Sphingosine-1-Phosphate-Cathelicidin Axis Plays a Pivotal Role in the Development of Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer caused by mutagenesis resulting from excess UVR or other types of oxidative stress. These stressors also upregulate the production of a cutaneous innate immune element, cathelicidin antimicrobial peptide (CAMP), through endoplasmic reticulum stress-initiated, sphingosine-1-phosphate (S1P) signaling pathway. Although CAMP has beneficial antimicrobial activities, it also can be proinflammatory and procarcinogenic. We addressed whether and how S1P-induced CAMP production leads to cSCC development. Our study demonstrated that (i) CAMP expression is increased in cSCC cells and skin from patients with cSCC; (ii) S1P levels are elevated in cSCC cells, whereas inhibition of S1P production attenuates CAMP-stimulated cSCC growth; (iii) exogenous CAMP stimulates cSCC but not normal human keratinocyte growth; (iv) blockade of FPRL1 protein, a CAMP receptor, attenuates cSCC growth as well as the growth and invasion of cSCC cells mediated by CAMP into an extracellular matrix-containing fibroblast substrate; (v) FOXP3+ regulatory T-cell (which decreases antitumor immunity) levels increase in cSCC skin; and (vi) CAMP induces endoplasmic reticulum stress in cSCC cells. Together, the endoplasmic reticulum stress-S1P-CAMP axis forms a vicious circle, creating a favorable environment for cSCC development, that is, cSCC growth and invasion impede anticancer immunity.

Stroke Measures Analysis of pRognostic Testing-Mortality nomogram predicts long-term mortality after ischemic stroke.

BACKGROUND: Predicting long-term mortality is essential for understanding prognosis and guiding treatment decisions in patients with ischemic stroke. Therefore, this study aimed to develop and validate the method for predicting 1- and 5-year mortality after ischemic stroke. METHODS: We used data from the linked dataset comprising the administrative claims database of the Health Insurance Review and Assessment Service and the Clinical Research Center for Stroke registry data for patients with acute stroke within 7 days of onset. The outcome was all-cause mortality following ischemic stroke. Clinical variables linked to long-term mortality following ischemic stroke were determined. A nomogram was constructed based on the Cox's regression analysis. The performance of the risk prediction model was evaluated using the Harrell's C-index. RESULTS: This study included 42,207 ischemic stroke patients, with a mean age of 66.6 years and 59.2% being male. The patients were randomly divided into training (n = 29,916) and validation (n = 12,291) groups. Variables correlated with long-term mortality in patients with ischemic stroke, including age, sex, body mass index, stroke severity, stroke mechanisms, onset-to-door time, pre-stroke dependency, history of stroke, diabetes mellitus, hypertension, coronary artery disease, chronic kidney disease, cancer, smoking, fasting glucose level, previous statin therapy, thrombolytic therapy, such as intravenous thrombolysis and endovascular recanalization therapy, medications, and discharge modified Rankin Scale were identified as predictors. We developed a predictive system named Stroke Measures Analysis of pRognostic Testing-Mortality (SMART-M) by constructing a nomogram using the identified features. The C-statistics of the nomogram in the developing and validation groups were 0.806 (95% confidence interval (CI), 0.802-0.812) and 0.803 (95% CI, 0.795-0.811), respectively. CONCLUSION: The SMART-M method demonstrated good performance in predicting long-term mortality in ischemic stroke patients. This method may help physicians and family members understand the long-term outcomes and guide the appropriate decision-making process.

Diesel Particulate Matter Permeation into Normal Human Skin and Intervention Using a Topical Ceramide Formulation.

INTRODUCTION: Diesel particulate matter (DPM) emitted from diesel engines is a major source of air pollutants. DPM is composed of elemental carbon, which adsorbs organic compounds including toxic polycyclic aromatic hydrocarbons (PAHs). The skin, as well as airways, is directly exposed to DPM, and association of atopic dermatitis, psoriasis flares, and premature skin aging with air pollutant levels has been documented. In skin, the permeation of DPM and DPM-adsorbed compounds is primarily blocked by the epidermal permeability barrier deployed in the stratum corneum. Depending upon the integrity of this barrier, certain amounts of DPM and DPM-adsorbed compounds can permeate into the skin. However, this permeation into human skin has not been completely elucidated. METHODS: We assessed the permeation of PAHs (adsorbed to DPM) into skin using ex vivo normal (barrier-competent) organ-cultured human skin after application of DPM. Two major PAHs, 2-methylnaphthalene and triphenylene, and a carcinogenic PAH, benzo(a)pyrene, all found in DPM, were measured in the epidermis and dermis using liquid chromatography electrospray ionization tandem mass spectrometry. In addition, we investigated whether a topical formulation can attenuate the permeation of DPM into skin. RESULTS: 2-Methylnaphthalene, triphenylene, and benzo(a)pyrene were recovered from the epidermis. Although these PAHs were also detected in the dermis after DPM application, these PAH levels were significantly lower than those found in the epidermis. We also demonstrated that a topical formulation that has the ability to form more uniform membrane structures can significantly suppress the permeation of PAHs adsorbed to DPM into the skin. CONCLUSION: Toxic compounds adsorbed by DPM can permeate even barrier-competent skin. Hence, barrier-compromised skin, such as in atopic dermatitis, psoriasis, and xerosis, is even more vulnerable to air pollutants. A properly formulated topical mixture that forms certain membrane structures on the skin surface can effectively prevent permeation of exogenous substances, including DPM, into skin.

Hydroethanolic extract of Cirsium setidens ameliorates doxorubicin-induced cardiotoxicity by AMPK-PGC-1α-SOD-mediated mitochondrial protection.

BACKGROUND: Doxorubicin (DOX) is an effective anticancer agent. However, the clinical outcomes of DOX-based therapies are severely hampered by their significant cardiotoxicity. PURPOSE: We investigated the beneficial effects of an ethanol extract of Cirsium setidens (CSE) on DOX-induced cardiomyotoxicity (DICT). METHODS: UPLC-TQ/MS analysis was used to identify CSE metabolite profiles. H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells were used to evaluate the effects of CSE on DICT-induced cell death. To elucidate the mechanism underlying it, AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma co-activator l-alpha (PGC1-α), nuclear respiratory factor 1 (NRF1), NRF2, superoxide dismutase (SOD1), and SOD2 expression was detected using western blot analysis. The oxygen consumption rate (OCR), cellular ROS, and mitochondrial membrane potential were measured. Finally, we confirmed the cardioprotective effect of CSE against DICT in both C57BL/6 mice and human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) by observing various parameters, such as electrophysiological changes, cardiac fibrosis, and cardiac cell death. RESULTS: Chlorogenic acid and nicotiflorin were the major compounds in CSE. Our data demonstrated that CSE blocked DOX-induced cell death of H9c2 cells without hindrance of its apoptotic effects on MDA-MB-231 cells. DOX-induced defects of OCR and mitochondrial membrane potential were recovered in a CSE through upregulation of the AMPK-PGC1-α-NRF1 signaling pathway. CSE accelerated NRF1 translocation to the nucleus, increased SOD activity, and consequently blocked apoptosis in H9c2 cells. In mice treated with 400 mg/kg CSE for 4 weeks, electrocardiogram data, creatine kinase and lactate dehydrogenase levels in the serum, and cardiac fibrosis, were improved. Moreover, various electrophysiological features indicative of cardiac function were significantly enhanced following the CSE treatment of hiPSCCMs. CONCLUSION: Our findings demonstrate CSE that ameliorates DICT by protecting mitochondrial dysfunction via the AMP- PGC1α-NRF1 axis, underscoring the therapeutic potential of CSE and its underlying molecular pathways, setting the stage for future investigations into its clinical applications.

Complementary Therapeutic Effect of Fecal Microbiota Transplantation in Ulcerative Colitis after the Response to Anti-Tumor Necrosis Factor Alpha Agent Was Lost: A Case Report.

In patients with ulcerative colitis (UC), the development of an antidrug antibody (ADA) to anti-tumor necrosis factor (TNF)α agent is a crucial problem which aggravates the clinical course of the disease, being cited as one of the most common causes for discontinuing anti-TNFα treatment. This is due to ADA eventually causing secondary LOR, leading to discontinuation of anti-TNFα treatment. Recently, research on the microbiome and relationship between worsening UC and dysbiosis has been conducted. Further, investigations on the association between the microbiome and secondary LOR are increasing. Here, we present the therapeutic effect of fecal microbiota transplantation (FMT) on a 42-year-old man with secondary LOR and high ADA levels. FMT has recently been used for the treatment of, and for overcoming, drug resistance through microbiome modification. Stool samples were collected from the patient before and 4 weeks after FMT. Symptoms, including hematochezia and Mayo endoscopy sub-scores, improved after FMT, while ADA levels decreased by one-third to less than half the value (29 ng/mL) compared to before FMT (79 ng/mL). Additionally, the trough level of infliximab became measurable, which reflects the improvement in the area under the concentration (AUC). Butyricicoccus, Faecalibacterium, Bifidobacterium, Ligilactobacillus, Alistipes, and Odoribacter, which regulate immune responses and alleviate inflammation, also increased after FMT. We report a case in which microbiome modification by FMT increased the AUC of anti-TNFα in a patient who developed secondary LOR during anti-TNFα treatment, thereby improving symptoms and mucosal inflammation.

Skin-whitening effects of Spergularia marina by suppressing MITF translocation.

Spergularia marina is a plant that grows in salty regions along the coastline and exerts radical-scavenging and anti-inflammatory effects. In this study, we investigated the skin-whitening effects of S. marina extract (SME) in B16F10 melanoma cells. SME was found to exert radical-scavenging effects. It suppressed α-melanocyte-stimulating hormone-induced melanogenesis and tyrosinase activity. We also assessed the melanin production signaling pathway to identify the inhibitory action mechanism of SME on melanogenesis. SME decreased the protein expression levels of tyrosinase-related protein (TRP)-1, TRP-2, and tyrosinase, which play important roles in melanogenesis. Furthermore, western blotting revealed that SME inhibited the nuclear translocation of melanocyte inducing transcription factor (MITF), which is a transcription factor for TRP-1, TRP-2, and tyrosinase, suggesting that SME exerts its skin-whitening effect by inhibiting MITF nuclear translocation. Therefore, SME may potentially be used in skin-whitening medicines and cosmetics.

Schisandrin A in Schisandra chinensis Upregulates the LDL Receptor by Inhibiting PCSK9 Protein Stabilization in Steatotic Model.

Schisandra chinensis extract (SCE) protects against hypocholesterolemia by inhibiting proprotein convertase subtilisin/kexin 9 (PCSK9) protein stabilization. We hypothesized that the hypocholesterolemic activity of SCE can be attributable to upregulation of the PCSK9 inhibition-associated low-density lipoprotein receptor (LDLR). Male mice were fed a low-fat diet or a Western diet (WD) containing SCE at 1% for 12 weeks. WD increased final body weight and blood LDL cholesterol levels as well as alanine transaminase and aspartate aminotransferase expression. However, SCE supplementation significantly attenuated the increase in blood markers caused by WD. SCE also attenuated WD-mediated increases in hepatic LDLR protein expression in the obese mice. In addition, SCE increased LDLR protein expression and attenuated cellular PCSK9 levels in HepG2 cells supplemented with delipidated serum (DLPS). Non-toxic concentrations of schisandrin A (SA), one of the active components of SCE, significantly increased LDLR expression and tended to decrease PCSK9 protein levels in DLPS-treated HepG2 cells. High levels of SA-mediated PCSK9 attenuation was not attributable to reduced PCSK9 gene expression, but was associated with free PCSK9 protein degradation in this cell model. Our findings show that PCSK9 secretion can be significantly reduced by SA treatment, contributing to reductions in free cholesterol levels.

Poncirus trifoliata Aqueous Extract Protects Cardiomyocytes against Doxorubicin-Induced Toxicity through Upregulation of NAD(P)H Dehydrogenase Quinone Acceptor Oxidoreductase 1.

Doxorubicin (DOX), an anthracycline-based chemotherapeutic agent, is widely used to treat various types of cancer; however, prolonged treatment induces cardiomyotoxicity. Although studies have been performed to overcome DOX-induced cardiotoxicity (DICT), no effective method is currently available. This study investigated the effects and potential mechanisms of Poncirus trifoliata aqueous extract (PTA) in DICT. Changes in cell survival were assessed in H9c2 rat cardiomyocytes and MDA-MB-231 human breast cancer cells. The C57BL/6 mice were treated with DOX to induce DICT in vivo, and alterations in electrophysiological characteristics, serum biomarkers, and histological features were examined. The PTA treatment inhibited DOX-induced decrease in H9c2 cell viability but did not affect the MDA-MB-231 cell viability. Additionally, the PTA restored the abnormal heart rate, R-R interval, QT interval, and ST segment and inhibited the decrease in serum cardiac and hepatic toxicity indicators in the DICT model. Moreover, the PTA administration protected against myocardial fibrosis and apoptosis in the heart tissue of mice with DICT. PTA treatment restored DOX-induced decrease in the expression of NAD(P)H dehydrogenase quinone acceptor oxidoreductase 1 in a PTA concentration-dependent manner. In conclusion, the PTA inhibitory effect on DICT is attributable to its antioxidant properties, suggesting the potential of PTA as a phytotherapeutic agent for DICT.

Patulin Ameliorates Hypertrophied Lipid Accumulation and Lipopolysaccharide-Induced Inflammatory Response by Modulating Mitochondrial Respiration.

Patulin (PAT) is a natural mycotoxin found in decaying pome fruits. Although some toxicological studies have been conducted on PAT, recent research has highlighted its anticancer and antifungal effects. However, studies have yet to examine the effects and molecular mechanisms of PAT in other metabolic diseases. Obesity is a chronic disease caused by excessive food intake and abnormal lifestyle, leading to low-grade inflammation. Therefore, this study aimed to elucidate the effect of PAT on obesity at the cellular level. PAT treatment reduced lipid accumulation, suppressed glucose and LDL uptake, inhibited lipid deposition and triglyceride synthesis, upregulated fatty acid oxidation-related genes (Pgc1α), and downregulated adipogenic/lipogenic genes (Pparγ and C/ebpα) in hypertrophied 3T3-L1 adipocytes. Additionally, PAT treatment enhanced mitochondrial respiration and mass in differentiated adipocytes and alleviated inflammatory response in activated RAW 264.7 macrophages. Moreover, PAT treatment downregulated pro-inflammatory genes (il-6, Tnf-α, Cox-2, and inos), suppressed lipopolysaccharide (LPS)-induced increase in inflammatory mediators (IL-6, TNF-α, and NO), and restored mitochondrial oxidative function in LPS-stimulated macrophages by improving oxygen consumption and mitochondrial integrity and suppressing ROS generation. Overall, these findings suggest a potential for PAT in the prevention of lipid accumulation and inflammation-related disorders.

Review of Patents for Anticancer Agents Targeting Adenosine Monophosphate-Activated Protein Kinase.

Cancer, caused by abnormal and excessive cellular proliferation, can invade and destroy surrounding tissues and organs through the spreading of cancer cells. A general strategy for developing anticancer agents is to identify biomarkers that, if targeted, can produce a robust cytotoxic effect with minimal side effects. Cell-cycle regulators, checkpoint regulatory genes, and apoptosis-related genes are well-known biomarkers that inhibit cancer cell proliferation. Several compounds that target such biomarkers have been patented and more are being developed as novel therapies. Recent additions to this list include anticancer drugs that target signaling pathway proteins, such as 5' adenosine monophosphate-activated protein kinase (AMPK), which plays a vital role in cancer and normal cell metabolism. Herein, we have reviewed recent patents related to AMPK-targeting anticancer drugs and discussed the mechanisms of action of these drugs. We conclude that these recently published patents include several attractive compounds and methods for targeting AMPK. Further research and clinical trials are required to elucidate the comprehensive role of AMPK in cancer cell metabolism, identify its associated signal transduction systems, and develop novel activators that may find applications in cancer therapy. Clinical Trial Registration number: NCT01904123.

Patulin alleviates hepatic lipid accumulation by regulating lipogenesis and mitochondrial respiration.

AIMS: The aim of this study is to evaluate the effects of patulin on hepatic lipid metabolism and mitochondrial oxidative function and elucidate the underlying molecular mechanisms. MAIN METHODS: The effects of patulin on hepatic lipid accumulation were evaluated in free fatty acid-treated AML12 or HepG2 cells through oil red O staining, triglyceride assay, real-time polymerase chain reaction, and western blotting. Alteration of mitochondrial oxidative capacity by patulin treatment was determined using Seahorse analysis to measure the oxygen consumption rate. KEY FINDINGS: The increased amounts of lipid droplets induced by free fatty acids were significantly reduced by patulin treatment. Patulin markedly activated the CaMKII/AMP-activated protein kinase (AMPK)/proliferator-activated receptor-γ coactivator (PGC)-1α signaling pathway in hepatocytes, reduced the expression of sterol regulatory element binding protein 1c (SREBP-1c) and lipogenic genes, and increased the expression of genes related to mitochondrial fatty acid oxidation. In addition, patulin treatment enhanced the mitochondrial consumption rate and increased the expression of mitochondrial oxidative phosphorylation proteins in HepG2 hepatocytes. The effects of patulin on anti-lipid accumulation; SREBP-1c, PGC-1α, and carnitine palmitoyltransferase 1 expression; and mitochondrial oxidative capacity were significantly prevented by compound C, an AMPK inhibitor. SIGNIFICANCE: Patulin is a potent inducer of the AMPK pathway, and AMPK-mediated mitochondrial activation is required for the efficacy of patulin to inhibit hepatic lipid accumulation. This study is the first to report that patulin is a promising bioactive compound that prevents the development and worsening of fatty liver diseases, including non-alcoholic fatty liver disease, by improving mitochondrial quality and lipid metabolism.

Physiologic and epigenetic effects of nutrients on disease pathways.

BACKGROUND/OBJECTIVES: Epigenetic regulation by nutrients can influence the development of specific diseases. This study sought to examine the effect of individual nutrients and nutrient families in the context of preventing chronic metabolic diseases via epigenetic regulation. The inhibition of lipid accumulation and inflammation by nutrients including proteins, lipids, vitamins, and minerals were observed, and histone acetylation by histone acetyltransferase (HAT) was measured. Correlative analyses were also performed. MATERIALS/METHODS: Nutrients were selected according to information from the Korean Ministry of Food and Drug Safety. Selected nutrient functionalities, including the attenuation of fatty acid-induced lipid accumulation and lipopolysaccharide-mediated acute inflammation were evaluated in mouse macrophage Raw264.7 and mouse hepatocyte AML-12 cells. Effects of the selected nutrients on in vitro HAT inhibition were also evaluated. RESULTS: Nitric oxide (NO) production correlated with HAT activity, which was regulated by the amino acids group, suggesting that amino acids potentially contribute to the attenuation of NO production via the inhibition of HAT activity. Unsaturated fatty acids tended to attenuate inflammation by inhibiting NO production, which may be attributable to the inhibition of in vitro HAT activity. In contrast to water-soluble vitamins, the lipid-soluble vitamins significantly decreased NO production. Water- and lipid-soluble vitamins both exhibited significant inhibitory activities against HAT. In addition, calcium and manganese significantly inhibited lipid accumulation, NO production, and HAT activity. CONCLUSIONS: Several candidate nutrients and their family members may have roles in the prevention of diseases, including hepatic steatosis and inflammation-related diseases (i.e., nonalcoholic steatohepatitis) via epigenetic regulation. Further studies are warranted to determine which specific amino acids, unsaturated fatty acids and lipid-soluble vitamins or specific minerals influence the development of steatosis and inflammatory-related diseases.

Combination of metformin/efavirenz/fluoxetine exhibits profound anticancer activity via a cancer cell-specific ROS amplification.

The possible anticancer activity of combination (M + E + F) of metformin (M), efavirenz (E), and fluoxetine (F) was investigated in normal HDF cells and HCT116 human colon cancer cells. Metformin increased cellular FOXO3a, p-FOXO3a, AMPK, p-AMPK, and MnSOD levels in HDFs but not in HCT116 cells. Cellular ATP level was decreased only in HDFs by metformin. Metformin increased ROS level only in HCT116 cells. Transfection of si-FOXO3a into HCT116 reversed the metformin-induced cellular ROS induction, indicating that FOXO3a/MnSOD is the key regulator for cellular ROS level. Viability readout with M, E, and F alone decreased slightly, but the combination of three drugs dramatically decreased cell survival in HCT116, A549, and SK-Hep-1 cancer cells but not in HDF cells. ROS levels in HCT116 cells were massively increased by M + E + F combination, but not in HDF cells. Cell cycle analysis showed that of M + E + F combination caused cell death only in HCT116 cells. The combination of M + E + F reduced synergistically mitochondrial membrane potential and mitochondrial electron transport chain complex I and III activities in HCT116 cells when compared with individual treatments. Western blot analysis indicated that DNA damage, apoptosis, autophagy, and necroptosis-realated factors increased in M + E + F-treated HCT116 cells. Oral administration with M + E + F combination for 3 weeks caused dramatic reductions in tumor volume and weight in HCT116 xenograft model of nude mice when compared with untreated ones. Our results suggest that M + E + F have profound anticancer activity both in vitro and in vivo via a cancer cell-specific ROS amplification (CASRA) through ROS-induced DNA damage, apoptosis, autophagy, and necroptosis.

Analysis of VOCs Emitted from Small Laundry Facilities: Contributions to Ozone and Secondary Aerosol Formation and Human Risk Assessment.

Volatile organic compounds (VOCs) emitted to the atmosphere form ozone and secondary organic aerosols (SOA) by photochemical reactions. As they contain numerous harmful compounds such as carcinogens, it is necessary to analyze them from a health perspective. Given the petroleum-based organic solvents used during the drying process, large amounts of VOCs are emitted from small laundry facilities. In this study, a laundry facility located in a residential area was selected, while VOCs data emitted during the drying process were collected and analyzed using a thermal desorption-gas chromatography/mass spectrometer (TD-GC/MS). We compared the results of the solvent composition, human risk assessment, contribution of photochemical ozone creation potential (POCP), and secondary organic aerosol formation potential (SOAP) to evaluate the chemical species. Alkane-based compounds; the main components of petroleum organic solvents, were dominant. The differences in evaporation with respect to the boiling point were also discerned. The POCP contribution exhibited the same trend as the emission concentration ratios for nonane (41%), decane (34%), and undecane (14%). However, the SOAP contribution accounted for o-xylene (28%), decane (27%), undecane (25%), and nonane (9%), thus confirming the high contribution of o-xylene to SOA formation. The risk assessment showed that acrylonitrile, carbon tetrachloride, nitrobenzene, bromodichloromethane, and chloromethane among carcinogenic compounds, and bromomethane, chlorobenzene, o-xylene, and hexachloro-1, 3-butadiene were found to be hazardous, thereby excessing the standard value. Overall these results facilitate the selection and control of highly reactive and harmful VOCs emitted from the dry-cleaning process.

Association between Disability and Edema Index Values in Rural Older Adult Osteosarcopenia Patients.

PURPOSE: This study analyzed the relationship between degree of disability and edema index [extracellular water/total body water (ECW/TBW) ratio] values in a rural population of older adult patients with osteopenia, sarcopenia, or osteosarcopenia (OS). MATERIALS AND METHODS: This study used data from the Namgaram-2 cohort. The degree of disability was measured using the World Health Organization Disability Assessment Schedule (WHODAS) 12, and ECW/TBW ratio was calculated using bioelectrical impedance analysis. Based on ECW/TBW ratio, the participants were stratified into normal (<0.391) and abnormal (≥0.391) groups, and the mean WHODAS 12 scores were compared between the two groups. Multiple regression analysis corrected for demographic factors, smoking history, hypertension, diabetes, and serological test results was also conducted. RESULTS: Significant differences in mean WHODAS 12 scores were observed in the healthy group (5.8±7.4 vs. 9.2±9.7, p=0.008), the osteopenia only group (7.4±8.7 vs. 12.9±12.0, p<0.001), and the OS group (16.0±13.2 vs. 23.1±17.1, p=0.004). However, no significant difference in mean WHODAS 12 score was observed in the sarcopenia only group (14.9±13.4 vs. 20.7±14.8, p= 0.051). There were significant differences in ECW/TBW ratio values between the abnormal and normal groups in the osteopenia only group (B=4.646 and p=0.001), the sarcopenia only group (B=5.097 and p=0.016), and the OS group (B=5.653 and p=0.043). CONCLUSION: This study found that the degree of disability is related to the edema index in older patients with osteopenia, sarcopenia, or OS. Since the edema index indicates the nutritional status of an individual, proper nutrition and fluid intake are important to reduce disability.

The first report on effect of fecal microbiota transplantation as a complementary treatment in a patient with steroid-refractory Cronkhite-Canada syndrome: A case report.

RATIONALE: Cronkhite-Canada syndrome (CCS) is a rare non-hereditary disease of unknown etiology that is characterized by the appearance of multiple polyps in the entire gastrointestinal (GI) tract, except in the esophagus, with GI and non-GI symptoms. Various factors are associated with the pathogenesis of CCS. Immune dysregulation has been discussed as one of the pathogeneses of CCS, and dysbiosis of the gut microbiota can affect the immune system. Currently, standard treatment has not been established. PATIENT CONCERNS AND DIAGNOSIS: We present the treatment with fecal microbiota transplantation (FMT) in a 67-year-old male patient with steroid-refractory CCS who could not undergo anti-tumor necrosis factor-a treatment due to suspected tuberculosis infection. INTERVENTIONS: FMT has recently attracted attention as a method of overcoming drug resistance through immunomodulatory effects through microbiome regulation. We collected the patient's stool samples before FMT and 8weeks after FMT. OUTCOMES: We analyzed the microbiome composition of patients by sequencing the V3-V4 region of the 16s rRNA gene (Miseq). After FMT, the number of episodes of diarrhea and hypoalbuminemia were also corrected. The Chao 1 index after FMT, which was significantly higher than that of donors before FMT, changed to a similar level for donors after FMT. Fusobacterium nucleatum, Pyramidobacter piscolens, and Campylobacter concisus disappeared after FMT, suggesting the presence of an association between gut microbiota and CCS. LESSONS: Furthermore, we provide the possibility that microbiome modulation by FMT could serve as a complementary treatment in patients with steroid-refractory CCS.

Anti-obesity effects of medicinal plants from Asian countries and related molecular mechanisms: a review.

Medicinal plants have been used as an alternative medicine for obesity prevention, and Asian countries, which are major habitats of various medicinal plant species, have traditionally used these medicines for centuries. Obesity is a global health problem caused by excessive fat accumulation linked to abnormal lipid metabolism, such as adipogenesis, lipogenesis, and lipolysis. Accordingly, the effects of medicinal plants on obesity-related mechanisms and biomarkers have been evaluated in various experimental studies. For example, adipogenesis and lipogenesis are regulated by several transcription factors, such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein alpha, and fatty acid synthase. Moreover, activation of the adenosine monophosphate-activated protein kinase pathway is accompanied by promotion of lipolysis. However, few reports have consolidated studies of the effects of various Asian medicinal plants on obesity and related mechanisms. Therefore, in this review, we examined the associations of medicinal plants originating from Asian countries with obesity and discussed the related mechanisms and biomarkers from in vitro and in vivo studies.

Purple corn extract alleviates 2,4-dinitrochlorobenzene-induced atopic dermatitis-like phenotypes in BALB/c mice.

Zea mays L. (Poaceae), also known as purple corn, is an annual herbaceous plant that is grown as food for human consumption in a variety of forms, including cooking oils and sweeteners in processed food and beverage products. The purpose of this study was to determine whether a novel purple corn extract, FB801, might have an anti-atopic dermatitis (AD) effect on AD-like skin lesions induced by 2,4-dinitrochlorobenzene (DNCB) in BALB/c mice. Topical sensitization (1%) and challenge (0.3%) by DNCB were performed on the dorsal skin and right ear of BALB/c mice to induce AD. Following FB801 and dexamethasone administered orally, the severity of skin lesions was examined macroscopically and histologically. Serum levels of immunoglobulin E (IgE) and various cytokines were determined by enzyme-linked immunosorbent assay. Oral administration of FB801 significantly reduced typical symptoms of AD (erythema/bleeding, swelling, molting/erosion and scaling/drying), scratching frequencies, and the recruitment of inflammatory and mast cells. In addition, FB801 suppressed serum levels of IgE and T helper (Th)2 type cytokines such as interleukin (IL)-4 and IL-10 in DNCB-treated BALB/c mice. Furthermore, FB801 reduced the degradation of inhibitor of nuclear factor-κB proteins (NF-κB) in tumor necrosis factor (TNF)-α-stimulated human keratinocyte (HaCaT) cells. These results suggest that FB801 inhibited the development of the AD-like skin symptoms by regulating Th1 and Th2 responses in the skin lesions in mice and suppressing TNF-α induced NF-κB activation in HaCaT cells, suggesting that FB801 has potential application as an effective alternative therapy for the prevention and management of AD.

Thromboembolic complications following intravenous immunoglobulin therapy in immune-mediated neurological disorders.

BACKGROUND: Minor adverse events of intravenous immunoglobulin (IVIg) include flu-like symptoms, eczematous skin reaction, electrolyte disturbance, and transient leukopenia. On rare occasions, serious complications such as aseptic meningitis, arrhythmia, decrease in blood pressure, and thromboembolic complications (TEC) have been described. The current study aimed to understand the frequency and clinical features of TEC related to IVIg administration in patients with immune-mediated neurological disorders. METHODS: We conducted a retrospective chart review of hospitalized patients with immune-mediated neuromuscular or neuroimmunological disorders treated with IVIg from January 2018 to March 2020 in a single tertiary hospital. RESULTS: During the study period, 61 patients were treated with a total of 364 IVIg infusions over 84 treatment courses. Among them, we identified 3 TEC cases that occurred during or after the completion of IVIg therapy: two patients with myasthenia gravis (F/60 and F/80) and one patient with Guillain-Barré syndrome (F/79) had undergone arterial TEC (two for ischemic stroke and one for pulmonary thromboembolism). The rates of TEC per patient, per treatment course, and per infusion were 4.91% (3/61), 3.57% (3/84), and 0.82% (3/364), respectively. CONCLUSION: The risk of developing TEC upon receiving IVIg infusions is generally low in patients with immune-mediated neurological disorders; however, IVIg-related TEC should be cautiously monitored for in critically ill elderly patients with vascular risk factors, especially those suffering from myasthenic crisis.

Metformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells.

Metformin increased cellular ROS levels in AsPC-1 pancreatic cancer cells, with minimal effect in HDF, human primary dermal fibroblasts. Metformin reduced cellular ATP levels in HDF, but not in AsPC-1 cells. Metformin increased AMPK, p-AMPK (Thr172), FOXO3a, p-FOXO3a (Ser413), and MnSOD levels in HDF, but not in AsPC-1 cells. p-AMPK and p-FOXO3a also translocated from the cytosol to the nucleus by metformin in HDF, but not in AsPC-1 cells. Transfection of si-FOXO3a in HDF increased ROS levels, while wt-FOXO3a-transfected AsPC-1 cells decreased ROS levels. Metformin combined with apigenin increased ROS levels dramatically and decreased cell viability in various cancer cells including AsPC-1 cells, with each drug used singly having a minimal effect. Metformin/apigenin combination synergistically decreased mitochondrial membrane potential in AsPC-1 cells but to a lesser extent in HDF cells. Metformin/apigenin combination in AsPC-1 cells increased DNA damage-, apoptosis-, autophagy- and necroptosis-related factors, but not in HDF cells. Oral administration with metformin/apigenin caused dramatic blocks tumor size in AsPC-1-xenografted nude mice. Our results suggest that metformin in cancer cells differentially regulates cellular ROS levels via AMPK-FOXO3a-MnSOD pathway and combination of metformin/apigenin exerts anticancer activity through DNA damage-induced apoptosis, autophagy and necroptosis by cancer cell-specific ROS amplification.