Angiogenesis and Apoptosis: Data Comparison of Similar Microenvironments in the Corpus Luteum and Tumors.

The corpus luteum is a temporary endocrine gland formed in the ovary after ovulation, and it plays a critical role in animal reproductive processes. Tumors rely on the development of an adequate blood supply to ensure the delivery of nutrients and oxygen and the removal of waste products. While angiogenesis occurs in various physiological and pathological contexts, the corpus luteum and tumors share similarities in terms of the signaling pathways that promote angiogenesis. In the corpus luteum and tumors, apoptosis plays a crucial role in controlling cell numbers and ensuring proper tissue development and function. Interestingly, there are similarities between the apoptotic-regulated signaling pathways involved in apoptosis in the corpus luteum and tumors. However, the regulation of apoptosis in both can differ due to their distinct physiological and pathological characteristics. Thus, we reviewed the biological events of the corpus luteum and tumors in similar microenvironments of angiogenesis and apoptosis.

Podocyte Disease Following Treatment with Intravenous Ibandronate in an Older Patient.

Bisphosphonates are commonly used to treat osteoporosis. While renal toxicity is common with pamidronate and zoledronate, few ibandronate-related cases are reported. We describe a rare case of ibandronate-associated nephrotoxicity. An 88-year-old woman was admitted for edema. She had been receiving intravenous ibandronate treatment for postmenopausal osteoporosis and had no other diagnosed diseases. She was presented with proteinuria, hypoalbuminemia (1.9 g/dL), and an elevated serum creatinine level (1.8 mg/dL). Renal biopsy revealed podocyte disease, favoring a diagnosis of focal segmental glomerulosclerosis. She was treated with diuretics, tacrolimus, and fimasartan. Steroids were avoided due to severe osteoporosis. Three months later, the edema had subsided and the laboratory findings had improved (serum albumin 3.5 g/dL, serum creatinine 0.97 mg/dL). This case emphasizes the importance of careful monitoring of proteinuria and renal function during ibandronate treatment. In older adult patients, kidney biopsy and immunosuppressive treatment may be considered based on physical activity and underlying diseases.

Hermetia illucens Fermented with Lactobacillus plantarum KCCM12757P Alleviates Dextran Sodium Sulfate-Induced Colitis in Mice.

Inflammatory bowel disease (IBD) can severely affect humans and animals and is difficult to treat. Black soldier fly (Hermetia illucens; Hi) larvae (BSFL) are a sustainable source of protein. However, no studies exist on the antioxidant and anti-inflammatory functions of BSFL or fermented BSFL with respect to IBD. In this study, riboflavin-producing Lactobacillus plantarum KCCM12757P was isolated from a fish farm tank, and in conjunction with hot water-extracted Hi (HeHi) (termed HeHi_Lp), was used to determine optimal fermentation conditions to increase vitamin B2 concentration. This in vivo study investigated the therapeutic effects and mechanistic role of HeHi_Lp in chronic colitis-induced murine models. Histological changes, inflammatory cytokine levels, and intestinal barrier function were explored. Gut microbial communities and gene expression in the nuclear factor (NF)-κB signaling pathway were also studied. HeHi_Lp remarkably reduced the disease activity index, inflammatory cytokine (inducible nitric oxide synthase, cyclooxygenase 2, tumor necrosis factor α, interleukin (IL-6 and IL-1ß) levels, and increased body weight and colon length. HeHi_Lp administration significantly raised zonula occludens 1, occludin and claudin 1 and improved the composition of the gut microbiota and beneficial intestinal bacteria. These results suggest that HeHi_Lp can be used as a dietary supplement in pet food to alleviate colitis.

Renoprotective Effect of Chrysanthemum coronarium L. Extract on Adenine-Induced Chronic Kidney Disease in Mice.

Chronic kidney disease (CKD) gradually leads to loss of renal function and is associated with inflammation and fibrosis. Chrysanthemum coronarium L., a leafy vegetable, possesses various beneficial properties, including anti-oxidative, anti-inflammatory, and antiproliferative effects. In this study, we investigated the renoprotective effect of Chrysanthemum coronarium L. extract (CC) on adenine (AD)-induced CKD in mice. CKD was induced by feeding mice with an AD diet (0.25% w/w) for 4 weeks. Changes in renal function, histopathology, inflammation, and renal interstitial fibrosis were analyzed. The adenine-fed mice were characterized by increased blood urea nitrogen, serum creatinine, and histological changes, including inflammation and fibrosis; however, these changes were significantly restored by treatment with CC. Additionally, CC inhibited the expression of the inflammatory markers, monocyte chemoattractant protein-1, interleukins-6 and -1ß, intercellular adhesion molecule-1, and cyclooxygenase 2. Moreover, CC suppressed the expression of the fibrotic markers, type IV collagen, and fibronectin. Furthermore, CC attenuated the expression of profibrotic genes (tumor growth factor-ß and α-smooth muscle actin) in AD-induced renal injury mice. Thus, our results suggest that CC has the potential to attenuate AD-induced renal injury and might offer a new option as a renoprotective agent or functional food supplement to manage CKD.

Efficacy and safety of Kumpe access catheter for pre-percutaneous nephrolithotomy renal access in modified supine percutaneous nephrolithotomy.

INTRODUCTION: Traditionally, a pigtail catheter (PCN) is placed for preoperative renal access before performing percutaneous nephrolithotomy (PCNL). However, PCN can hamper the passage of the guidewire to the ureter, due to which, access tract can be lost. Therefore, Kumpe Access Catheter (KMP) has been proposed for preoperative renal access before PCNL. In this study, we analyzed the efficacy and safety of KMP for surgical outcomes in modified supine PCNL compared to those in PCN. MATERIALS AND METHODS: From July 2017 to December 2020, 232 patients underwent modified supine PCNL at a single tertiary center, of which 151 patients were enrolled in this study after excluding patients who underwent bilateral surgery, multiple punctures, or combined operations. Enrolled patients were divided into two groups according to the type of pre-PCNL nephrostomy catheter used: PCN versus KMP. A pre-PCNL nephrostomy catheter was selected based on the radiologist's preference. A single surgeon performed all PCNL procedures. Patient characteristics and surgical outcomes, including stone-free rate, operation time, radiation exposure time (RET), and complications, were compared between the two groups. RESULTS: Of the 151 patients, 53 underwent PCN placement, and 98 underwent KMP placement for pre-PCNL nephrostomy. Patient baseline characteristics were comparable between the two groups, except for the renal stone type and multiplicity. The operation time, stone-free rate, and complication rate were not significantly different between the two groups; however, RET was significantly shorter in the KMP group. CONCLUSION: The surgical outcomes of KMP placement were comparable to those of PCN and showed shorter RET during modified supine PCNL. Based on our results, we recommend KMP placement for pre-PCNL nephrostomy, particularly for reducing RET during supine PCNL.

CrebH protects against liver injury associated with colonic inflammation via modulation of exosomal miRNA.

BACKGROUND: Hepatic liver disease, including primary sclerosing cholangitis (PSC), is a serious extraintestinal manifestations of colonic inflammation. Cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CrebH) is a transcription factor expressed mostly in the liver and small intestine. However, CrebH's roles in the gut-liver axis remain unknown. METHODS: Inflammatory bowel disease (IBD) and PSC disease models were established in wild-type and CrebH-/- mice treated with dextran sulfate sodium, dinitrobenzene sulfonic acid, and diethoxycarbonyl dihydrocollidine diet, respectively. RNA sequencing were conducted to investigate differential gene expression. Exosomes were isolated from plasma and culture media. miRNA expression profiling was performed using the NanoString nCounter Mouse miRNA Panel. Effects of miR-29a-3p on adhesion molecule expression were investigated in bEnd.3 brain endothelial cells. RESULTS: CrebH-/- mice exhibited accelerated liver injury without substantial differences in the gut after administration of dextran sulfate sodium (DSS), and had similar features to PSC, including enlarged bile ducts, enhanced inflammation, and aberrant MAdCAM-1 expression. Furthermore, RNA-sequencing analysis showed that differentially expressed genes in the liver of CrebH-/- mice after DSS overlapped significantly with genes changed in PSC-liver. Analysis of plasma exosome miRNA isolated from WT and CrebH-/- mice indicates that CrebH can contribute to the exosomal miRNA profile. We also identified miR-29a-3p as an effective mediator for MAdCAM-1 expression. Administration of plasma exosome from CrebH-/- mice led to prominent inflammatory signals in the liver of WT mice with inflammatory bowel disease (IBD). CONCLUSIONS: CrebH deficiency led to increased susceptibility to IBD-induced liver diseases via enhanced expression of adhesion molecules and concomitant infiltration of T lymphocytes. Exosomes can contribute to the progression of IBD-induced liver injury in CrebH-/- mice. These study provide novel insights into the role of CrebH in IBD-induced liver injury.

Effect of Menaquinone-4 on Receptor Activator of Nuclear Factor κB Ligand-Induced Osteoclast Differentiation and Ovariectomy-Induced Bone Loss.

Osteoporosis is a progressive metabolic disease characterized by decreased bone mineral density and increased fracture risk. Previous studies have shown that higher intake of vitamin K (VK) correlates with a reduced risk of osteoporosis. However, the effect of menaquinone-4 (MK-4), a specific form of VK, still remains obscure. Therefore, in this study, we investigated the effects of MK-4 on osteoclast differentiation by differentiating RAW 264.7 cells into osteoclasts with the help of receptor activator of nuclear factor-kappa B ligand (RANKL), assessed the mRNA expression of osteoclast-specific genes, and studied the effects of MK-4 in vivo in ovariectomized mice, a postmenopausal osteoporosis murine model. MK-4 inhibited osteoclast differentiation, decreased the mRNA expression of nuclear factor of activated T cells c1 (NFATc1), osteoclast-associated receptor (OSCAR), and cathepsin K (CTSK), and inhibited bone loss in ovariectomized mice. The findings strongly suggest that MK-4 is a therapeutic alternative for postmenopausal osteoporosis.

Targeting ERRα promotes cytotoxic effects against acute myeloid leukemia through suppressing mitochondrial oxidative phosphorylation.

Acute myeloid leukemia (AML) is an aggressive blood cancer with poor clinical outcomes. Emerging data suggest that mitochondrial oxidative phosphorylation (mtOXPHOS) plays a significant role in AML tumorigenesis, progression, and resistance to chemotherapies. However, how the mtOXPHOS is regulated in AML cells is not well understood. In this study, we investigated the oncogenic functions of ERRα in AML by combining in silico, in vitro, and in vivo analyses and showed ERRα is a key regulator of mtOXPHOS in AML cells. The increased ERRα level was associated with worse clinical outcomes of AML patients. Single cell RNA-Seq analysis of human primary AML cells indicated that ERRα-expressing cancer cells had significantly higher mtOXPHOS enrichment scores. Blockade of ERRα by pharmacologic inhibitor (XCT-790) or gene silencing suppressed mtOXPHOS and increased anti-leukemic effects in vitro and in xenograft mouse models.

Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors.

In an effort to discover novel scaffolds of non-nucleotide-derived Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors to stimulate the Stimulator of Interferon Genes (STING) pathway, we designed and synthesised pyrrolopyrimidine and pyrrolopyridine derivatives and performed structure-activity relationship (SAR) study. We found 18p possessed high potency (IC50 = 25.0 nM) against ENPP1, and activated STING pathway in a concentration dependent manner. Also, in response to STING pathway activation, cytokines such as IFN-ß and IP-10 were induced by 18p in a concentration dependent manner. Finally, we discovered that 18p causes inhibition of tumour growth in 4T1 syngeneic mouse model. This study provides new insight into the designing of novel ENPP1 inhibitors and warrants further development of small molecule immune modulators for cancer immunotherapy.

Risk Factors for Postoperative Pneumonia in the Elderly Following Hip Fracture Surgery: A Systematic Review and Meta-Analysis.

Introduction: Pneumonia is a serious complication following hip fracture surgery in older people. However, the prevalence and risk factors of postoperative pneumonia (POP) are not well-established. This study identified pre- and peri-operative factors associated with the development of POP following hip fracture surgery. Methods: We searched the Cochrane library, PubMed, and Embase databases for relevant articles published up to June 2021. Studies involving older patients who underwent hip fracture surgery were considered if they detailed the demographic or surgical characteristics of the participants. For all analyses, the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results: A total of 24 studies (288819 participants) were included. The overall prevalence of POP following hip fracture surgery was 5.0%. There were 36 risk factors for POP, and the meta-analysis included the five most common: delayed surgery (OR: 1.84, 95% CI: 1.29-2.63), low serum albumin (OR: 2.34, 95% CI: .82-6.73), chronic respiratory diseases (OR: 2.42, 95% CI: 1.82-3.24), increased age (OR: 1.25, 95% CI:1.11-1.40), and male sex (OR: 2.22, 95% CI: 2.00-2.47). Conclusions: The prevalence of POP was 5.0% following hip fracture surgery in the elderly. Older age, male sex, chronic respiratory diseases, delayed surgery, and low serum albumin were significant risk factors. Clinicians treating hip fracture patients must remain be aware of these risk factors.

Chemical modulation of SQSTM1/p62-mediated xenophagy that targets a broad range of pathogenic bacteria.

The N-degron pathway is a proteolytic system in which the N-terminal degrons (N-degrons) of proteins, such as arginine (Nt-Arg), induce the degradation of proteins and subcellular organelles via the ubiquitin-proteasome system (UPS) or macroautophagy/autophagy-lysosome system (hereafter autophagy). Here, we developed the chemical mimics of the N-degron Nt-Arg as a pharmaceutical means to induce targeted degradation of intracellular bacteria via autophagy, such as Salmonella enterica serovar Typhimurium (S. Typhimurium), Escherichia coli, and Streptococcus pyogenes as well as Mycobacterium tuberculosis (Mtb). Upon binding the ZZ domain of the autophagic cargo receptor SQSTM1/p62 (sequestosome 1), these chemicals induced the biogenesis and recruitment of autophagic membranes to intracellular bacteria via SQSTM1, leading to lysosomal degradation. The antimicrobial efficacy was independent of rapamycin-modulated core autophagic pathways and synergistic with the reduced production of inflammatory cytokines. In mice, these drugs exhibited antimicrobial efficacy for S. Typhimurium, Bacillus Calmette-Guérin (BCG), and Mtb as well as multidrug-resistant Mtb and inhibited the production of inflammatory cytokines. This dual mode of action in xenophagy and inflammation significantly protected mice from inflammatory lesions in the lungs and other tissues caused by all the tested bacterial strains. Our results suggest that the N-degron pathway provides a therapeutic target in host-directed therapeutics for a broad range of drug-resistant intracellular pathogens.Abbreviations: ATG: autophagy-related gene; BCG: Bacillus Calmette-Guérin; BMDMs: bone marrow-derived macrophages; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CFUs: colony-forming units; CXCL: C-X-C motif chemokine ligand; EGFP: enhanced green fluorescent protein; IL1B/IL-1ß: interleukin 1 beta; IL6: interleukin 6; LIR: MAP1LC3/LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; OPTN: optineurin; PB1: Phox and Bem1; SQSTM1/p62: sequestosome 1; S. Typhimurium: Salmonella enterica serovar Typhimurium; TAX1BP1: Tax1 binding protein 1; TNF: tumor necrosis factor; UBA: ubiquitin-associated.

Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice.

BACKGROUND: Mitochondrial oxidative phosphorylation (OxPhos) is a critical regulator of skeletal muscle mass and function. Although muscle atrophy due to mitochondrial dysfunction is closely associated with bone loss, the biological characteristics of the relationship between muscle and bone remain obscure. We showed that muscle atrophy caused by skeletal muscle-specific CR6-interacting factor 1 knockout (MKO) modulates the bone marrow (BM) inflammatory response, leading to low bone mass. METHODS: MKO mice with lower muscle OxPhos were fed a normal chow or high-fat diet and then evaluated for muscle mass and function, and bone mineral density. Immunophenotyping of BM immune cells was also performed. BM transcriptomic analysis was used to identify key factors regulating bone mass in MKO mice. To determine the effects of BM-derived CXCL12 (C-X-C motif chemokine ligand 12) on regulation of bone homeostasis, a variety of BM niche-resident cells were treated with recombinant CXCL12. Vastus lateralis muscle and BM immune cell samples from 14 patients with hip fracture were investigated to examine the association between muscle function and BM inflammation. RESULTS: MKO mice exhibited significant reductions in both muscle mass and expression of OxPhos subunits but increased transcription of mitochondrial stress response-related genes in the extensor digitorum longus (P < 0.01). MKO mice showed a decline in grip strength and a higher drop rate in the wire hanging test (P < 0.01). Micro-computed tomography and von Kossa staining revealed that MKO mice developed a low mass phenotype in cortical and trabecular bone (P < 0.01). Transcriptomic analysis of the BM revealed that mitochondrial stress responses in skeletal muscles induce an inflammatory response and adipogenesis in the BM and that the CXCL12-CXCR4 (C-X-C chemokine receptor 4) axis is important for T-cell homing to the BM. Antagonism of CXCR4 attenuated BM inflammation and increased bone mass in MKO mice. In humans, patients with low body mass index (BMI = 17.2 ± 0.42 kg/m2 ) harboured a larger population of proinflammatory and cytotoxic senescent T-cells in the BMI (P < 0.05) and showed reduced expression of OxPhos subunits in the vastus lateralis, compared with controls with a normal BMI (23.7 ± 0.88 kg/m2 ) (P < 0.01). CONCLUSIONS: Defects in muscle mitochondrial OxPhos promote BM inflammation in mice, leading to decreased bone mass. Muscle mitochondrial dysfunction is linked to BM inflammatory cytokine secretion via the CXCL12-CXCR4 signalling axis, which is critical for inducing low bone mass.

Effect of Peptide Receptor Radionuclide Therapy in Combination with Temozolomide against Tumor Angiogenesis in a Glioblastoma Model.

Cell adhesion receptor integrin αvß3 is a promising biomarker for developing tumor-angiogenesis targeted theranostics. In this study, we aimed to examine the therapeutic potential of peptide receptor radionuclide therapy (PRRT) with 188Re-IDA-D-[c(RGDfK)]2 (11.1 MBq). The results showed that the tumor volume was significantly decreased by 81% compared with the vehicle-treated group in U87-MG xenografts. The quantitative in vivo anti-angiogenic responses of PRRT were obtained using 99mTc-IDA-D-[c(RGDfK)]2 SPECT and corresponded to the measured tumor volume. PRRT combined with temozolomide (TMZ) resulted in a 93% reduction in tumor volume, which was markedly greater than that of each agent used individually. In addition, histopathological characterization showed that PRRT combined with TMZ was superior to PRRT or TMZ alone, even when TMZ was used at half dose. Overall, our results indicated that integrin-targeted PRRT and TMZ combined therapy might be a new medical tool for the effective treatment of glioblastoma.

Mitofusin-2 boosts innate immunity through the maintenance of aerobic glycolysis and activation of xenophagy in mice.

Mitochondrial function and innate immunity are intimately linked; however, the mechanisms how mitochondrion-shaping proteins regulate innate host defense remains largely unknown. Herein we show that mitofusin-2 (MFN2), a mitochondrial fusion protein, promotes innate host defense through the maintenance of aerobic glycolysis and xenophagy via hypoxia-inducible factor (HIF)-1α during intracellular bacterial infection. Myeloid-specific MFN2 deficiency in mice impaired the antimicrobial and inflammatory responses against mycobacterial and listerial infection. Mechanistically, MFN2 was required for the enhancement of inflammatory signaling through optimal induction of aerobic glycolysis via HIF-1α, which is activated by mitochondrial respiratory chain complex I and reactive oxygen species, in macrophages. MFN2 did not impact mitophagy during infection; however, it promoted xenophagy activation through HIF-1α. In addition, MFN2 interacted with the late endosomal protein Rab7, to facilitate xenophagy during mycobacterial infection. Our findings reveal the mechanistic regulations by which MFN2 tailors the innate host defense through coordinated control of immunometabolism and xenophagy via HIF-1α during bacterial infection.

Targeting YAP-p62 signaling axis suppresses the EGFR-TKI-resistant lung adenocarcinoma.

BACKGROUND: Despite the progress of advanced target therapeutic agents and immune checkpoint inhibitors, EGFR-TKI resistance is still one of the biggest obstacles in treating lung cancer. Clinical studies with autophagy inhibitors are actively underway to overcome drug resistance. METHODS: We used PC9, PC9/GR, and HCC827/GR cell lines to evaluate the activation of autophagy and EGFR-TKI resistance. Chloroquine was applied as an autophagic blocker and verteporfin was utilized as a YAP inhibitor. RESULTS: In this study, we tried to reveal the effect of autophagy adaptor p62 which is accumulated by autophagy inhibitor in EGFR-TKI-resistant lung adenocarcinoma. We identified that p62 has oncogenic functions that induce cell proliferation and invasion of EGFR-TKI-resistant lung adenocarcinoma. Interestingly, we found for the first time that YAP regulates p62 transcription through ERK, and YAP inhibition can suppress the expression of oncogenic p62. We also confirmed that the expressions of p62 and YAP have a positive correlation in EGFR-mutant lung adenocarcinoma patients. To block cell survival via perturbing YAP-p62 axis, we treated EGFR-TKI-resistant lung cancer cells with YAP inhibitor verteporfin. Remarkably, verteporfin effectively caused the death of EGFR-TKI-resistant lung cancer cells by decreasing the expressions of p62 with oncogenic function, YAP, and its target PD-L1. So, the cumulative effect of oncogenic p62 should be considered when using autophagy inhibitors, especially drugs that act at the last stage of autophagy such as chloroquine and bafilomycin A1. CONCLUSION: Finally, we suggest that targeting YAP-p62 signaling axis can be useful to suppress the EGFR-TKI-resistant lung cancer. Therefore, drug repurposing of verteporfin for lung cancer treatment may be valuable to consider because it can inhibit critical targets: p62, YAP, and PD-L1 at the same time.

ESRRA (estrogen related receptor alpha) is a critical regulator of intestinal homeostasis through activation of autophagic flux via gut microbiota.

The orphan nuclear receptor ESRRA (estrogen related receptor alpha) is critical in mitochondrial biogenesis and macroautophagy/autophagy function; however, the roles of ESRRA in intestinal function remain uncharacterized. Herein we identified that ESRRA acts as a key regulator of intestinal homeostasis by amelioration of colonic inflammation through activation of autophagic flux and control of host gut microbiota. Esrra-deficient mice presented with increased susceptibility to dextran sodium sulfate (DSS)-induced colitis with upregulation of intestinal inflammation. In addition, esrra-null mice had depressed AMP-activated protein kinase phosphorylation (AMPK), lower levels of TFEB (transcription factor EB), and accumulation of SQSTM1/p62 (sequestosome 1) with defective mitochondria in intestinal tissues. Esrra-deficient mice showed distinct gut microbiota composition and significantly higher microbial diversity than wild-type (WT) mice. Cohousing or fecal microbiota transplantation from WT mice to Esrra-deficient mice ameliorated DSS-induced colitis severity. Importantly, patients with ulcerative colitis (UC) had significantly decreased ESRRA expression in intestinal mucosal tissues that correlated with disease activity, suggesting clinical relevance of ESRRA in UC. Taken together, our results show that ESRRA contributes to intestinal homeostasis through autophagy activation and gut microbiota control to protect the host from detrimental inflammation and dysfunctional mitochondria.Abbreviations: ABX, antibotics; AMPK, AMP-activated protein kinase; ATP5A1, ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1; BECN1, beclin1, autophagy related, CCL, C-C motif chemokine ligand; CD, Crohn disease; CLDN, claudin; COX4I1, cytochrome c oxidase subunit 4I1; cKO, conditional knockout; cWT, conditional wild-type; CXCL, C-X-C motif chemokine ligand; DAI, disease activity index; DSS, dextran sodium sulfate; EGFP, enhanced green fluorescent protein; ESRR, estrogen related receptor; ESRRA, estrogen related receptor alpha; Esrra+/+, Esrra wild type; esrra-/-, esrra homozygous knockout; FMT, fecal microbiota transplantation; GABARAP, gamma-aminobutyric acid receptor associated protein; GSEA, gene set enrichment analysis; IBD, inflammatory bowel disease; IL, interleukin; KO, knockout; LAMP1, lysosomal-associated membrane protein 1; LCN2, lipocalin 2; LEfSe, linear discriminant analysis (LDA) effect size; LPS, lipopolysachharide; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; NDUFAB1, NADH: ubiquinone oxidoreductase subunit AB1; OCLN, occludin; OUT, operational taxonomic unit; OXPHOS, oxidative phosphorylation; PCoA, principal coordinate analysis; PPARGC1A, PPARG coactiva- tor 1 alpha; PRKAA, 5'-AMP-activated protein kinase catalytic subunit alpha; PTGS2/COX2, prostaglandin-endoperoxide synthase 2; RAB7, member RAS oncogene family; SDHB, succinate dehydrogenase complex, subunit B, iron sulfur (Ip); SQSTM1/p62, sequestosome 1; S100A9, S100 calcium binding protein A9 (calgranulin B); TCA, tricarboxylic acid; TFEB, transcription factor EB; TNF, tumor necrosis factor; UC, ulcerative colitis; UCP2, uncoupling protein 2 (mitochondrial, proton carrier); UQCRC1, ubiquinol-cytochrome c reductase core protein 1; UVRAG, UV radiation resistance associated gene; Vil1, villin; VPS11, VPS11, CORVET/HOPS core sub-unit; WT, wild type.

Association between fetoplacental Doppler results, placental pathology, and angiogenic factors among pregnant women with anxiety.

OBJECTIVE: This study aimed to evaluate whether state and trait anxiety among pregnant women were associated with fetoplacental Doppler findings, abnormal placental pathology, and placental angiogenic factors. MATERIALS AND METHODS: A total of 102 pregnant women at 32-35 gestational weeks were recruited and examined prospectively. State and trait anxiety were measured using the State-Trait Anxiety Inventory. Using Doppler ultrasound, pulsatility index (PI) of the umbilical artery (UA), middle cerebral artery (MCA), and uterine artery (UtA) and cerebroplacental ratio (CPR) were determined. Doppler parameters were converted into multiples of the median (MoM). Abnormal placental pathology was classified into 2 groups: vascular underperfusion (VU) and histological chorioamnionitis (HCA). Immunohistochemical analysis was performed to examine placental cells staining positive for placental growth factor (PLGF) and hypoxia-inducible factor-1-α (HIF-1α), which are markers for angiogenesis and hypoxic status, respectively. RESULTS: Women with high state anxiety scores had low MCA-PI MoM and CPR MoM, while those with high trait anxiety scores had low MCA-PI MoM. VU was associated with a higher incidence of high trait anxiety scores, and HCA was associated with a higher incidence of high state and trait anxiety scores. Regression analysis showed a relationship between maternal state anxiety on MCA-PI MoM and HCA after controlling for covariates. Maternal trait anxiety exhibited relationships with VU and HCA after adjustment. CONCLUSION: Our results demonstrated that maternal anxiety is associated with altered fetal cerebral blood flow and abnormal placental pathology but is not associated with uteroplacental insufficiency and placental angiogenic factors.

Quercitrin Ameliorates Hyperlipidemia and Hepatic Steatosis in Ovariectomized Mice.

Nonalcoholic fatty liver disease (NAFLD) is associated with progressive metabolic diseases. Estrogen deficiency increases the NAFLD risk among postmenopausal women. Thus, effective agents to prevent and treat NAFLD in postmenopausal women are required. Quercitrin (Quer) is a natural glycosylated flavonoid with antimicrobial, anti-inflammatory, and hypolipidemic effects. This study investigated whether Quer improves dysregulated lipid metabolism and suppresses hepatic steatosis in ovariectomized (OVX) mice as an experimental model mimicking postmenopausal women. Mice were assigned to the following four groups: SHAM, OVX, OVX + ß-estradiol (0.4 mg/kg diet), and OVX + Quer (500 mg/kg diet). Mice were administered a diet with or without Quer for three months. OVX mice displayed significantly higher body mass, epidermal fat, and liver weights than those of SHAM mice. However, these levels were reduced in Quer-treated mice. Quer treatment reduced the levels of serum lipid metabolites, including triglycerides, total cholesterol, and low-density lipoprotein cholesterol. Furthermore, Quer reduced liver lipid steatosis and inhibited the expression of proinflammatory cytokines, such as tumor necrosis factor-α, IL-6, and IL-1ß. The results of the present study indicate that Quer improves dysregulated lipid metabolism and reduces hepatic steatosis and inflammation by compensating for estrogen deficiency, suggesting that Quer may potentially exert protective effects during hepatic steatosis in postmenopausal women.

Sirtuin 3 is essential for host defense against Mycobacterium abscessus infection through regulation of mitochondrial homeostasis.

The global incidence of Mycobacterium abscessus (Mabc), a rapidly growing nontuberculous mycobacterial strain that causes treatment-refractory pulmonary diseases, is increasing. Despite this, the host factors that allow for protection against infection are largely unknown. In this study, we found that sirtuin 3 (SIRT3), a mitochondrial protein deacetylase, plays a critical role in host defense against Mabc infection. Mabc decreased SIRT3 and upregulated mitochondrial oxidative stress in macrophages. SIRT3 deficiency led to increased bacterial loads, histopathological, and mitochondrial damage, and pathological inflammation during Mabc infection. Administration of scavengers of mitochondrial reactive oxygen species significantly decreased the in vivo Mabc burden and excessive inflammation, and induced SIRT3 expression in infected lungs. Notably, SIRT3 agonist (resveratrol) significantly decreased Mabc growth and attenuated inflammation in mice and zebrafishes, indicating the key role for SIRT3 in metazoan host defense. Collectively, these data strongly suggest that SIRT3 is a host-directed therapeutic target against Mabc infection by controlling mitochondrial homeostasis.

Toxicological evaluation of exosomes derived from human adipose tissue-derived mesenchymal stem/stromal cells.

Several studies report that the therapeutic mechanism of action of mesenchymal stem/stromal cells (MSCs) is mainly mediated by paracrine factors that are released from MSCs such as exosomes. Exosomes are nano-sized extracellular vesicles that are transferred to target cells for cell-to-cell communication. Although MSC-derived exosomes (MSC-exosomes) are suggested as novel cell-free therapeutics for various human diseases, evaluation studies for the safety and toxicity of MSC-exosomes are limited. The purpose of our study was to evaluate the toxicological profile, including skin sensitization, photosensitization, eye and skin irritation, and acute oral toxicity using exosomes derived from human adipose tissue-derived MSCs (ASC-exosomes) in accordance with the OECD guidelines and the principles of Good Laboratory Practice. The ASC-exosomes were classified as a potential non-sensitizer in the skin sensitization test, UN GHS no category in the eye irritation test, and as a skin non-irritant in the skin irritation test, and did not induce any toxicity in the phototoxicity test or in acute oral toxicity testing. Our findings are the first to suggest that ASC-exosomes are safe for use as a topical treatment, with no adverse effects in toxicological testing, and have potential application as a therapeutic agent, cosmetic ingredient, or for other biological uses.