here we examined the preventive effects of Bee Venom (BV) derived phospholipase A2 (bvPLA2) on oxaliplatin-induced neuropathic pain in mice and its immunological mechanism. The cold and mechanical allodynia signs were evaluated by acetone and von Frey hair test on the hind paw, respectively. The most significant allodynia signs were observed at three days after an injection of oxaliplatin (6 mg/kg, i.p.) and then decreased gradually to a normal level on days 7-9. The oxaliplatin injection also induced infiltration of macrophages and upregulated levels of the pro-inflammatory cytokine interleukin (IL)-1ß in the lumbar dorsal root ganglia (DRG). Daily treatment with bvPLA2 (0.2 mg/kg, i.p.) for five consecutive days prior to the oxaliplatin injection markedly inhibited the development of cold and mechanical allodynia, and suppressed infiltration of macrophages and the increase of IL-1ß level in the DRG. Such preventive effects of bvPLA2 were completely blocked by depleting regulatory T cells (Tregs) with CD25 antibody pre-treatments. These results suggest that bvPLA2 may prevent oxaliplatin-induced neuropathic pain by suppressing immune responses in the DRG by Tregs.