Ilex paraguariensis A.St.-Hil. improves lipid metabolism in high-fat diet-fed obese rats and suppresses intracellular lipid accumulation in 3T3-L1 adipocytes via the AMPK-dependent and insulin signaling pathways.

Background: Obesity is closely associated with several chronic diseases, and adipose tissue plays a major role in modulating energy metabolism. Objective: This study aimed to determine whether Mate, derived from I. paraguariensis A.St.-Hil., ameliorates lipid metabolism in 3T3-L1 adipocytes and high-fat diet (HFD)-fed obese Sprague-Dawley (SD) rats. Design: 3T3-L1 adipocytes were cultured for 7 days, following which intracellular lipid accumulation and expression levels of lipid metabolism-related factors were examined. Dorsomorphin was used to investigate the potential pathways involved, particularly the adenosine monophosphate-activated protein kinase (AMPK)- dependent pathway. Mate was administered to rat HFD-fed obese SD models for 8 consecutive weeks. The expression of lipid metabolism-related factors in the organs and tissues collected from dissected SD rats was evaluated. Results: Mate suppressed intracellular lipid accumulation in 3T3-L1 adipocytes, increased the protein and gene expression levels of AMPK, hormone sensitive lipase (HSL), calmodulin kinase kinase (CaMKK), liver kinase B1 (LKB1), protein kinase A (PKA), CCAAT/enhancer binding protein ß (C/EBPß), insulin receptor b (IRß), and insulin receptor substrate 1 (IRS1) (Tyr465), and decreased those of sterol regulatory element binding protein 1C (Srebp1c), fatty acid synthase (FAS), peroxisome-activated receptor γ (PPARγ), and IRS1 (Ser1101). Furthermore, an AMPK inhibitor abolished the effects exerted by Mate on intracellular lipid accumulation and HSL and FAS expression levels. Mate treatment suppressed body weight gain and improved serum cholesterol levels in HFD-fed obese SD rats. Treatment with Mate increased the protein and gene expression levels of AMPK, PKA, Erk1/Erk2 (p44/p42), and uncoupling protein 1 and reduced those of mammalian target of rapamycin, S6 kinase, Srebp1c, ap2, FAS, Il6, Adiponectin, Leptin, and Fabp4 in rat HFD-fed obese SD models. Discussion and conclusions: Mate suppressed intracellular lipid accumulation in 3T3-L1 adipocytes and improved lipid metabolism in the epididymal adipose tissue of HFD-fed obese SD rats via the activation of AMPK-dependent and insulin signaling pathways.

Long-term retention rates of anti-tumour necrosis factor and anti-interleukin-17 antibodies for patients with psoriatic arthritis.

OBJECTIVE: While biologics have been used for the patients with psoriatic arthritis, there remains to be unknown concerning long-term retention rates. This study aims to present real-world data about long-term retention rates of biologics for the patients with psoriatic arthritis, and to undertake an analysis of the contributing factors. METHODS: We examined retention rates and the reasons for discontinuation for biologics (adalimumab, certolizumab pegol, secukinumab, and ixekizumab) in 146 prescriptions (of which, 109 prescriptions were as naive) at our hospital since March 2010. RESULTS: Throughout the entire course of the study, the 10-year retention rates were approximately 70% for adalimumab, 50% for ixekizumab, and 40% for secukinumab. When evaluating retention rates in the biologic-naïve subgroups, the 10-year retention rates were all approximately 70%. Regarding certolizumab pegol, the 3-year retention rate was approximately 75%. For adalimumab, a higher degree of arthritis at the initiation of treatment was found to correlate with an increased likelihood of secondary inefficacy. The main reason for discontinuation was secondary inefficacy, except for ixekizumab. CONCLUSIONS: Each biologic exhibited a favourable long-term retention rate. The main reason for discontinuation was secondary inefficacy. Regarding adalimumab, secondary inefficacy was linked to the extent of arthritis upon treatment initiation.

Verification of the efficacy of topical sirolimus gel for systemic rare vascular malformations: a pilot study.

Numerous clinical trials of sirolimus, an inhibitor of mechanistic/mammalian target of rapamycin complex 1, for the treatment of vascular malformations have been conducted. However, aside from lymphatic malformations, the efficacy of sirolimus for venous and capillary malformations has not been established. Moreover, no generalized venous or capillary malformations have been treated with topical sirolimus. To evaluate the safety and efficacy of topical sirolimus for venous and capillary malformations and to compare the efficacy of topical and systemic sirolimus therapy, an open-label single-arm pilot study with 0.2% sirolimus gel was conducted from July 19, 2019, to January 30, 2020, in four patients diagnosed with different vascular malformations (blue rubber bleb nevus syndrome, common venous malformation, phakomatosis pigmentovascularis type IVb, and angiokeratoma in Fabry disease). The primary endpoint was the safety evaluation of sirolimus gel. The main secondary endpoint was the improvement rate evaluated by the Central Judgment Committee at 12 weeks using photographs. No adverse events were observed. Blood sirolimus was not detected in any patient. Two patients (50%) had mild improvement, and the remaining two patients (50%) showed no change after 12 weeks of treatment. Blue rubber bleb nevus syndrome, a generalized venous malformation, showed the greatest response. In conclusion, 0.2% sirolimus gel was found to be as clinically effective as systemic sirolimus treatment in patients with venous and capillary malformations and more effective for early active lesions, even systemic venous malformations.

Palmoplantar pustulosis and pustulotic arthro-osteitis associated with multiple venous occlusion: A case report and literature review.

Pustulotic arthro-osteitis (PAO) is a rare chronic inflammatory arthropathy associated with palmoplantar pustulosis. The pathogenesis of PAO remains unclear. The most common musculoskeletal involvement in PAO is ossification of the sternoclavicular joints. A combination of parietal inflammation and hyperostosis-induced mechanical compression in this region is hypothesized to contribute to multiple venous thrombosis. Here, we present a 66-year-old man with PAO-associated multiple venous occlusion who was successfully treated with guselkumab. We also discuss its clinical manifestation and cause by reviewing the literature.

TangNaiKang, herbal formulation, alleviates obesity in diabetic SHR/cp rats through modulation of gut microbiota and related metabolic functions.

CONTEXT: Tangnaikang (TNK) is a Chinese herbal formulation that has lipid-lowering effects, but its effect on reducing obesity has not been studied. OBJECTIVE: To observe the effect of TNK on obesity and explore its effect on gut microbiota of obese rats. MATERIALS AND METHODS: The SHR/NDmcr-cp rats were divided into three groups: (1) 3.24 g/kg TNK (High TNK), (2) 1.62 g/kg TNK (Low TNK), and (3) an untreated control (CON). Wistar-Kyoto rats were used as normal controls (WKY). After 8 weeks of TNK oral administration, body weight, abdominal circumference, triglycerides (TC) and total cholesterol (CHO) were measured. Gut microbiota diversity was studied by 16S rDNA sequencing, and metagenomes analysis was conducted to determine alteration in functional gene expression. RESULTS: The body weight (496.60 ± 6.0 g vs. 523.40 ± 5.6 g), abdomen circumference (24.00 ± 0.11 cm vs. 24.87 ± 0.25 cm), TC (3.04 ± 0.16 mmol/L vs. 4.97 ± 0.21 mmol/L), CHO (2.42 ± 0.15 mmol/L vs. 2.84 ± 0.09 mmol/L) of rats in the High TNK group were decreased significantly (all p < 0.05). TNK administration regulates intestinal flora, up-regulates Eisenbergiella and down-regulates Clostridium_sensu_stricto_1, which is beneficial to the production of short-chain fatty acids (SCFAs). Metagenomes analysis shows that TNK is closely related to the fatty acid synthesis pathway. DISCUSSION AND CONCLUSIONS: TNK can regulate gut microbiota to reduce obesity, which may be related to fatty acid metabolism. Our research supports the clinical application of TNK preparation and provides a new perspective for the treatment of obesity.

Amycenone reduces excess body weight and attenuates hyperlipidaemia by inhibiting lipogenesis and promoting lipolysis and fatty acid ß-oxidation in KK-Ay obese diabetic mice.

Excess body weight and hyperlipidaemia cause severe health problems and have social implications. Amycenone is an active substance extracted from Yamabushitake mushrooms with no reports of its activity against excess body weight and hyperlipidaemia. This research clarifies the effects and mechanisms of action of amycenone on the inhibition of body weight excess and hyperlipidaemia attenuation using KK-Ay mice. Amycenone or water was administered to 8-week-old male KK-Ay mice by gavage for 8 weeks. Their body weight and food intake were recorded during the experiment. At the end of the experimental period, the mice were dissected, and blood samples, lipid metabolism-related organs and tissues were collected and stored for further analysis. Amycenone treatment suppressed body weight gain and improved serum levels of fasting blood glucose and non-esterified fatty acids. Additionally, serum and hepatic cholesterol and triacylglycerol levels were reduced after this treatment, whereas the phosphorylation levels of AMPK, PKA and HSL increased and the expression level of FAS decreased. The protein level of C/EBPß and gene expression level of Cpt1 were higher in the perirenal adipose tissue of amycenone-treated KK-Ay mice. Furthermore, amycenone phosphorylated AMPK, PKA and ACC, and PPARγ expression was lower in the mesenteric adipose tissue. The phosphorylation levels of AMPK, LKB1, PKA and ACC were also induced, and FAS expression level was reduced in the liver of the amycenone-treated group. Amycenone could reduce excess body weight and attenuate hyperlipidaemia in KK-Ay mice by inhibiting lipogenesis and promoting lipolysis through lipid metabolism pathway stimulation and fatty acid ß-oxidation acceleration.

Plasmalogen Inhibits Body Weight Gain by Activating Brown Adipose Tissue and Improving White Adipose Tissue Metabolism.

Plasmalogen, a phospholipid, exhibits preventive and therapeutic effects on dementia. Phospholipids improve fat metabolism, but it is unknown whether plasmalogen has an effect on fat metabolism. In this study, the effects of plasmalogen were determined by administering plasmalogen to KK-Ay mice. As a result, weight gain was significantly suppressed in the plasmalogen-treated group compared with the control group from 7 wk after the start of administration. In addition, plasmalogen administration increased uncoupling protein 1 (UCP1) expression in brown adipose tissue. The effect is thought to result from liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)/PR domain containing 16 (PRDM16)/peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) pathway activation via adrenergic ß3 receptors. Furthermore, the expression of the carnitine palmitoyltransferase-1 (CPT-1) gene associated with thermogenic factors and ß-oxidation was increased. We investigated the browning of white adipose tissue, but no increase in UCP1 gene expression was observed in perirenal adipose tissue, epididymis adipose tissue, mesenteric adipose tissue and inguinal region white adipose tissue. In contrast, plasmalogen increased the activity of AMPK, which is a central enzyme in lipid metabolism, in perirenal adipose tissue. Furthermore, the activity of the protein kinase A (PKA)/LKB1/AMPK/acetyl-coenzyme A carboxylase (ACC), stearoyl-CoA desaturase-1 (SCD-1), and hormone-sensitive lipase (HSL) pathways was confirmed. Plasmalogen may inhibit weight gain by activating brown fat to increase heat production, inhibiting lipid synthesis, and promoting lipolysis in white fat.

L-citrulline inhibits body weight gain and hepatic fat accumulation by improving lipid metabolism in a rat nonalcoholic fatty liver disease model.

BACKGROUND: Body weight gain is a social issue all over the world. When body weight increased, hepatic fat accumulation also increased and it causes fatty liver disease. Therefore, developing a new treatment method and elucidating its mechanism is necessary. L-citrulline (L-Cit) is a free amino acid found mainly in watermelon. No reports regarding its effects on the improvement of hepatic steatosis and fibrogenesis are currently available. The aim of this study was to clarify the effect and the mechanism of L-Cit on inhibition of body weight gain and hepatic fat accumulation in high-fat and high-cholesterol fed SHRSP5/Dmcr rats. METHODS: L-Cit or water (controls) was administered to six-week-old male SHRSP5/Dmcr rats by gavage for nine weeks. We recorded the level of body weight and food intake while performing the administration and sacrificed rats. After that, the blood and lipid metabolism-related organs and tissues were collected and analyzed. RESULTS: L-Cit treatment reduced body weight gain and hepatic TC and TG levels, and serum levels of AST and ALT. L-Cit enhanced AMPK, LKB1, PKA, and hormone-sensitive lipase (HSL) protein phosphorylation levels in the epididymal fat. L-Cit treatment improved steatosis as revealed by HE staining of liver tissues and enhanced AMPK and LKB1 phosphorylation levels. Moreover, activation of Sirt1 was higher, while the liver fatty acid synthase (FAS) level was lower. Azan staining of liver sections revealed a reduction in fibrogenesis following L-Cit treatment. Further, the liver levels of TGF-ß, Smad2/3, and α-SMA, fibrogenesis-related proteins and genes, were lower in the L-Cit-treated group. CONCLUSIONS: From the results of analysis of the epididymal fat and the liver, L-Cit inhibits body weight gain and hepatic fat accumulation by activating lipid metabolism and promoting fatty acid ß-oxidation in SHRSP5/Dmcr rats.

Madecassoside Inhibits Body Weight Gain via Modulating SIRT1-AMPK Signaling Pathway and Activating Genes Related to Thermogenesis.

Background: Pre-clinical research studies have shown that Madecassoside (MA) has favorable therapeutic effects on arthritis, acne, vitiligo and other diseases. However, the effects of MA on obesity have not yet been studied. This study mainly aimed to investigate the effects of MA in protecting against obesity and its underlying mechanism in reducing obesity. Methods: Obese diabetic KKay/TaJcl mice model was adopted to the study. The body weight of all animals was recorded daily, and the blood glucose, blood lipid, and serum aminotransferase levels were examined, respectively. The expression of P-AMPK, SIRT1, P-LKB1, P-ACC, and P-HSL in abdominal fat, mesenteric fat, and epididymal fat was measured by western blotting, and the levels of PPARα, CPT1a, PGC-1α, UCP-1, Cidea, Cox7a1, and Cox8b were examined by real-time quantitative PCR (RT-qPCR). Results: The results revealed that the body weight of the mice in MA group was significantly reduced, and the body mass index (BMI) showed significant difference between the two groups after 8 weeks of MA treatment. Further research revealed that it affected the mesenteric fat and epididymis fat by activating SIRT1/AMPK signaling pathway, and then promoted fatty acid oxidation of epididymal fat (PPARα ↑, CPT1a↑, and PGC-1α↑). Last but not the least, it also promoted the expression of UCP-1 and stimulated thermoregulatory genes (Cidea, Cox7a1, and Cox8b) in brown fat and mesenteric fat. Conclusions: Taken together, these findings suggest that MA can inhibit the weight gain in obese diabetic mice, and reduce triglyceride levels, inhibit lipogenesis of mesenteric fat, promote epididymal fat lipolysis and fatty acid oxidation. Furthermore, MA treatment might promote mesenteric fat browning and activate mitochondrial function in brown fat as well as mesenteric fat.

Expression of TAS2R14 in the intestinal endocrine cells of non-human primates.

BACKGROUND: Recent studies have demonstrated that genes related to bitter taste receptors (TAS2Rs) on various chromosomes are expressed in extra-oral organs of various animals. The bitter taste receptor TAS2R14 is conserved among primate species and shows broad ligand sensitivity. Mice have a number of orthologues to primate TAS2R14 located in tandem on chromosome 16; however, their expression patterns are not unique. OBJECTIVE: We characterized the expression of TAS2R14 in various cell types in the intestines of the rhesus macaque and evaluated its role in hormone production in the gut. METHODS: TAS2R14 expression was examined in the intestines of rhesus macaques, a common non-human primate model, by RT-qPCR and immunohistochemical staining. RESULTS: Mean expression levels of TAS2R14 in the duodenum, ileum, and colon were similar to each other and were lower than those in circumvallate papillae. An immunohistochemical analysis revealed TAS2R14 immunoreactivity in enteroendocrine cells positive for cholecystokinin, serotonin, and the G protein GNAT3. CONCLUSION: These results suggest that primate TAS2R14 is broadly expressed in the intestine, mainly in enteroendocrine cells, and promotes gut hormone secretion in response to bitter stimuli.

Mucinous Syringometaplasia: Surrounding Acanthosis With Hyperkeratosis Tends to Conceal the Change.

A 57-year-old man had a 2-year history of a painful nodule on the right sole. Physical examination revealed an 8 × 8 mm hyperkeratotic plaque with a central fissure. Excisional biopsy disclosed epithelial invagination surrounded by the acanthotic epidermis with parakeratotic hyperkeratosis and focal hypergranulosis. The invaginated epithelium lacked a cornified layer and was composed of a mixture of small basaloid squamous cells and goblet cells showing tubular structures. The patient was diagnosed with mucinous syringometaplasia. Our literature review established that surrounding acanthosis with hyperkeratosis typically tends to conceal mucinous syringometaplastic changes. Because mucinous syringometaplasia often presents as an asymptomatic papule/nodule with no distinct ulcer, fissure, or depressed area, cases may be overlooked.

Therapeutic Potential of Centella asiatica and Its Triterpenes: A Review.

Centella asiatica (also known as Centella asiatica (L.) Urb. or Gotu kola) is a traditional Chinese medicine with extensive medicinal value, which is commonly used in Southeast Asian countries. This study aimed to summarize the effects of C. asiatica and its main components on neurological diseases, endocrine diseases, skin diseases, cardiovascular diseases, gastrointestinal diseases, immune diseases, and gynecological diseases, as well as potential molecular mechanisms, to study the pathological mechanism of these diseases based on the changes at the molecular level. The results showed that C. asiatica and its triterpenoids had extensive beneficial effects on neurological and skin diseases, which were confirmed through clinical studies. They exhibited anti-inflammatory, anti-oxidative stress, anti-apoptotic effects, and improvement in mitochondrial function. However, further clinical studies are urgently required due to the low level of evidence and lack of patients.

Expression of Bitter Taste Receptors in the Intestinal Cells of Non-Human Primates.

(1) Background: Recent studies have investigated the expression of taste-related genes in the organs of various animals, including humans; however, data for additional taxa are needed to facilitate comparative analyses within and among species. (2) Methods: We investigated the expression of taste-related genes in the intestines of rhesus macaques, the non-human primates most commonly used in experimental models. (3) Results: Based on RNAseq and qRT-PCR, genes encoding bitter taste receptors and the G-protein gustducin were expressed in the gut of rhesus macaques. RNAscope analysis showed that one of the bitter receptors, TAS2R38, was expressed in some cells in the small intestine, and immunohistochemical analysis revealed the presence of T2R38-positive cells in the villi of the intestines. (4) Conclusions: These results suggest that bitter receptors are expressed in the gut of rhesus macaques, supporting the use of macaques as a model for studies of human taste, including gut analyses.

Investigator-initiated clinical study of a functional peptide, SR-0379, for limb ulcers of patients with Werner syndrome as a pilot study.

AIM: An investigator-initiated clinical study was carried out to evaluate the therapeutic potency of SR-0379 for the treatment of leg ulcers in patients with Werner syndrome. METHODS: A multicenter, open-label study was carried out from September 2017 to February 2018. The inclusion criteria for leg ulcers were: (i) leg ulcers in patients with Werner syndrome, diabetes or critical limb ischemia/venous stasis; and (ii) a wound size of >1 cm and <6 cm in diameter. Four individuals with Werner syndrome and diabetic ulcers, respectively, were enrolled. SR-0379 (0.1%) was sprayed on skin ulcers once per day for 4 weeks. Efficacy was evaluated by determining the rate of wound size reduction as a primary end-point at 4 weeks after the first treatment compared with the pretreatment wound size. As secondary end-points, the DESIGN-R score index, the 50% wound size reduction ratio, time to wound closure and quantification of wound bacteria were also evaluated. The safety of SR-0379 was evaluated during the study period. RESULTS: The reduction rate of ulcer size treated with 0.1% SR-0379 was 22.90% (mean) in the Werner syndrome ulcers group (n = 4) and 35.70% (mean) in the diabetic ulcers group (n = 4), respectively. The DESIGN-R score decreased by 4.0 points in the Werner syndrome ulcers group and 4.3 points in the diabetic ulcers group. Two mild adverse events were reported in two patients, and causal relationships were denied in any events. CONCLUSION: Treatment with SR-0379 was safe, well-tolerated, and effective for leg ulcers of both Werner syndrome and diabetes patients. Geriatr Gerontol Int 2019; 19: 1118-1123.