A crucial role of adenosine deaminase in regulating gluconeogenesis in mice.

Adenosine deaminase (ADA) catalyzes the irreversible deamination of adenosine (ADO) to inosine and regulates ADO concentration. ADA ubiquitously expresses in various tissues to mediate ADO-receptor signaling. A significant increase in plasma ADA activity has been shown to be associated with the pathogenesis of type 2 diabetes mellitus. Here, we show that elevated plasma ADA activity is a compensated response to high level of ADO in type 2 diabetes mellitus and plays an essential role in the regulation of glucose homeostasis. Supplementing with more ADA, instead of inhibiting ADA, can reduce ADO levels and decrease hepatic gluconeogenesis. ADA restores a euglycemic state and recovers functional islets in db/db and high-fat streptozotocin diabetic mice. Mechanistically, ADA catabolizes ADO and increases Akt and FoxO1 phosphorylation independent of insulin action. ADA lowers blood glucose at a slower rate and longer duration compared to insulin, delaying or blocking the incidence of insulinogenic hypoglycemia shock. Finally, ADA suppresses gluconeogenesis in fasted mice and insulin-deficient diabetic mice, indicating the ADA regulating gluconeogenesis is a universal biological mechanism. Overall, these results suggest that ADA is expected to be a new therapeutic target for diabetes.

Crosslinking ability of hydrolyzed distarch phosphate and its stabilizing effect on rehydrated sea cucumber.

Effective crosslinking among food constituents has the potential to enhance their overall quality. Distarch phosphate (DSP), a common food additive employed as a thickening agent, bears a pre-crosslinked oligosaccharide (PCO) moiety within its molecular structure. Once this moiety is released, its double reducing end has the potential to undergo crosslinking with amino-rich macromolecules through Maillard reaction. In this study, hydrolyzed distarch phosphate (HDSP) was synthesized, and spectroscopic analysis verified the presence of PCO within HDSP. Preliminary validation experiment showed that HDSP could crosslink chitosan to form a hydrogel and significant browning was also observed during the process. Furthermore, rehydrated sea cucumber (RSC) crosslinked with HDSP exhibited a more intact appearance, higher mechanical strength, better color profile, and increased water-holding capacity. This series of results have confirmed that HDSP is capable to crosslink amino-rich macromolecules and form more stable three-dimensional network.

Corrigendum to "Assessing pripherally inserted central catheter tip location in multiple postures: A case report" [Asia-Pacific J Oncol Nurs 10 (2023) 100238].

[This corrects the article DOI: 10.1016/j.apjon.2023.100238.].

High efficient preparation of low molecular weight galactomannan from Leucaena leucocephala galactomannan through the combination of hydrogen peroxide and oxalic acid.

Researchers have always been interested in polysaccharide degradation because of the increased biological activity and usability following degradation. In this work, low molecular weight galactomannan (LMW-GM) was produced through the degradation of galactomannan by H2O2 and oxalic acid (OA). The optimal reaction conditions were found by conducting the response surface optimization experiment based on single-factor experiment and kinetics analysis. Under these conditions, the LMW-GM yield was 69.48 ± 1.02 %. Ultimately, an analysis of the degradation process revealed that OA attacked GM indiscriminately, and H2O2 has a stronger effect on the removal of branched chains while degrading GM. Hence, the degradation steps were rearranged as H2O2 was added 20 min before OA at a constant total time. The LMW-GM yield was successfully increased to 76.49 ± 1.27 %. The goal of this work is hopefully to give a theoretical foundation for the low-cost preparation and industrial production of the degradation of galactomannan.

PER2/P65-driven glycogen synthase 1 transcription in macrophages modulates gut inflammation and pathogenesis of rectal prolapse.

Rectal prolapse in serious inflammatory bowel disease is caused by abnormal reactions of the intestinal mucosal immune system. The circadian clock has been implicated in immune defense and inflammatory responses, but the mechanisms by which it regulates gut inflammation remain unclear. In this study, we investigate the role of the rhythmic gene Period2 (Per2) in triggering inflammation in the rectum and its contribution to the pathogenesis of rectal prolapse. We report that Per2 deficiency in mice increased susceptibility to intestinal inflammation and resulted in spontaneous rectal prolapse. We further demonstrated that PER2 was essential for the transcription of glycogen synthase 1 by interacting with the NF-κB p65. We show that the inhibition of Per2 reduced the levels of glycogen synthase 1 and glycogen synthesis in macrophages, impairing the capacity of pathogen clearance and disrupting the composition of gut microbes. Taken together, our findings identify a novel role for Per2 in regulating the capacity of pathogen clearance in macrophages and gut inflammation and suggest a potential animal model that more closely resembles human rectal prolapse.

ATP-induced hypothermia improves burn injury and relieves burn pain in mice.

Thermal burn injury is a severe and life-threatening form of trauma that presents a significant challenge to clinical therapy. Therapeutic hypothermia has been shown to be beneficial in various human pathologies. Adenosine triphosphate (ATP) induces a hypothermic state that resembles hibernation-like suspended animation in mammals. This study investigates the potential protective role of ATP-induced hypothermia in thermal burn injury. Male C57BL/6 mice underwent a sham procedure or third-degree burn, and ATP-induced hypothermia was applied immediately or 1 h after burn injury. Our results show that ATP-induced hypothermia significantly improved burn depth progression and reduced collagen degradation. Moreover, hypothermia induced by ATP alleviated burn-induced hyperinflammatory responses and oxidative stress. Metabolomic profiling revealed that ATP-induced hypothermia reversed the shifts of metabolic profiles of the skin in burn mice. In addition, ATP-induced hypothermia relieved nociceptive and inflammatory pain, as observed in the antinociceptive test. Our findings suggest that ATP-induced hypothermia attenuates burn injury and provides new insights into first-aid therapy after thermal burn injury.

Assessing pripherally inserted central catheter tip location in multiple postures: A case report.

This report presents a case involving a 21-year-old male patient with acute promyelocytic leukemia, where the peripherally inserted central catheter (PICC) tip location was diagnosed differently using ultrasound and computed tomography. The PICC was inserted into the left upper arm via the basilic vein. Echocardiography performed in the left lateral recumbent position suggested the PICC tip to be in the right atrium, deepest at the level of the tricuspid annulus. However, trans-catheter contrast-enhanced echocardiography, performed with a different posture involving left shoulder abduction and slight external rotation, revealed the tip to be at the cavo-atrial junction. Additionally, chest computed tomography, conducted in the supine position with raised arms, indicated the tip to be located at the upper one-third of the superior vena cava. These contradictory diagnoses can be attributed to the use of different body postures during the assessments. Considering the clinical efficacy and safety, it is crucial to fully consider the influence of multiple postures on PICC tip location during placement and determination. We recommend incorporating at least two opposite extreme daily postures to assess the nearest and farthest positions of the tip, ensuring effective and safe PICC placement and reducing the risk of complications.

Circadian PER1 controls daily fat absorption with the regulation of PER1-PKA on phosphorylation of bile acid synthetase.

Several epidemiological studies suggest a correlation between eating time and obesity. Night eating syndrome characterized by a time-delayed eating pattern is positively associated with obesity in humans as well as in experimental animals. Here, we show that oil intake at night significantly makes more fat than that at day in wild-type mice, and circadian Period 1 (Per1) contributes to this day-night difference. Per1-knockout mice are protected from high-fat diet-induced obesity, which is accompanied by a reduction in the size of the bile acid pool, and the oral administration of bile acids restores fat absorption and accumulation. We identify that PER1 directly binds to the major hepatic enzymes involved in bile acid synthesis such as cholesterol 7alpha-hydroxylase and sterol 12alpha-hydroxylase. A biosynthesis rhythm of bile acids is accompanied by the activity and instability of bile acid synthases with PER1/PKA-mediated phosphorylation pathways. Both fasting and high fat stress enhance Per1 expression, increasing the fat absorption and accumulation. Our findings reveal that Per1 is an energy regulator and controls daily fat absorption and accumulation. Circadian Per1 controls daily fat absorption and accumulation, suggesting Per1 is a potential candidate of a key regulator in stress response and the relevant obesity risk.

Blood donation improves skin aging through the reduction of iron deposits and the increase of TGF-ß1 in elderly skin.

Skin aging is characterized by a wide range of physiological and structural changes, including wrinkling, dyschromia, and roughness, as well as the reduction of dermal thickness and collagen content. Here, we showed that blood donation increased dermal thickness and collagen content and decreased the number of senescent cells in old mice. Transcriptomic and metabolomic studies revealed blood donation significantly altered aging-related pathways in the skin of old mice. Molecular genes analysis indicated blood donation decreased the expression of genes associated with inflammation such as Fols1, Cox-2, and IL-1ß, and increased the expression of collagen-associated genes including TGF-ß1, TGF-ß2, and Col3a1. The improvement of skin aging by blood donation was associated with the reduction of iron deposits and the increase of TGF-ß1 in elderly skin. Our results suggested that appropriate blood donation could promote collagen re-synthesis and improve skin aging.

Riclin-Capped Silver Nanoparticles as an Antibacterial and Anti-Inflammatory Wound Dressing.

Purpose: In order to overcome the inflammatory response to bacterial infection during wound healing, we have fabricated an antibacterial and anti-inflammatory wound dressing based on polysaccharide riclin and silver nanoparticles (AgNPs). Methods: The riclin-AgNPs nanocomposite was developed by borohydride method and was characterized by UV-Vis, TEM, XRD, Zeta potential, DLS. In vitro, we assessed the cumulative release, antibacterial activities and cytotoxicity. In vivo, we examined the wound healing in mice wound infection experiment and inflammatory mediators using histological observations and gene expression analysis. Results: The riclin/AgNPs nanocomposite hydrogel exhibited nanosized orbicular particles with high purity and stability. In vitro, the riclin/AgNPs showed sustained release of AgNPs, effective suppression in pathogen growth and negligible toxicity toward mammalian fibroblasts and macrophage cells. In vivo, the riclin/AgNPs treatment leads to faster and smoother growth of fresh skin with suppressed expression of inflammatory mediators. Conclusion: The reported Riclin-AgNPs nanocomposite hydrogel showed both antibacterial and anti-inflammatory functions, which induce significantly accelerated wound healing, indicating great potential as a novel attractive wound dressing material.

Iron accumulation with age alters metabolic pattern and circadian clock gene expression through the reduction of AMP-modulated histone methylation.

Iron accumulates with age in mammals, and its possible implications in altering metabolic responses are not fully understood. Here, we report that both high-iron diet and advanced age in mice consistently altered gene expression of many pathways, including those governing the oxidative stress response and the circadian clock. We used a metabolomic approach to reveal similarities between metabolic profiles and the daily oscillation of clock genes in old and iron-overloaded mouse livers. In addition, we show that phlebotomy decreased iron accumulation in old mice, partially restoring the metabolic patterns and amplitudes of the oscillatory expression of clock genes Per1 and Per2. We further identified that the transcriptional regulation of iron occurred through a reduction in AMP-modulated methylation of histone H3K9 in the Per1 and H3K4 in the Per2 promoters, respectively. Taken together, our results indicate that iron accumulation with age can affect metabolic patterns and the circadian clock.

Dietary Succinoglycan Riclin Improves Glycemia Control in Mice with Type 2 Diabetes.

Riclin is a typical succinoglycan produced by an agrobacterium isolate. Our previous investigation has revealed that oral riclin restores the islet function in type 1 diabetic mice. However, whether dietary riclin improves glycemic control in type 2 diabetes (T2D) is unknown. Here, we found that dietary riclin (20 and 40 mg/kg) for 4 weeks significantly decreased fasting blood glucose (55 and 67%), improved insulin sensitivity, and decreased insulin resistance in high-fat-diet/streptozocin (HFD/STZ)-induced T2D. Riclin reduced the proportion of T helper 1 cell subsets in diabetic mice, alleviated pancreatic inflammation, and protected islet function. Moreover, dietary riclin enriched the diversity of gut microflora and restored the relative abundance of several bacterial genera in diabetes, including the strains of Clostridium, Parasutterella, Klebsiella, and Bacteroides. In db/db diabetic mice, riclin also improves glycemia control as observed in HFD/STZ-induced T2D mice. These data suggest that riclin has potential to be a functional food to treat T2D.

Safety assessment of functional oligooctasaccharide riclinoctaose: A pilot study of genotoxicity, acute toxicity, and subchronic toxicity.

Riclinoctaose was produced by enzymatic hydrolysis of a succinoglycan-type exopolysaccharide riclin. It can be used as a prebiotic to regulate the composition of gut microbiota. Therefore, a safety evaluation is needed. Here, we reported the safety data generated on riclinoctaose. Standard in vitro genotoxicity tests such as the bacterial reverse mutation assay and in vivo micronucleus assay were performed and no mutagenic or clastogenic potential was found. In the acute toxicity study, ICR mice were administered with riclinoctaose via gavage in 14-day studies at the level corresponding to 3000 mg/kg BW/day. In the subchronic study, the diets containing 0%, 1.0%, 2.5%, and 5.0% of riclinoctaose (weight/weight) were prepared for ICR mice for 13 weeks. No test item-related adverse effects were observed in the acute and subchronic studies. No riclinoctaose-induced differences in the overall health, body weight gain, food and water consumption, hematology, blood chemistry, gross pathology, histopathology, or animal death were observed. A no-observed-adverse-effect level of 8842 mg/kg BW/day for male and 9230 mg/kg BW/day for female mice was identified for riclinoctaose when administered for 13 weeks. In conclusion, these findings demonstrated the safety of riclinoctaose and indicated the possibility that riclinoctaose may be used as a functional food. PRACTICAL APPLICATION: Functional oligosaccharide is a low-calorie sweetener, which is beneficial to human health. Dietary riclinoctaose can improve intestinal health and understanding the safety of riclinoctaose is the first step to evaluate its potential use in functional food. Therefore, genotoxicity, acute toxicity, and subchronic toxicity of riclinoctaose were studied.

The suppression of pancreatic lipase-related protein 2 ameliorates experimental hepatic fibrosis in mice.

Quiescent hepatic stellate cells (HSCs) store vitamin A as lipid droplets in the cytoplasm. When activated, these cells lose vitamin A and exhibit an increased capacity for proliferation, mobility, contractility, and the synthesis of collagen and other components of the extracellular matrix. Our previous work demonstrated that the lipid hydrolytic gene pancreatic lipase-related protein 2 (mPlrp2) is involved in the hydrolysis of retinyl esters (REs) in the liver. Here, we showed that bile duct ligation (BDL)-induced liver injury triggered the conditional expression of mPlrp2 in livers and describe evidence of a strong relationship between the expression of mPlrp2 and Acta-2, a marker for activated HSCs. RNA interference targeting mPlrp2 inhibited HSC activation and ameliorated hepatic fibrosis induced by BDL in mice. Liver BDL markedly reduced the adenosine level and increased the ratio between S-adenosyl-L-methionine (SAM) and S-adenosyl-L-homocysteine (SAH). Chromatin immunoprecipitation (ChIP) analysis demonstrated an increase in trimethylated histone H3K4 at the mPlrp2 promoter in BDL mice, which was associated with the conditional expression of mPlrp2 in the liver. SAM, a well-known hepatoprotective substance, inhibited mPlrp2 expression and reduced RE hydrolysis in mice with hepatic fibrosis induced by chronic CCl4 treatment. Liver fibrosis induced by CCl4 or BDL was improved in Plrp2-/- mice. Our results reveal that mPlrp2 suppression is a potential approach for treating hepatic fibrosis.

Riclinoctaose Attenuates Renal Ischemia-Reperfusion Injury by the Regulation of Macrophage Polarization.

Renal ischemia-reperfusion injury is a major trigger of acute kidney injury and leads to permanent renal impairment, and effective therapies remain unresolved. Riclinoctaose is an immunomodulatory octasaccharide composed of glucose and galactose monomers. Here we investigated whether riclinoctaose protects against renal ischemia-reperfusion injury. In mice, pretreatment with riclinoctaose significantly improved renal function, structure, and the inflammatory response after renal ischemia-reperfusion. Flow cytometry analysis revealed that riclinoctaose inhibited ischemia-reperfusion-induced M1 macrophage polarization and facilitated M2 macrophage recruitment into the kidneys. In isolated mouse bone marrow-derived macrophages, pretreatment with riclinoctaose promoted the macrophage polarization toward M2-like phenotype. The inhibitor of Nrf-2/HO-1 brusatol diminished the effects of riclinoctaose on macrophage polarization. In mice, intravenous injection with riclinoctaose-pretreated bone marrow-derived macrophages also protected against renal ischemia-reperfusion injury. Fluorescence-labeled riclinoctaose specifically bound to the membrane of macrophages. Interfering with mDC-SIGN blocked the riclinoctaose function on M2 polarization of macrophages, consequently impairing the renoprotective effect of riclinoctaose. Our results revealed that riclinoctaose is a potential therapeutic agent in preventing renal ischemia-reperfusion injury.

The circular RNA circSLC7A11 functions as a mir-330-3p sponge to accelerate hepatocellular carcinoma progression by regulating cyclin-dependent kinase 1 expression.

BACKGROUND: Circular RNAs (circRNAs), which are endogenous non-coding RNAs, are associated with various biological processes including development, homeostatic maintenance, and pathological responses. Accumulating evidence has implicated non-coding RNAs in cancer progression, and the role of circRNAs in particular has drawn wide attention. However, circRNA expression patterns and functions in hepatocellular carcinoma (HCC) remain poorly understood. METHODS: CircRNA sequencing was performed to screen differentially expressed circRNAs in HCC. Northern blotting, quantitative real-time polymerase chain reaction, nucleocytoplasmic fractionation, and fluorescence in situ hybridization analyses were conducted to evaluate the expression and localization of circSLC7A11 in HCC tissues and cells. CircSLC7A11 expression levels were modified in cultured HCC cell lines to explore the association between the expression of circSLC7A11 and the malignant behavior of these cells using several cell-based assays. The modified cells were implanted into immunocompetent nude mice to assess tumor growth and metastasis in vivo. We applied bioinformatics methods, RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays to explore the mechanisms of circSLC7A11 in HCC. RESULTS: CircSLC7A11 (hsa_circ_0070975) was conserved and dramatically overexpressed in HCC tissues and cells. HCC patients showing high circSLC7A11 expression had worse prognoses. Our in vitro and in vivo experiments showed that circSLC7A11 markedly accelerated HCC progression and metastasis through the circSLC7A11/miR-330-3p/CDK1 axis. CONCLUSIONS: The acceleration of HCC progression and metastasis by circSLC7A11 through the circSLC7A11/miR-330-3p/CDK1 axis suggests that circSLC7A11 is a potential novel diagnostic and therapeutic target for HCC treatment.

The succinoglycan riclin restores beta cell function through the regulation of macrophages on Th1 and Th2 differentiation in type 1 diabetic mice.

Bacterial succinoglycan is found suitable as a viscosifying and emulsifying agent in the food industry. Riclin is a de-succinyl succinoglycan from an Agrobacterium isolate. Our previous study has revealed that riclin exerts special anti-inflammatory effects in vitro and in vivo. This study aims to determine the effects of riclin on preventing against immunological injury of beta cells in a type 1 diabetic model. We found that orally riclin effectively restores beta-cell function and improves the complications of streptozotocin (STZ)-induced diabetes. Riclin also reduces STZ-induced liver and kidney damage, and balances the inappropriate ratio of T helper type 1 cell (Th1)/type 2 cell (Th2) in the spleen and pancreatic draining lymph nodes of the STZ-induced diabetic mice. In a co-culture system with the islet ß cell MIN6 and macrophage RAW 264.7, riclin reduces the levels of IFN-γ and IL-1ß, protecting against STZ-caused MIN6 cell injury. We identified that riclin specifically binds to the membrane of macrophages and regulates the ratio of IL-10 and IL-12, thereby inhibiting the macrophage-mediated polarization of Th1 cells and promoting the differentiation of Th2 cells, which depends on the dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) receptor. Moreover, orally riclin significantly decreases the incidence of STZ-induced hyperglycemia (7.1% in riclin vs. 92.9% in STZ), and prevents autoimmune diabetes in non-obese diabetic (NOD) mice, with 87.5% of mice free of diabetes compared to 46.6% of the control mice. These results suggest that riclin has potential to be a functional food to prevent and improve autoimmune diabetes and related diseases.

[The role of adenine nucleotide and its metabolites in regulating the homeostasis of glucose and lipid metabolism].

Glucose and lipid metabolism is the most fundamental metabolic activity of higher organisms. This process is affected by both genetic polymorphisms and environmental factors. Excessive uptake and accumulation of lipids lead to obesity and disorder of glucose metabolic homeostasis characterized by insulin resistance and hyperglycemia, suggesting that the cross-regulation between lipid and glucose metabolism happens precisely at organ, cellular and molecular levels by known mechanisms. Adenine nucleotides and their metabolites have emerged as mediators in the mutual regulation of glucose and lipid metabolism. This review summarizes the roles of purinergic signaling induced by fatty acids in glucose metabolism and the development of type 2 diabetes.

Type 2 diabetic mice enter a state of spontaneous hibernation-like suspended animation following accumulation of uric acid.

Hibernation is an example of extreme hypometabolic behavior. How mammals achieve such a state of suspended animation remains unclear. Here we show that several strains of type 2 diabetic mice spontaneously enter into hibernation-like suspended animation (HLSA) in cold temperatures. Nondiabetic mice injected with ATP mimic the severe hypothermia analogous to that observed in diabetic mice. We identified that uric acid, an ATP metabolite, is a key molecular in the entry of HLSA. Uric acid binds to the Na+ binding pocket of the Na+/H+ exchanger protein and inhibits its activity, acidifying the cytoplasm and triggering a drop in metabolic rate. The suppression of uric acid biosynthesis blocks the occurrence of HLSA, and hyperuricemic mice induced by treatment with an uricase inhibitor can spontaneously enter into HLSA similar to that observed in type 2 diabetic mice. In rats and dogs, injection of ATP induces a reversible state of HLSA similar to that seen in mice. However, ATP injection fails to induce HLSA in pigs due to the lack of their ability to accumulate uric acid. Our results raise the possibility that nonhibernating mammals could spontaneously undergo HLSA upon accumulation of ATP metabolite, uric acid.

An insulin-independent mechanism for transcriptional regulation of Foxo1 in type 2 diabetic mice.

Hepatic gluconeogenesis is the major contributor to the hyperglycemia observed in both patients and animals with type 2 diabetes. The transcription factor FOXO1 plays a dominant role in stimulating hepatic gluconeogenesis. FOXO1 is mainly regulated by insulin under physiological conditions, but liver-specific disruption of Foxo1 transcription restores normal gluconeogenesis in mice in which insulin signaling has been blocked, suggesting that additional regulatory mechanisms exist. Understanding the transcriptional regulation of Foxo1 may be conducive to the development of insulin-independent strategies for the control of hepatic gluconeogenesis. Here, we found that elevated plasma levels of adenine nucleotide in type 2 diabetes are the major regulators of Foxo1 transcription. We treated lean mice with 5'-AMP and examined their transcriptional profiles using RNA-seq. KEGG analysis revealed that the 5'-AMP treatment led to shifted profiles that were similar to db/db mice. Many of the upregulated genes were in pathways associated with the pathology of type 2 diabetes including Foxo1 signaling. As observed in diabetic db/db mice, lean mice treated with 5'-AMP displayed enhanced Foxo1 transcription, involving an increase in cellular adenosine levels and a decrease in the S-adenosylmethionine to S-adenosylhomocysteine ratio. This reduced methylation potential resulted in declining histone H3K9 methylation in the promoters of Foxo1, G6Pc, and Pepck. In mouse livers and cultured cells, 5'-AMP induced expression of more FOXO1 protein, which was found to be localized in the nucleus, where it could promote gluconeogenesis. Our results revealed that adenine nucleotide-driven Foxo1 transcription is crucial for excessive glucose production in type 2 diabetic mice.