Consumption of Limosilactobacillus fermentum Inhibits Corneal Damage and Inflammation in Dry Eye Disease Mouse Model through Regulating the Gut Microbiome.

The present study investigated the effect of orally administered Limosilactobacillus fermentum HY7302 (HY7302) on the relationship between ocular tissue and the microbiome in a corneal injury dry eye mouse model. Specifically, 0.1% benzalkonium chloride (BAC) was applied to the ocular surface for 14 days to induce corneal injury in male Balb/c mice. During the BAC treatment period, HY7302 (1 × 108 CFU/kg/day or 1 × 109 CFU/kg/day) or an omega-3 positive control (400 mg/kg/day) were administered orally (n = eight/group). To examine the signaling pathways affected by the HY7302 treatment, the in vitro effects of HY7302 on the tight junctions and the inflammatory response were investigated in the mouse colon epithelial cell line, CMT-93. BAC exposure decreased tear production, induced ocular inflammation and corneal epithelial detachment, and altered the gut microbiota. However, oral administration of HY7302 restored tear secretion and decreased corneal epithelial detachment in BAC-treated corneal injury mice. Further, HY7302 alleviated corneal inflammation via modulation of matrix metalloproteinase-9 (MMP-9) expression and affeted alterations in gut microbiota composition. These findings suggest that the gut-eye axis interaction between gut microbiota and corneal tissue affects disease severity in corneal injury, and that the alteration of the microbiota by HY7302 could improve eye health by regulating the inflammatory response.

Lactiplantibacillus plantarum HY7718 Improves Intestinal Integrity in a DSS-Induced Ulcerative Colitis Mouse Model by Suppressing Inflammation through Modulation of the Gut Microbiota.

Inflammatory bowel disease (IBD), a chronic condition that causes persistent inflammation in the digestive system, is closely associated with the intestinal microbiome. Here, we evaluated the effects of Lactiplantibacillus plantarum HY7718 (HY7718) on IBD symptoms in mice with dextran sulfate sodium (DSS)-induced colitis. Oral administration of HY7718 led to significant improvement in the disease activity index score and the histological index, as well as preventing weight loss, in model mice. HY7718 upregulated the expression of intestinal tight junction (TJ)-related genes and downregulated the expression of genes encoding pro-inflammatory cytokines and genes involved in the TLR/MyD88/NF-κB signaling pathway. Additionally, HY7718 reduced the blood levels of pro-inflammatory cytokines, as well as reversing DSS-induced changes to the composition of the intestinal microbiome. HY7718 also increased the percentage of beneficial bacteria (Lactiplantibacillus and Bifidobacterium), which correlated positively with the expression of intestinal TJ-related genes. Finally, HY7718 decreased the population of pathogens such as Escherichia, which correlated with IBD symptoms. The data suggest that HY7718 improves intestinal integrity in colitis model mice by regulating the expression of TJ proteins and inflammatory cytokines, as well as the composition of the intestinal microflora. Thus, L. plantarum HY7718 may be suitable as a functional supplement that improves IBD symptoms and gut health.

Effect of HY7602 Fermented Deer Antler on Physical Fatigue and Antioxidant Activity in Mice.

Lactobacillus curvatus HY7602 fermented antler (FA) ameliorates sarcopenia and improves exercise performance by increasing muscle mass, muscle fiber regeneration, and mitochondrial biogenesis; however, its anti-fatigue and antioxidant effects have not been studied. Therefore, this study aimed to investigate the anti-fatigue and antioxidant effects and mechanisms of FA. C2C12 and HepG2 cells were stimulated with 1 mM of hydrogen peroxide (H2O2) to induce oxidative stress, followed by treatment with FA. Additionally, 44-week-old C57BL/6J mice were orally administered FA for 4 weeks. FA treatment (5-100 µg/mL) significantly attenuated H2O2-induced cytotoxicity and reactive oxygen species (ROS) production in both cell lines in a dose-dependent manner. In vivo experiments showed that FA treatment significantly increased the mobility time of mice in the forced swimming test and significantly downregulated the serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), creatine kinase (CK), and lactate. Notably, FA treatment significantly upregulated the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione/oxidized glutathione ratio (GSH/GSSG) and increased the mRNA expression of antioxidant genes (SOD1, SOD2, CAT, GPx1, GPx2, and GSR) in the liver. Conclusively, FA is a potentially useful functional food ingredient for improving fatigue through its antioxidant effects.

Lactobacillus fermentum HY7302 Improves Dry Eye Symptoms in a Mouse Model of Benzalkonium Chloride-Induced Eye Dysfunction and Human Conjunctiva Epithelial Cells.

(1) We investigated the effects of the Lactobacillus fermentum HY7302 (HY7302) in a mouse model of benzalkonium chloride (BAC)-induced dry eye, and the possibility of using HY7302 as a food supplement for preventing dry eye. (2) The ocular surface of Balb/c mice was exposed to 0.2% BAC for 14 days to induce dry eye (n = 8), and the control group was treated with the same amount of saline (n = 8). HY7302 (1 × 109 CFU/kg/day, 14 days, n = 8) was orally administered daily to the mice, and omega-3 (200 mg/kg/day) was used as a positive control. To understand the mechanisms by which HY7302 inhibits BAC-induced dry eye, we performed an in vitro study using a human conjunctival cell line (clone-1-5c-4). (3) The probiotic HY7302 improved the BAC-induced decreases in the corneal fluorescein score and tear break-up time. In addition, the lactic acid bacteria increased tear production and improved the detached epithelium. Moreover, HY7302 lowered the BAC-induced increases in reactive oxygen species production in a conjunctival cell line and regulated the expression of several apoptosis-related factors, including phosphorylated protein kinase B (AKT), B-cell lymphoma protein 2 (Bcl-2), and activated caspase 3. Also, HY7302 alleviated the expression of pro-inflammatory cytokines, such as interleukin-1ß (IL-1ß), IL-6, and IL-8, and also regulated the matrix metallopeptidase-9 production in the conjunctival cell line. (4) In this study, we showed that L. fermentum HY7302 helps prevent dry eye disease by regulating the expression of pro-inflammatory and apoptotic factors, and could be used as a new functional food composition to prevent dry eye disease.

Selective deletion of the endothelial sphingosine-1-phosphate 1 receptor exacerbates kidney ischemia-reperfusion injury.

The role for the endothelial sphingosine-1-phosphate 1 receptor (S1P1R) in acute kidney injury (AKI) remains unclear as germline endothelial S1P1R deletion is embryonically lethal. Here, we generated conditional endothelial S1P1R deficiency by crossing mice with floxed S1P1R with mice expressing a tamoxifen-inducible form of Cre recombinase under the transcriptional control of the platelet-derived growth factor-ß (Pdgfß) gene. Mice with tamoxifen-induced deletion of endothelial S1P1R had increased renal tubular necrosis, inflammation, and impaired vascular permeability, as well as exacerbated renal tubular apoptosis after ischemic AKI compared with tamoxifen-treated wild-type mice. Moreover, endothelial S1P1R deletion resulted in increased hepatic injury after ischemic AKI. As a potential mechanism for exacerbated renal injury, conditional endothelial S1P1R-null mice had markedly reduced endothelial HSP27 expression compared with wild-type mice. Cultured glomerular endothelial cells treated with a specific S1P1R antagonist (W146) for 3 days also showed reduced HSP27 expression compared with vehicle-treated cells. Finally, mice treated with W146 for 3 days also showed reduced endothelial HSP27 expression as well as exacerbated renal and hepatic injury after ischemic AKI. Thus, our studies demonstrate a protective role for endothelial S1P1R against ischemic AKI most likely by regulating endothelial barrier integrity and endothelial HSP27 expression.

Differential effects of low and high doses of lipoteichoic acid on lipopolysaccharide-induced interleukin-6 production.

OBJECTIVE: Interleukin-6 (IL-6), which is increased in patients who are suffering from septic shock, is an important mediator of the inflammatory response. Here, we examined the priming effect of lipoteichoic acid (LTA) and lipopolysaccharide (LPS) on IL-6 production in a monocyte-like cell line. METHODS: THP-1 cells were primed by treatingwith a low or high dose of LTA isolated from Staphylococcus aureus (aLTA) and then re-treated with LPS. IL-6 production, receptor expression, and the variation of signaling molecules were examined by ELISA, reverse transcriptase polymerase chain reaction, and western blotting, respectively. RESULTS: LPS-mediated IL-6 production was dramatically increased in THP-1 cells pretreated with a low dose aLTA, while it was significantly decreased when a high dose of aLTA was given along with LPS. LPS-induced IL-6 production in low dose aLTA priming cells mediated by NF-κB and MAPKs pathways, and Akt functioned as a negative regulator of IL-6 production. Together, the results of this study suggest that different doses of bacterial cell surface components can mediate a diverse range of responses with respect to inflammatory cytokine production.

Paneth cell-mediated multiorgan dysfunction after acute kidney injury.

Acute kidney injury (AKI) is frequently complicated by extrarenal multiorgan injury, including intestinal and hepatic dysfunction. In this study, we hypothesized that a discrete intestinal source of proinflammatory mediators drives multiorgan injury in response to AKI. After induction of AKI in mice by renal ischemia-reperfusion or bilateral nephrectomy, small intestinal Paneth cells increased the synthesis and release of IL-17A in conjunction with severe intestinal apoptosis and inflammation. We also detected significantly increased IL-17A in portal and systemic circulation after AKI. Intestinal macrophages appear to transport released Paneth cell granule constituents induced by AKI, away from the base of the crypts into the liver. Genetic or pharmacologic depletion of Paneth cells decreased small intestinal IL-17A secretion and plasma IL-17A levels significantly and attenuated intestinal, hepatic, and renal injury after AKI. Similarly, portal delivery of IL-17A in macrophage-depleted mice decreased markedly. In addition, intestinal, hepatic, and renal injury following AKI was attenuated without affecting intestinal IL-17A generation. In conclusion, AKI induces IL-17A synthesis and secretion by Paneth cells to initiate intestinal and hepatic injury by hepatic and systemic delivery of IL-17A by macrophages. Modulation of Paneth cell dysregulation may have therapeutic implications by reducing systemic complications arising from AKI.

Renalase protects against ischemic AKI.

Elevated levels of plasma catecholamines accompany ischemic AKI, possibly contributing the inflammatory response. Renalase, an amine oxidase secreted by the proximal tubule, degrades circulating catecholamines and reduces myocardial necrosis, suggesting that it may protect against renal ischemia reperfusion injury. Here, mice subjected to renal ischemia reperfusion injury had significantly lower levels of renalase in the plasma and kidney compared with sham-operated mice. Consistent with this, plasma NE levels increased significantly after renal ischemia reperfusion injury. Furthermore, renal tubular inflammation, necrosis, and apoptosis were more severe and plasma catecholamine levels were higher in renalase-deficient mice subjected to renal ischemia reperfusion compared with wild-type mice. Administration of recombinant human renalase reduced plasma catecholamine levels and ameliorated ischemic AKI in wild-type mice. Taken together, these data suggest that renalase protects against ischemic AKI by reducing renal tubular necrosis, apoptosis, and inflammation, and that plasma renalase might be a biomarker for AKI. Recombinant renalase therapy may have potential for the prevention and treatment of AKI.

IL-11 is required for A1 adenosine receptor-mediated protection against ischemic AKI.

A1 adenosine receptor activation ameliorates ischemic AKI through the induction of renal proximal tubular sphingosine kinase-1. However, systemic adverse effects may limit A1 adenosine receptor-based therapy for ischemic AKI, indicating a need to identify alternative therapeutic targets within this pathway. Here, we evaluated the function of renal proximal tubular IL-11, a clinically approved hematopoietic cytokine, in A1 adenosine receptor-mediated induction of sphingosine kinase-1 and renal protection. Treatment of human proximal tubule epithelial (HK-2) cells with a selective A1 adenosine receptor agonist, chloro-N(6)-cyclopentyladenosine (CCPA), induced the expression of IL-11 mRNA and protein in an extracellular signal-regulated kinase-dependent manner, and administration of CCPA in mice induced renal synthesis of IL-11. Pretreatment with CCPA protected against renal ischemia-reperfusion injury in wild-type mice, but not in IL-11 receptor-deficient mice. Administration of an IL-11-neutralizing antibody abolished the renal protection provided by CCPA. Similarly, CCPA did not induce renal IL-11 expression or protect against renal ischemia-reperfusion injury in mice lacking the renal proximal tubular A1 adenosine receptor. Finally, treatment with CCPA induced sphingosine kinase-1 in HK-2 cells and wild-type mice, but not in IL-11 receptor-deficient or renal proximal tubule A1 adenosine receptor-deficient mice. Taken together, these results suggest that induction of renal proximal tubule IL-11 is a critical intermediary in A1 adenosine receptor-mediated renal protection that warrants investigation as a novel therapeutic target for the treatment of ischemic AKI.

Critical role of interleukin-17A in murine intestinal ischemia-reperfusion injury.

Intestinal ischemia-reperfusion (I/R) injury causes severe illness frequently complicated by remote multiorgan dysfunction and sepsis. Recent studies implicated interleukin-17A (IL-17A) in regulating inflammation, autoimmunity, and I/R injury. Here, we determined whether IL-17A is critical for generation of intestinal I/R injury and subsequent liver and kidney injury. Mice subjected to 30 min of superior mesenteric artery ischemia not only developed severe small intestinal injury (necrosis, apoptosis, and neutrophil infiltration) but also developed significant renal and hepatic injury. We detected large increases in IL-17A in the small intestine, liver, and plasma. IL-17A is critical for generating these injuries, since genetic deletion of IL-17A- or IL-17A-neutralizing antibody treatment markedly protected against intestinal I/R injury and subsequent liver and kidney dysfunction. Intestinal I/R caused greater increases in portal plasma and small intestine IL-17A, suggesting an intestinal source for IL-17A generation. We also observed that intestinal I/R caused rapid small intestinal Paneth cell degranulation and induced murine α-defensin cryptdin-1 expression. Furthermore, genetic or pharmacological depletion of Paneth cells significantly attenuated the intestinal I/R injury as well as hepatic and renal dysfunction. Finally, Paneth cell depletion significantly decreased small intestinal, hepatic, and plasma IL-17A levels after intestinal I/R. Taken together, we propose that Paneth cell-derived IL-17A may play a critical role in intestinal I/R injury as well as extraintestinal organ dysfunction.

Critical role of interleukin-11 in isoflurane-mediated protection against ischemic acute kidney injury in mice.

BACKGROUND: Isoflurane releases renal tubular transforming growth factor-ß1 (TGF-ß1) and protects against ischemic acute kidney injury. Recent studies suggest that TGF-ß1 can induce a cytoprotective cytokine interleukin (IL)-11. In this study, the authors tested the hypothesis that isoflurane protects against ischemic acute kidney injury by direct induction of renal tubular IL-11 synthesis. METHODS: Human kidney proximal tubule cells were treated with 1.25-2.5% isoflurane or carrier gas (room air + 5% carbon dioxide) for 0-16 h. The authors also anesthetized C57BL/6 mice with 1.2% isoflurane or with equianesthetic dose of pentobarbital for 4 h. In addition, the authors subjected IL-11 receptor (IL-11R) wild-type, IL-11R-deficient, or IL-11 neutralized mice to 30-min renal ischemia followed by reperfusion under 4 h of anesthesia with pentobarbital or isoflurane (1.2%). RESULTS: Isoflurane increased IL-11 synthesis in human (approximately 300-500% increase, N = 6) and mouse (23 ± 4 [mean ± SD] fold over carrier gas group, N = 4) proximal tubule cells that were attenuated by a TGF-ß1-neutralizing antibody. Mice anesthetized with isoflurane showed significantly increased kidney IL-11 messenger RNA (13.8 ± 2 fold over carrier gas group, N = 4) and protein (31 ± 9 vs. 18 ± 2 pg/mg protein or approximately 80% increase, N = 4) expression compared with pentobarbital-anesthetized mice, and this increase was also attenuated by a TGF-ß1-neutralizing antibody. Furthermore, isoflurane-mediated renal protection in IL-11R wild-type mice was absent in IL-11R-deficient mice or in IL-11R wild-type mice treated with IL-11-neutralizing antibody (N = 4-6). CONCLUSION: In this study, the authors suggest that isoflurane induces renal tubular IL-11 via TGF-ß1 signaling to protect against ischemic acute kidney injury.

Lactobacillus helveticus HY7801 ameliorates bacterial vaginosis by inhibiting biofilm formation and epithelial cell adhesion of Gardnerella vaginalis.

Bacterial vaginosis (BV) is caused by a microbial imbalance in the vaginal ecosystem, which causes genital discomfort and a variety of potential complications in women. This study validated the potential of Lactobacillus helveticus HY7801 as a probiotic to benefit vaginal health. In vivo, HY7801 reduced the number of Gardnerella vaginalis (GV) and pro-inflammatory cytokines in the vagina of GV-induced BV mice and ameliorated vaginal histological changes. In vitro, HY7801 exhibited positive resistance to simulated gastrointestinal conditions, showed excellent adherence ability to the female genital epithelium, and had high lactic acid and H2O2 production capacity. Furthermore, it was found that HY7801 can alleviate BV because it can suppress the expression of virulence factor genes of GV involved in epithelial cell adhesion and biofilm formation along with antibacterial activity against GV. These results indicate that HY7801 can be used as a promising probiotic strain for the maintenance of a healthy vaginal physiological state. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-022-01208-7.

Effect of fermented red ginseng on gut microbiota dysbiosis- or immobilization stress-induced anxiety, depression, and colitis in mice.

Background: Red ginseng (RG) alleviates psychiatric disorders. Fermented red ginseng (fRG) alleviates stress-induced gut inflammation. Gut dysbiosis causes psychiatric disorders with gut inflammation. To understand the gut microbiota-mediated action mechanism of RG and fRG against anxiety/depression (AD), we investigated the effects of RG, fRG, ginsenoside Rd, and 20(S)-ß-D-glucopyranosyl protopanaxadiol (CK) on gut microbiota dysbiosis-induced AD and colitis in mice. Methods: Mice with AD and colitis were prepared by exposing to immobilization stress (IS) or transplanting the feces of patients with ulcerative colitis and depression (UCDF). AD-like behaviors were measured in the elevated plus maze, light/dark transition, forced swimming, and tail suspension tests. Results: Oral gavage of UCDF increased AD-like behaviors and induced neuroinflammation, gastrointestinal inflammation, and gut microbiota fluctuation in mice. Oral administration of fRG or RG treatment reduced UCDF-induced AD-like behaviors, hippocampal and hypothalamic IL-6 expression, and blood corticosterone level, whereas UCDF-suppressed hippocampal BDNF+NeuN+ cell population and dopamine and hypothalamic serotonin levels increased. Furthermore, their treatments suppressed UCDF-induced colonic inflammation and partially restored UCDF-induced gut microbiota fluctuation. Oral administration of fRG, RG, Rd, or CK also decreased IS-induced AD-like behaviors, blood IL-6 and corticosterone and colonic IL-6 and TNF-α levels, and gut dysbiosis, while IS-suppressed hypothalamic dopamine and serotonin levels increased. Conclusion: Oral gavage of UCDF caused AD, neuroinflammation, and gastrointestinal inflammation in mice. fRG mitigated AD and colitis in UCDF-exposed mice by the regulation of the microbiota-gut-brain axis and IS-exposed mice by the regulation of the hypothalamic-pituitary-adrenal axis.

Probiotic Properties and Safety Evaluation of Lactobacillus plantarum HY7718 with Superior Storage Stability Isolated from Fermented Squid.

The aim of this study was to identify new potential probiotics with improved storage stability and to evaluate their efficacy and safety. Sixty lactic acid bacteria strains were isolated from Korean traditional fermented foods, and their survival was tested under extreme conditions. Lactobacillus plantarum HY7718 (HY7718) showed the greatest stability during storage. HY7718 also showed a stable growth curve under industrial conditions. Whole genome sequencing revealed that the HY7718 genome comprises 3.26 Mbp, with 44.5% G + C content, and 3056 annotated Protein-coding DNA sequences (CDSs). HY7718 adhered to intestinal epithelial cells and was tolerant to gastric fluids. Additionally, HY7718 exhibited no hemolytic activity and was not resistant to antibiotics, confirming that it has probiotic properties and is safe for consumption. Additionally, we evaluated its effects on intestinal health using TNF-induced Caco-2 cells. HY7718 restored the expression of tight junction proteins such as zonular occludens (ZO-1, ZO-2), occludin (OCLN), and claudins (CLDN1, CLDN4), and regulated the expression of myosin light-chain kinase (MLCK), Elk-1, and nuclear factor kappa B subunit 1 (NFKB1). Moreover, HY7718 reduced the secretion of proinflammatory cytokines such as interleukin-6 (IL-6) and IL-8, as well as reducing the levels of peroxide-induced reactive oxygen species. In conclusion, HY7718 has probiotic properties, is safe, is stable under extreme storage conditions, and exerts positive effects on intestinal cells. These results suggest that L. plantarum HY7718 is a potential probiotic for use as a functional supplement in the food industry.

Lactobacillus casei and Its Supplement Alleviate Stress-Induced Depression and Anxiety in Mice by the Regulation of BDNF Expression and NF-κB Activation.

Stress-induced depression and anxiety (DA) are closely connected to gastrointestinal inflammation and dysbiosis, which can suppress brain-derived neurotrophic factor (BDNF) in the brain. Herein, we isolated the BDNF expression-inducing probiotics Lactobacillus casei HY2782 and Bifidobacterium lactis HY8002 in lipopolysaccharide-stimulated SH-SY5Y cells. Then, we investigated the effects of HY2782, HY8002, anti-inflammatory L-theanine, and their supplement (PfS, probiotics-fermented L-theanine-containing supplement) on DA in mice exposed to restraint stress (RS) or the fecal microbiota of patients with inflammatory bowel disease and depression (FMd). Oral administration of HY2782, HY8002, or L-theanine alleviated RS-induced DA-like behaviors. They also decreased RS-induced hippocampal interleukin (IL)-1ß and IL-6 levels, as well as NF-κB-positive cell numbers, blood corticosterone level, and colonic IL-1ß and IL-6 levels and NF-κB-positive cell numbers. L-theanine more potently suppressed DA-like behaviors and inflammation-related marker levels than probiotics. However, these probiotics more potently increased RS-suppressed hippocampal BDNF level and BDNF+NeuN+ cell numbers than L-theanine. Furthermore, HY2782 and HY8002 suppressed RS-increased Proteobacteria and Verrucomicrobia populations in gut microbiota. In particular, they increased Lachnospiraceae and Lactobacillacease populations, which are closely positively associated with hippocampal BDNF expression, and suppressed Sutterellaceae, Helicobacteriaceae, Akkermansiaceae, and Enterobacteriaceae populations, which are closely positively associated with hippocampal IL-1ß expression. HY2782 and HY8002 potently alleviated FMd-induced DA-like behaviors and increased FMd-suppressed BDNF, serotonin levels, and BDNF-positive neuronal cell numbers in the brain. They alleviated blood corticosterone level and colonic IL-1ß α and IL-6 levels. However, L-theanine weakly, but not significantly, alleviated FMd-induced DA-like behaviors and gut inflammation. BDNF expression-inducing probiotic (HY2782, HY8002, Streptococcus thermophilus, and Lactobacillus acidophilus)-fermented and anti-inflammatory L-theanine-containing supplement PfS alleviated DA-like behaviors, inflammation-related biomarker levels, and gut dysbiosis more than probiotics or L-theanine. Based on these findings, a combination of BDNF expression-inducing probiotics with anti-inflammatory L-theanine may additively or synergistically alleviate DA and gut dysbiosis by regulating gut microbiota-mediated inflammation and BDNF expression, thereby being beneficial for DA.

Lactobacillus helveticus Isolated from Raw Milk Improves Liver Function, Hepatic Steatosis, and Lipid Metabolism in Non-Alcoholic Fatty Liver Disease Mouse Model.

Here, we show that Lactiplantibacillus plantarum LP158 (LP158), Lactobacillus helveticus HY7804 (HY7804), and Lacticaseibacillus paracasei LPC226 (LPC226) isolated from raw milk alleviate non-alcoholic fatty acid disease (NAFLD) in a C57BL/6 mouse model. Lactic acid bacteria (LAB) were screened for their ability to inhibit fatty acid accumulation in palmitic acid (PA)-treated HepG2 cells, and three strains were selected based on the results. We also investigated hemolytic activity and antibiotic resistance of the three strains. LP158, HY7804, and LPC226 suppressed expression of mRNA encoding genes related to lipogenesis, and increased expression of genes related to ß-oxidation, in a PA-induced HepG2 cell model. Moreover, when LP158, HY7804, and LPC226 were administered at 109 CFU/kg/day for 8 weeks to mice with dietary-induced NAFLD, they all modulated blood biochemistry markers and reduced steatosis in liver tissue. Also, all three strains significantly reduced expression of mRNA encoding lipogenesis genes (Fasn, Acaca, and Srebp-1c) and inflammatory factors (Tnfα and Ccl-2) and fibrosis factors, and increased expression of a ß-oxidation gene (Acox1) in the liver. In particular, HY7804 showed the strongest effects both in vitro and in vivo. Therefore, HY7804, LP158, and LPC226 can be proposed as potential supplements that can improve NAFLD through anti-steatosis, anti-inflammatory, and anti-fibrotic effects.

Corrigendum to 'Effect of fermented red ginseng on gut microbiota dysbiosis- or immobilization stress-induced anxiety, depression, and colitis in mice'[Journal of Ginseng Research Volume 47, Issue 2, March 2023, Pages 255-264].

[This corrects the article DOI: 10.1016/j.jgr.2022.08.004.].

A1 adenosine receptor allosteric enhancer PD-81723 protects against renal ischemia-reperfusion injury.

Activation of A(1) adenosine receptors (ARs) protects against renal ischemia-reperfusion (I/R) injury by reducing necrosis, apoptosis, and inflammation. However, extrarenal side effects (bradycardia, hypotension, and sedation) may limit A(1)AR agonist therapy for ischemic acute kidney injury. Here, we hypothesized that an allosteric enhancer for A(1)AR (PD-81723) protects against renal I/R injury without the undesirable side effects of systemic A(1)AR activation by potentiating the cytoprotective effects of renal adenosine generated locally by ischemia. Pretreatment with PD-81723 produced dose-dependent protection against renal I/R injury in A(1)AR wild-type mice but not in A(1)AR-deficient mice. Significant reductions in renal tubular necrosis, neutrophil infiltration, and inflammation as well as tubular apoptosis were observed in A(1)AR wild-type mice treated with PD-81723. Furthermore, PD-81723 decreased apoptotic cell death in human proximal tubule (HK-2) cells in culture, which was attenuated by a specific A(1)AR antagonist (8-cyclopentyl-1,3-dipropylxanthine). Mechanistically, PD-81723 induced sphingosine kinase (SK)1 mRNA and protein expression in HK-2 cells and in the mouse kidney. Supporting a critical role of SK1 in A(1)AR allosteric enhancer-mediated renal protection against renal I/R injury, PD-81723 failed to protect SK1-deficient mice against renal I/R injury. Finally, proximal tubule sphingosine-1-phosphate type 1 receptors (S1P(1)Rs) are critical for PD-81723-induced renal protection, as mice selectively deficient in renal proximal tubule S1P(1)Rs (S1P(1)R(flox/flox) PEPCK(Cre/-) mice) were not protected against renal I/R injury with PD-81723 treatment. Taken together, our experiments demonstrate potent renal protection with PD-81723 against I/R injury by reducing necrosis, inflammation, and apoptosis through the induction of renal tubular SK1 and activation of proximal tubule S1P(1)Rs. Our findings imply that selectively enhancing A(1)AR activation by locally produced renal adenosine may be a clinically useful therapeutic option to attenuate ischemic acute kidney injury without systemic side effects.

3-O-acetyloleanolic acid induces apoptosis in human colon carcinoma HCT-116 cells.

The cytotoxic effect of 3-O-acetyloleanolic acid, an oleanolic acid derivative isolated from the seeds of Vigna sinensis K., was investigated in human colon carcinoma HCT-116 cells. 3-O-acetyloleanolic acid dose-dependently inhibited the viability of HCT-116 cells. Apoptosis was characterized by detection of cell surface annexin V and sub-G1 apoptotic cell populations. The number of immunostained cells with annexin V-FITC was increased after treatment with 3-O-acetyloleanolic acid. The sub-G1 cell population was also increased. Expression of TRAIL-mediated apoptosis signaling-related death receptor DR5 was increased in 3-O-acetyloleanolic acid-treated HCT-116 cells. Activation of caspase-8 and caspase-3, critical mediators of extrinsic apoptosis signaling, was also increased by 3-O-acetyloleanolic acid. The results indicate that 3-O-acetyloleanolic acid induces apoptosis in HCT-116 cells mediated by an extrinsic apoptosis signaling cascade via up-regulation of DR5.

The Probiotic Strain Bifidobacterium animalis ssp. lactis HY8002 Potentially Improves the Mucosal Integrity of an Altered Intestinal Microbial Environment.

Intestinal microbiota mediate the development and regulation of the intestinal immune system either directly or indirectly. Particularly, Bifidobacterium spp. play an important role in regulating the intestinal immunity and intestinal barrier. We demonstrated that Bifidobacterium animalis ssp. lactis HY8002, selected from eight Bifidobacterium strains by in vitro experimentation, had exceptional resistance to digestive tract conditions and high adhesion to intestinal epithelial cells and a positive effect on immunoglobulin A (IgA) secretion by Peyer's patch cells. Moreover, HY8002 restored the expression of tight junction-related genes, initially reduced by lipopolysaccharide treatment, to normal levels in human intestinal epithelial cells. Notably, HY8002 restored kanamycin-induced reduction in Peyer's patch cell numbers, serum and fecal IgA levels, and zonula occludens 1 and Toll-like receptor 2 levels in the mouse small intestine. In addition, HY8002 restores microbiome composition disturbed by kanamycin, and these microbiome changes have been found to correlate with TLR2 levels in the small intestine. Moreover, the ability of HY8002 to enhance IgA in Peyer's patch cells and ZO-1 levels in intestinal epithelial cells was significantly inhibited by a TLR2 blocking antibody, which suggests that the HY8002 improve intestinal barrier function via TLR2. Finally, whole-genome sequencing of HY8002 revealed that it did not possess any known virulence factors. Therefore, HY8002 is a promising, functional probiotic supplement to improve intestinal barrier function by improving intestinal immunity and microbiota balance.