High-dose Glycerol Monolaurate Up-Regulated Beneficial Indigenous Microbiota without Inducing Metabolic Dysfunction and Systemic Inflammation: New Insights into Its Antimicrobial Potential

Glycerol monolaurate (GML) has potent antimicrobial and anti-inflammatory activities. The present study aimed to assess the dose-dependent antimicrobial-effects of GML on the gut microbiota, glucose and lipid metabolism and inflammatory response in C57BL/6 mice. Mice were fed on diets supplemented with GML at dose of 400, 800 and 1600 mg kg−1 for 4 months, respectively. Results showed that supplementation of GML, regardless of the dosages, induced modest body weight gain without affecting epididymal/brown fat pad, lipid profiles and glycemic markers. A high dose of GML (1600 mg kg−1) showed positive impacts on the anti-inflammatory TGF-β1 and IL-22. GML modulated the indigenous microbiota in a dose-dependent manner. It was found that 400 and 800 mg kg−1 GML improved the richness of Barnesiella, whereas a high dosage of GML (1600 mg kg−1) significantly increased the relative abundances of Clostridium XIVa, Oscillibacter and Parasutterella. The present work indicated that GML could upregulate the favorable microbial taxa without inducing systemic inflammation and dysfunction of glucose and lipid metabolism.

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Effects of Neohesperidin Dihydrochalcone (NHDC) on Oxidative Phosphorylation, Cytokine Production, and Lipid Deposition

Foods ◽

10.3390/foods10061408 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1408

Author(s):

Sooyeon Choi ◽

Seungmin Yu ◽

Jonghun Lee ◽

Wooki Kim

Keyword(s):

Oxidative Phosphorylation ◽

Cytokine Production ◽

Body Weight Gain ◽

Fat Deposition ◽

Marginal Effect ◽

Dependent Manner ◽

Inhibitory Effects ◽

Anti Inflammatory ◽

Dose Dependent ◽

Anti Inflammatory Cytokine

The sweetener neohesperidin dihydrochalcone (NHDC) is a precursor for anthocyanins and has been reported to have various bioactivities, including antioxidant and hepatitis inhibitory effects. However, its inflammatory functions and mechanisms of action are poorly understood. In this study, RAW 264.7 murine macrophages were treated with NHDC and its metabolite dihydrocaffeic acid (DHCA), after which cytokine production and mitochondrial respiration were assessed. DHCA significantly down-regulated the secretion of pro-inflammatory cytokines. In contrast, NHDC had a marginal effect, suggesting that the biological metabolism of NHDC to DHCA is required for its anti-inflammatory function. However, both NHDC and DHCA rescued LPS-induced suppression of oxidative phosphorylation, which is a hallmark of anti-inflammatory M2 macrophages. 3T3-L1 adipocytes showed lower fat deposition in the presence of DHCA, while sugar-containing NHDC showed a slight increase in fat deposition. In high-fat diet-induced obese mice, treatment with NHDC successfully down-regulated body weight gain in a dose-dependent manner. Furthermore, M2 polarized bone-marrow-derived macrophages (BMDM) from NHDC-fed mice secreted an increased amount of the anti-inflammatory cytokine IL-10. Overall, these results indicate that NHDC and its physiological metabolite DHCA have the potential to suppress the inflammatory response and obese status.

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Meloxicam induced toxicopathology studies in Wistar rats

Indian Journal of Animal Research ◽

10.18805/ijar.b-3766 ◽

2019 ◽

Author(s):

S. Pramod Bharani ◽

A. K. Naik ◽

S. C. Parija ◽

S. K. Panda

Keyword(s):

Wistar Rats ◽

Hematological Parameters ◽

Clinical Signs ◽

High Dose ◽

Dependent Manner ◽

Group Iii ◽

Group I ◽

Anti Inflammatory ◽

Group Ii ◽

Dose Dependent

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used class of drugs for treating inflammation and pain. Meloxicam has analgesic, anti-inflammatory and antipyretic properties and is a commonly used NSAID in veterinary practice. The present study was done to evaluate effect of meloxicam on toxico-pathological and hematological parameters in Wistar rats. Eighteen Wistar rats were equally divided into three groups i.e. Group I, Group II and Group III. Group I (negative control) rats received only Normal saline (0.9%) @ 1ml/kg. Group II (Low dose) received meloxicam@ 4 mg/kg B.W. and Group III (High dose) rats received meloxicam@8 mg/kg B.W. orally by gavage for 28 days. Dose-dependent clinical signs and lesions were observed after meloxicam treatment. Kidneys and liver were severely hemorrhagic at the high dose, while intestine and stomach had ulcers and erosions. Hematological values were altered after 28 days of administration. Total Erythrocyte Count (TEC), Packed Cell Volume (PCV), Haemoglobin values were decreased and TLC count was significantly increased in both doses of meloxicam treated groups in a dose-dependent manner. It was concluded that meloxicam caused GIT lesions, nephrotoxicity, hepatotoxicity and variation in the hematological parameters at selected dose and duration.

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Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽

10.3390/pharmaceutics13030386 ◽

2021 ◽

Vol 13 (3) ◽

pp. 386

Author(s):

Tung-Hu Tsai ◽

Yu-Jen Chen ◽

Li-Ying Wang ◽

Chen-Hsi Hsieh

Keyword(s):

Stereotactic Body Radiation Therapy ◽

In Vivo Studies ◽

Control Group ◽

High Dose ◽

Dependent Manner ◽

Hep G2 ◽

Time Curve ◽

Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

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Prolactin stimulates food intake in a dose-dependent manner

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1989.256.1.r276 ◽

1989 ◽

Vol 256 (1) ◽

pp. R276-R280 ◽

Cited By ~ 6

Author(s):

T. Gerardo-Gettens ◽

B. J. Moore ◽

J. S. Stern ◽

B. A. Horwitz

Keyword(s):

Food Intake ◽

Female Rats ◽

High Dose ◽

Dependent Manner ◽

Additional Control ◽

The Mean ◽

Ovine Prolactin ◽

Dose Dependent ◽

Medium Dose ◽

Cumulative Food Intake

Lactation in the rat is marked by pronounced hyperphagia and suppression of brown fat (BAT) thermogenic capacity. We previously examined the possibility that elevated prolactin levels mediate these changes. The present study evaluated the effect of varying prolactin levels on food intake, BAT mitochondrial GDP binding, and carcass adiposity. Female rats were injected daily for 10 days with ovine prolactin at one of three doses: high = 3.0, medium = 1.0, or low = 0.3 micrograms/g body wt. Controls were injected with 0.9% NaCl. A group of uninjected rats served as an additional control. Cumulative food intake was significantly elevated in a dose-dependent manner in the prolactin-treated animals relative to the saline-injected and uninjected controls. Compared with the saline controls, the mean cumulative food intake was greatest at the high dose (20% increase), intermediate at the medium dose (17%), and smallest at the low dose (12%). Prolactin-treated rats gained significantly more weight during the experiment than did controls. Despite the hyperphagia in the prolactin-treated rats, no significant differences in BAT mitochondrial GDP binding were observed among the five groups. These data indicate that elevated prolactin levels stimulate food intake in a dose-dependent manner and that this hyperphagia is not accompanied by an increase in BAT mitochondrial GDP binding.

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Effects of esculentoside A on turnour necrosis factor production by mice peritoneal macrophages

Mediators of Inflammation ◽

10.1155/s0962935192000565 ◽

1992 ◽

Vol 1 (6) ◽

pp. 375-377 ◽

Cited By ~ 5

Author(s):

Fang Jun ◽

Zheng Qin Yue ◽

Wang Hong Bin ◽

Ju Dian Wen ◽

Yi Yang Hua

Keyword(s):

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Inflammatory Mediator ◽

Platelet Activating Factor ◽

Peritoneal Macrophages ◽

Dependent Manner ◽

Anti Inflammatory ◽

Dose Dependent ◽

Necrosis Factor ◽

Inflammatory Effect

Esculentoside A (EsA) is a saponin isolated from the roots of Phytolacca esculenta. Previous experiments showed that it had strong anti-inflammatory effects. Tumour necrosis factor (TNF) is an important inflammatory mediator. In order to study the mechanism of the anti-inflammatory effect of EsA, it was determined whether TNF production from macrophages was altered by EsA under lipopolysaccharide (LPS) stimulated conditions. EsA was found to decrease both extracellular and cell associated TNF production in a dose dependent manner at concentrations higher than 1 μmol/l EsA. Previous studies have showed that EsA reduced the releasing of platelet activating factor (PAF) from rat macrophages. The reducing effects of EsA on the release of TNF and PAF may explain its anti-inflammatory effect.

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Ascorbic acid attenuates activation and cytokine production in sepsis-like monocytes

10.1101/2021.04.15.21255504 ◽

2021 ◽

Author(s):

Tobias Schmidt ◽

Robin Kahn ◽

Fredrik Kahn

Keyword(s):

Flow Cytometry ◽

Ascorbic Acid ◽

Cytokine Production ◽

In Vitro Study ◽

Surface Expression ◽

High Dose ◽

Functional Assay ◽

Dependent Manner ◽

Dose Dependent

Objective To investigate the effects of high dose ascorbic acid (AA) on monocyte polarization and cytokine production in vitro Design Experimental in vitro study of cells from healthy subjects and patients with sepsis Setting University research laboratory and academic hospital Subjects Six healthy controls and three patients with sepsis Interventions Monocytes were isolated from whole blood of healthy donors (n=6) and polarized in vitro for 48hrs using LPS or LTA. Polarization was confirmed by surface marker expression using flow cytometry. As a comparison, monocytes were also isolated from septic patients (n=3) and analyzed for polarization markers. The effect of AA on monocyte polarization was evaluated. As a functional assay, AA-treated monocytes were analyzed for cytokine production of TNF and IL-8 by intracellular staining and flow cytometry following activation with LPS or LTA. Measurements and Main Results Both LPS and LTA induced polarization in healthy monocytes in vitro, with increased expression of both pro- (CD40 and PDL1, p<0.05) and anti-inflammatory (CD16 and CD163, p<0.05) polarization markers, with non-significant effects on CD86 and CD206. This pattern resembled, at least partly, that of monocytes from septic patients. Treatment with AA significantly inhibited the upregulation of surface expression of CD16 and CD163 (p<0.05) in a dose dependent manner, but not CD40 or PDL-1. Finally, AA attenuated LPS or LTA-induced cytokine production of IL-8 and TNF in a dose-dependent manner (both p<0.05). Conclusions AA inhibits upregulation of anti-, but not pro-inflammatory related markers in LPS or LTA polarized monocytes. Additionally, AA attenuates cytokine production from in vitro polarized monocytes, displaying functional involvement. This study provides important insight into the immunological effects of high dose AA on monocytes, and potential implications in sepsis.

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Compound Traditional Chinese Medicine Dermatitis Ointment Ameliorates Inflammatory Responses and Dysregulation of Itch-Related Molecules in AD

10.21203/rs.3.rs-783506/v1 ◽

2021 ◽

Author(s):

Rongrong Zhang ◽

Shuai Shao ◽

Yingxin Shen ◽

Jiaming Sun ◽

Songlan Piao ◽

...

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Inflammatory Responses ◽

Dependent Manner ◽

Inflammatory Skin Disease ◽

Fingerprint Analysis ◽

Hplc Fingerprint ◽

Effective Components ◽

Anti Inflammatory ◽

Dose Dependent

Abstract Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease accompanied by an itchy and scaly rash. Compound traditional Chinese medicine dermatitis ointment (CTCMDO) is a traditional classics aimed at AD composed of a mixture of extracts from five plants known to have anti-inflammatory and antiallergic effects. Materials and methods: In this study, we used HPLC and LC/MS to analyze the effective components of CTCMDO in detail and establish its HPLC fingerprint analysis. On this basis, this article studied the anti-inflammatory and antipruritic activities of CTCMDO in the treatment of DNCB-induced AD in mice.Results: Through comparison with literature data, a total of 43 compounds were identified, including phenylpropionic acid compounds; alkaloid compounds; curcumin compounds and lignans. On this basis, a fingerprint with 17 common peaks was established. In AD-like mice, CTCMDO treatment suppressed the scratching behavior induced by DNCB in a dose-dependent manner and inhibited the production of Th1/2 cytokines in serum. CTCMDO treatment reversed the up regulation of P substance levels of itch-related genes in the skin. Furthermore, CTCMDO suppressed the phosphorylation of JNK、ERK and p38 in the skin. Conclusion: In all, our work indicated that CTCMDO can signifificantly attenuate the pathological alterations of Th1/2 cytokines and itch-related mediators, and inhibit the phosphorylation of MAPKs to treat AD.

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Calcitriol Exerts Prophylactic Anti-Mycobacterium Effect In A Dose-Dependent Manner

10.21203/rs.3.rs-346581/v1 ◽

2021 ◽

Author(s):

Jianguo Li ◽

Zhen Li ◽

Zefeng Gao ◽

Juan Xia ◽

Jia Cui ◽

...

Keyword(s):

Vitamin D ◽

1H Nmr ◽

Low Dose ◽

Bacterial Load ◽

High Dose ◽

Dependent Manner ◽

Prophylactic Effect ◽

Moderate Dose ◽

Metabolism Pathway ◽

Dose Dependent

Abstract Vitamin D was empirically applied for Tuberculosis (TB) treatment in the past, and is currently used as an adjuvant for TB therapy. Although an increasing pile of evidences suggests that vitamin D has no therapeutic effect against TB infection, the prophylactic effect of vitamin D in preventing TB remains largely undetermined. To experimentally valuate the potential prophylactic effect of calcitriol (the active form of vitamin D) against mycobacterium infection, we performed dose-gradient calcitriol soaking in 30-day-old zebrafish before Mycobacterium marinum (M. marinum) challenge through tail vein injection. 1H-NMR metabolomics analysis was further performed for illustration of potential mechanisms underlying the prophylactic effect of calcitriol against M. marinum. The results suggested that calcitriol exerts dose-dependent prophylactic anti-mycobacterium effects, i.e., the bacterial load and the corresponding inflammatory factors (IL-1β, TNF-α, and IFN-γ) expressions in M. marinum challenged zebrafish were reduced by low-dose (25 µg/L) or high-dose (2500 µg/L) calcitriol soaking, rather than by moderate-dose (250 µg/L) calcitriol soaking. Body weight of the M. marinum challenged zebrafish was recovered by high-dose prophylactic calcitriol soaking rather than by low-dose or moderate-dose calcitriol. The 1H-NMR metabolomic profiling identified 29 metabolites with altered abundance among the dose-gradient calcitriol groups, among which 22 metabolites were co-varied with the dose of calcitriol, the rest 7 metabolites were co-varied with the bacterial load and the inflammatory response in term of cytokine expression. Further pathway analysis indicated that the glycine, serine, and threonine metabolism pathway was the activated in both of the two metabolite groups, indicating that the pathway was altered by dose-gradient of calcitriol and was in response to M. marinum infection in zebrafish. The results of the present study suggested that the activation of glycine, serine and threonine metabolism pathway may play a potential role for the dose-dependent anti-mycobacterium effect induced by prophylactic calcitriol soaking.

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Dose-dependent roles of aspirin and other non-steroidal anti-inflammatory drugs in abnormal bone remodeling and skeletal regeneration

Cell & Bioscience ◽

10.1186/s13578-019-0369-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 6

Author(s):

Yong Xie ◽

Meng Pan ◽

Yanpan Gao ◽

Licheng Zhang ◽

Wei Ge ◽

...

Keyword(s):

Bone Formation ◽

Bone Remodeling ◽

Low Dose ◽

High Dose ◽

Dose Aspirin ◽

Low Dose Aspirin ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

Dose Dependent ◽

High Dose Aspirin

AbstractThe failure of remodeling process that constantly regenerates effete, aged bone is highly associated with bone nonunion and degenerative bone diseases. Numerous studies have demonstrated that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) activate cytokines and mediators on osteoclasts, osteoblasts and their constituent progenitor cells located around the remodeling area. These cells contribute to a complex metabolic scenario, resulting in degradative or synthetic functions for bone mineral tissues. The spatiotemporal effects of aspirin and NSAIDs in the bone remodeling are controversial according the specific therapeutic doses used for different clinical conditions. Herein, we review in vitro, in vivo, and clinical studies on the dose-dependent roles of aspirin and NSAIDs in bone remodeling. Our results show that low-dose aspirin (< 100 μg/mL), which is widely recommended for prevention of thrombosis, is very likely to be benefit for maintaining bone mass and qualities by activation of osteoblastic bone formation and inhibition of osteoclast activities via cyclooxygenase-independent manner. While, the roles of high-dose aspirin (150–300 μg/mL) and other NSAIDs in bone self-regeneration and fracture-healing process are difficult to elucidate owing to their dual effects on osteoclast activity and bone formation of osteoblast. In conclusion, this study highlighted the potential clinical applications of low-dose aspirin in abnormal bone remodeling as well as the risks of high-dose aspirin and other NSAIDs for relieving pain and anti-inflammation in fractures and orthopedic operations.

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Metabolic inhibition impairs ATP-sensitive K+ channel block by sulfonylurea in pancreatic β-cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.274.1.e38 ◽

1998 ◽

Vol 274 (1) ◽

pp. E38-E44 ◽

Cited By ~ 5

Author(s):

Eri Mukai ◽

Hitoshi Ishida ◽

Seika Kato ◽

Yoshiyuki Tsuura ◽

Shimpei Fujimoto ◽

...

Keyword(s):

Metabolic Inhibition ◽

K Channel ◽

High Dose ◽

Dependent Manner ◽

Channel Activity ◽

Β Cells ◽

Pancreatic Β Cells ◽

Patch Clamp Technique ◽

Channel Inhibition ◽

Dose Dependent

The effect of metabolic inhibition on the blocking of β-cell ATP-sensitive K+ channels (KATP channels) by glibenclamide was investigated using a patch-clamp technique. Inhibition of KATP channels by glibenclamide was attenuated in the cell-attached mode under metabolic inhibition induced by 2,4-dinitrophenol. Under a low concentration (0.1 μM) of ATP applied in the inside-out mode, KATP channel activity was not fully abolished, even when a high dose of glibenclamide was applied, in contrast to the dose-dependent and complete KATP channel inhibition under 10 μM ATP. On the other hand, cibenzoline, a class Ia antiarrhythmic agent, inhibits KATP channel activity in a dose-dependent manner and completely blocks it, even under metabolic inhibition. In sulfonylurea receptor (SUR1)- and inward rectifier K+ channel (Kir6.2)-expressed proteins, cibenzoline binds directly to Kir6.2, unlike glibenclamide. Thus, KATPchannel inhibition by glibenclamide is impaired under the condition of decreased intracellular ATP in pancreatic β-cells, probably because of a defect in signal transmission between SUR1 and Kir6.2 downstream of the site of sulfonylurea binding to SUR1.

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