ABCG2-Expressing Clonal Repopulating Endothelial Cells Serve to Form and Maintain Blood Vessels.

BACKGROUND: Most organs are maintained lifelong by resident stem/progenitor cells. During development and regeneration, lineage-specific stem/progenitor cells can contribute to the growth or maintenance of different organs, whereas fully differentiated mature cells have less regenerative potential. However, it is unclear whether vascular endothelial cells (ECs) are also replenished by stem/progenitor cells with EC-repopulating potential residing in blood vessels. It has been reported recently that some EC populations possess higher clonal proliferative potential and vessel-forming capacity compared with mature ECs. Nevertheless, a marker to identify vascular clonal repopulating ECs (CRECs) in murine and human individuals is lacking, and, hence, the mechanism for the proliferative, self-renewal, and vessel-forming potential of CRECs is elusive. METHODS: We analyzed colony-forming, self-renewal, and vessel-forming potential of ABCG2 (ATP binding cassette subfamily G member 2)-expressing ECs in human umbilical vessels. To study the contribution of Abcg2-expressing ECs to vessel development and regeneration, we developed Abcg2CreErt2;ROSA TdTomato mice and performed lineage tracing during mouse development and during tissue regeneration after myocardial infarction injury. RNA sequencing and chromatin methylation chromatin immunoprecipitation followed by sequencing were conducted to study the gene regulation in Abcg2-expressing ECs. RESULTS: In human and mouse vessels, ECs with higher ABCG2 expression (ABCECs) possess higher clonal proliferative potential and in vivo vessel-forming potential compared with mature ECs. These cells could clonally contribute to vessel formation in primary and secondary recipients after transplantation. These features of ABCECs meet the criteria of CRECs. Results from lineage tracing experiments confirm that Abcg2-expressing CRECs (AbcCRECs) contribute to arteries, veins, and capillaries in cardiac tissue development and vascular tissue regeneration after myocardial infarction. Transcriptome and epigenetic analyses reveal that a gene expression signature involved in angiogenesis and vessel development is enriched in AbcCRECs. In addition, various angiogenic genes, such as Notch2 and Hey2, are bivalently modified by trimethylation at the 4th and 27th lysine residue of histone H3 (H3K4me3 and H3K27me3) in AbcCRECs. CONCLUSIONS: These results are the first to establish that a single prospective marker identifies CRECs in mice and human individuals, which holds promise to provide new cell therapies for repair of damaged vessels in patients with endothelial dysfunction.

Proteogenomic landscape and clinical characterization of GH-producing pituitary adenomas/somatotroph pituitary neuroendocrine tumors.

The clinical characteristics of growth hormone (GH)-producing pituitary adenomas/somatotroph pituitary neuroendocrine tumors (GHomas/somatotroph PitNETs) vary across patients. In this study, we aimed to integrate the genetic alterations, protein expression profiles, transcriptomes, and clinical characteristics of GHomas/somatotroph PitNETs to identify molecules associated with acromegaly characteristics. Targeted capture sequencing and copy number analysis of 36 genes and nontargeted proteomics analysis were performed on fresh-frozen samples from 121 sporadic GHomas/somatotroph PitNETs. Targeted capture sequencing revealed GNAS as the only driver gene, as previously reported. Classification by consensus clustering using both RNA sequencing and proteomics revealed many similarities between the proteome and the transcriptome. Gene ontology analysis was performed for differentially expressed proteins between wild-type and mutant GNAS samples identified by nontargeted proteomics and involved in G protein-coupled receptor (GPCR) pathways. The results suggested that GNAS mutations impact endocrinological features in acromegaly through GPCR pathway induction. ATP2A2 and ARID5B correlated with the GH change rate in the octreotide loading test, and WWC3, SERINC1, and ZFAND3 correlated with the tumor volume change rate after somatostatin analog treatment. These results identified a biological connection between GNAS mutations and the clinical and biochemical characteristics of acromegaly, revealing molecules associated with acromegaly that may affect medical treatment efficacy.

MicroRNA-874 targets phosphomevalonate kinase and inhibits cancer cell growth via the mevalonate pathway.

The microRNA (miR) miR-874, a potential tumour suppressor, causes cell death via target gene suppression in various cancer types. Mevalonate pathway inhibition also causes cell death in breast cancer. However, the relationship between the mevalonate pathway and miR-874-induced apoptosis or its association with the tumour suppressor p53 has not been elucidated. We identified phosphomevalonate kinase (PMVK), a key mevalonate pathway enzyme, and sterol regulatory element-binding factor 2 (SREBF2), the master cholesterol biosynthesis regulator, as direct miR­874 targets. Next-generation sequencing analysis revealed a significant miR-874-mediated downregulation of PMVK and SREBF2 gene expression and p53 pathway enrichment. Luciferase reporter assays showed that miR-874 directly regulated PMVK and SREBF2. miR-874-induced apoptosis was p53 dependent, and single-cell RNA sequencing analysis demonstrated that miR-874 transfection resulted in apoptosis and p53 pathway activation. Downregulation of PMVK expression also caused cell cycle arrest and p53 pathway activation, which was rescued by geranylgeranyl pyrophosphate (GGPP) supplementation. Analysis of The Cancer Genome Atlas (TCGA) database indicated a negative correlation between miR-874 and PMVK expression and between miR-874 and SREBF2 expression. These findings suggest that miR-874 suppresses the mevalonate pathway by targeting SREBF2 and PMVK, resulting in GGPP depletion, which activates the p53 pathway and promotes cycle arrest or apoptosis.

Epigenetic modifications underlie the differential adipogenic potential of preadipocytes derived from human subcutaneous fat tissue.

Ceiling culture-derived preadipocytes (ccdPAs) and adipose-derived stem cells (ASCs) can be harvested from human subcutaneous fat tissue using the specific gravity method. Both cell types possess a similar spindle shape without lipid droplets. We previously reported that ccdPAs have a higher adipogenic potential than ASCs, even after a 7-wk culture. We performed a genome-wide epigenetic analysis to examine the mechanisms contributing to the adipogenic potential differences between ccdPAs and ASCs. Methylation analysis of cytosines followed by guanine (CpG) using a 450-K BeadChip was performed on human ccdPAs and ASCs isolated from three metabolically healthy females. Chromatin immunoprecipitation sequencing was performed to evaluate trimethylation at lysine 4 of histone 3 (H3K4me3). Unsupervised machine learning using t-distributed stochastic neighbor embedding to interpret 450,000-dimensional methylation assay data showed that the cells were divided into ASC and ccdPA groups. In Kyoto Encyclopedia of Genes and Genomes pathway analysis of 1,543 genes with differential promoter CpG methylation, the peroxisome proliferator-activated receptor (PPAR) and adipocytokine signaling pathways ranked in the top 10 pathways. In the PPARγ gene, H3K4me3 peak levels were higher in ccdPAs than in ASCs, whereas promoter CpG methylation levels were significantly lower in ccdPAs than in ASCs. Similar differences in promoter CpG methylation were also seen in the fatty acid-binding protein 4 and leptin genes. In conclusion, we analyzed the epigenetic status of adipogenesis-related genes as a potential mechanism underlying the differences in adipogenic differentiation capability between ASCs and ccdPAs.

TAS4464, a NEDD8-activating enzyme inhibitor, activates both intrinsic and extrinsic apoptotic pathways via c-Myc-mediated regulation in acute myeloid leukemia.

TAS4464, a potent, selective small molecule NEDD8-activating enzyme (NAE) inhibitor, leads to inactivation of cullin-RING E3 ubiquitin ligases (CRLs) and consequent accumulations of its substrate proteins. Here, we investigated the antitumor properties and action mechanism of TAS4464 in acute myeloid leukemia (AML). TAS4464 induced apoptotic cell death in various AML cell lines. TAS4464 treatments resulted in the activation of both the caspase-9-mediated intrinsic apoptotic pathway and caspase-8-mediated extrinsic apoptotic pathway in AML cells; combined treatment with inhibitors of these caspases markedly diminished TAS4464-induced apoptosis. In each apoptotic pathway, TAS4464 induced the mRNA transcription of the intrinsic proapoptotic factor NOXA and decreased that of the extrinsic antiapoptotic factor c-FLIP. RNA-sequencing analysis showed that the signaling pathway of the CRL substrate c-Myc was enriched after TAS4464 treatment. Chromatin immunoprecipitation (ChIP) assay revealed that TAS4464-induced c-Myc bound to the PMAIP1 (encoding NOXA) and CFLAR (encoding c-FLIP) promoter regions, and siRNA-mediated c-Myc knockdown neutralized both TAS4464-mediated NOXA induction and c-FLIP downregulation. TAS4464 activated both caspase-8 and caspase-9 along with an increase in NOXA and a decrease in c-FLIP, resulting in complete tumor remission in a human AML xenograft model. These findings suggest that NAE inhibition leads to anti-AML activity via a novel c-Myc-dependent apoptosis induction mechanism.

Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis.

Endothelial cells adopt tissue-specific characteristics to instruct organ development and regeneration1,2. This adaptability is lost in cultured adult endothelial cells, which do not vascularize tissues in an organotypic manner. Here, we show that transient reactivation of the embryonic-restricted ETS variant transcription factor 2 (ETV2)3 in mature human endothelial cells cultured in a serum-free three-dimensional matrix composed of a mixture of laminin, entactin and type-IV collagen (LEC matrix) 'resets' these endothelial cells to adaptable, vasculogenic cells, which form perfusable and plastic vascular plexi. Through chromatin remodelling, ETV2 induces tubulogenic pathways, including the activation of RAP1, which promotes the formation of durable lumens4,5. In three-dimensional matrices-which do not have the constraints of bioprinted scaffolds-the 'reset' vascular endothelial cells (R-VECs) self-assemble into stable, multilayered and branching vascular networks within scalable microfluidic chambers, which are capable of transporting human blood. In vivo, R-VECs implanted subcutaneously in mice self-organize into durable pericyte-coated vessels that functionally anastomose to the host circulation and exhibit long-lasting patterning, with no evidence of malformations or angiomas. R-VECs directly interact with cells within three-dimensional co-cultured organoids, removing the need for the restrictive synthetic semipermeable membranes that are required for organ-on-chip systems, therefore providing a physiological platform for vascularization, which we call 'Organ-On-VascularNet'. R-VECs enable perfusion of glucose-responsive insulin-secreting human pancreatic islets, vascularize decellularized rat intestines and arborize healthy or cancerous human colon organoids. Using single-cell RNA sequencing and epigenetic profiling, we demonstrate that R-VECs establish an adaptive vascular niche that differentially adjusts and conforms to organoids and tumoroids in a tissue-specific manner. Our Organ-On-VascularNet model will permit metabolic, immunological and physiochemical studies and screens to decipher the crosstalk between organotypic endothelial cells and parenchymal cells for identification of determinants of endothelial cell heterogeneity, and could lead to advances in therapeutic organ repair and tumour targeting.

Identification of risk factors for post-induction hypotension in patients receiving 5-aminolevulinic acid: a single-center retrospective study.

BACKGROUND: 5-Aminolevulinic acid (5-ALA) is useful as a photodynamic agent, but its use commonly leads to hypotension. Although avoiding a mean arterial pressure (MAP) < 60 mmHg is important, the incidence of MAP < 60 mmHg when using 5-ALA is unclear. Therefore, we conducted a retrospective study to assess the incidence of post-induction hypotension and identified risk factors of this phenomenon. METHODS: One-hundred and seventy-two consecutive patients who underwent transurethral resection of the bladder tumor or craniotomy with the use of 5-ALA were enrolled. The primary outcome was the incidence of post-induction hypotension, defined as MAP < 60 mmHg during the first 1 h after anesthesia induction. We divided participants into the normal blood pressure group (group N) and the hypotension group (group L). RESULTS: The incidence of post-induction hypotension was 70% (group L = 121, group N = 51). Multivariate analysis revealed that female sex was an independent factor of post-induction hypotension (odds ratio [OR] 3.95; 95% confidence interval [CI] 1.21-12.97; p = 0.02). Systolic blood pressure < 100 mmHg before anesthesia induction and general anesthesia were also identified as significant independent factors (OR 13.30; 95% CI 1.17-151.0; p = 0.04 and OR 25.84; 95% CI 9.80-68.49; p < 0.001, respectively). CONCLUSIONS: The incidence of post-induction hypotension was 70% in patients using 5-ALA. Female sex, systolic blood pressure < 100 mmHg before anesthesia induction, and general anesthesia might be independent factors of post-induction hypotension when using 5-ALA.

Molecular determinants of nephron vascular specialization in the kidney.

Although kidney parenchymal tissue can be generated in vitro, reconstructing the complex vasculature of the kidney remains a daunting task. The molecular pathways that specify and sustain functional, phenotypic and structural heterogeneity of the kidney vasculature are unknown. Here, we employ high-throughput bulk and single-cell RNA sequencing of the non-lymphatic endothelial cells (ECs) of the kidney to identify the molecular pathways that dictate vascular zonation from embryos to adulthood. We show that the kidney manifests vascular-specific signatures expressing defined transcription factors, ion channels, solute transporters, and angiocrine factors choreographing kidney functions. Notably, the ontology of the glomerulus coincides with induction of unique transcription factors, including Tbx3, Gata5, Prdm1, and Pbx1. Deletion of Tbx3 in ECs results in glomerular hypoplasia, microaneurysms and regressed fenestrations leading to fibrosis in subsets of glomeruli. Deciphering the molecular determinants of kidney vascular signatures lays the foundation for rebuilding nephrons and uncovering the pathogenesis of kidney disorders.

Influence of hyperuricemia treatment on postoperative acute kidney injury among hyperuricemia patients: a single-center retrospective database analysis.

OBJECTIVE: Hyperuricemia has been reported to be associated with the development of postoperative acute kidney injury (pAKI). However, it remains underdetermined whether hyperuricemia treatment could decrease the potential risk of pAKI. Here, we investigated this hypothesis among hyperuricemia patients with previously normal renal function by performing a retrospective database analysis. RESULTS: The study screened 18,169 patients, and were examined preoperative serum creatinine, uric acid, and postoperative serum creatinine. Eight hundred thirty-six patients were finally analyzed for the study, of whom 232 were in the treatment group and 604 were in the non-treatment control group. After adjustment for multi-covariates including baseline (pre-treatment) serum uric acid (SUA) levels, the incidence of pAKI in the treatment group (9.05%; 95% CI 6.04-12.1%) was significantly lower than that in the control group (14.2%; 95% CI 11.2-17.2%). On the other hand, further adjusting for preoperative SUA levels, there was no significant difference in the expected incidence of pAKI between the groups.

Acute and long-term effects of haloperidol on surgery-induced neuroinflammation and cognitive deficits in aged rats.

PURPOSE: Neuroinflammation may contribute to the pathogenesis of the cognitive symptoms of postoperative delirium (POD) and its subsequent long-term cognitive impairment. Haloperidol (HAL), a dopamine receptor antagonist, is widely used to treat POD, whereas the effects of HAL on postoperative neuroinflammation and related cognitive deficits have been underdetermined. METHODS: Aged rats underwent sham or abdominal surgery and were subcutaneously treated with either vehicle, low-dose (0.5 mg/kg bolus, then 0.5 mg/kg/day infusion), or high-dose (2.0 mg/kg bolus, then 2.0 mg/kg/day infusion) HAL. All treatments were initiated immediately after surgery and continued for 48 h. On either postoperative day 2 (early) or 7 (late), all rats were tested for trace and context fear memory retention after acquisition of trace fear conditioning. Following the cognitive testing, the levels of pro-inflammatory cytokines, as well as dopamine and its metabolite, in hippocampus and medial prefrontal cortex (mPFC) were measured. RESULTS: In the early postoperative period, surgery induced acute neuroinflammation along with related trace and context memory dysfunction. Dopamine turnover was increased in both hippocampus and mPFC, whereas no relationship with memory functions was observed. However, HAL even at high-dose failed to restore the surgery-induced neuroinflammation and related cognitive deficits. In the late postoperative period, chronic neuroinflammation was detected only in hippocampus, which was associated with context, but not trace memory dysfunction. Neither low- nor high-dose HAL could prevent the development of these late-phase neurocognitive deficits. CONCLUSION: Our findings indicate that perioperative administration with HAL may have no effects on postoperative neuroinflammation and related cognitive impairment.

Acute postoperative pain exacerbates neuroinflammation and related delirium-like cognitive dysfunction in rats.

The acute neuroinflammatory response to surgery may play a key pathogenic role in postoperative delirium (POD). Here, we investigated the contribution of acute postoperative pain to neuroinflammation and related delirium-like behaviors after surgery in adult and aged rats. Animals were assigned into four groups: control, abdominal surgery, surgery with analgesia using local ropivacaine, and surgery with analgesia using systemic morphine. Pain was assessed by the Rat Grimace Scale (RGS). Trace and context memory retention was evaluated following trace fear conditioning during the first 2 days after surgery. Pro-inflammatory cytokines in medial prefrontal cortex and hippocampus were measured by enzyme-linked immunosorbent assay. In both age groups, the RGS increased significantly from baseline until 6 h after surgery. The postoperative analgesia with either local or systemic regimens comparably alleviated the RGS increase in adult and aged animals. The two analgesic regimens attenuated the surgery-induced trace and context memory deficits, as well as cytokines overproduction in both medial prefrontal cortex and hippocampus. No age-related differences were found in the neuro-cognitive effectiveness of postoperative analgesia. Our experimental findings provide proof-of-concept for adequate postoperative pain management as one of the main preventive strategies of POD.

p53 plays a crucial role in endothelial dysfunction associated with hyperglycemia and ischemia.

p53 is a guardian of the genome that protects against carcinogenesis. There is accumulating evidence that p53 is activated with aging. Such activation has been reported to contribute to various age-associated pathologies, but its role in vascular dysfunction is largely unknown. The aim of this study was to investigate whether activation of endothelial p53 has a pathological effect in relation to endothelial function. We established endothelial p53 loss-of-function and gain-of-function models by breeding endothelial-cell specific Cre mice with floxed Trp53 or floxed Mdm2/Mdm4 mice, respectively. Then we induced diabetes by injection of streptozotocin. In the diabetic state, endothelial p53 expression was markedly up-regulated and endothelium-dependent vasodilatation was significantly impaired. Impairment of vasodilatation was significantly ameliorated in endothelial p53 knockout (EC-p53 KO) mice, and deletion of endothelial p53 also significantly enhanced the induction of angiogenesis by ischemia. Conversely, activation of endothelial p53 by deleting Mdm2/Mdm4 reduced both endothelium-dependent vasodilatation and ischemia-induced angiogenesis. Introduction of p53 into human endothelial cells up-regulated the expression of phosphatase and tensin homolog (PTEN), thereby reducing phospho-eNOS levels. Consistent with these results, the beneficial impact of endothelial p53 deletion on endothelial function was attenuated in EC-p53 KO mice with an eNOS-deficient background. These results show that endothelial p53 negatively regulates endothelium-dependent vasodilatation and ischemia-induced angiogenesis, suggesting that inhibition of endothelial p53 could be a novel therapeutic target in patients with metabolic disorders.

Short- and Long-Term Outcomes of Patients With Hypertrophic Cardiomyopathy After Noncardiac Surgery: A Single-Center Retrospective Study.

OBJECTIVE: Although several studies have demonstrated that noncardiac surgery in patients with hypertrophic cardiomyopathy (HCM) is safe, the long-term outcomes remain unclear. Therefore, the authors investigated the postoperative long-term outcomes of patients with HCM who underwent noncardiac surgery at their hospital. DESIGN: Retrospective review. SETTING: Single university hospital. PARTICIPANTS: Seventy-two consecutive patients with HCM who underwent noncardiac surgery. INTERVENTION: No intervention. MEASUREMENTS AND MAIN RESULTS: The incidence of HCM-related events during the patient's hospital stay were evaluated as the short-term outcomes, and HCM-related events after discharge were evaluated as the long-term outcomes. HCM-related events were defined as sudden death, implantable cardioverter-defibrillator discharge with successful recovery from cardiopulmonary arrest, death due to heart failure, hospitalization for heart failure, myocardial infarction, and thrombosis caused by atrial fibrillation. The median postoperative follow-up was 1,382 days (3.8 years). Short-term mortality and morbidity rates were both 1.3%, whereas long-term mortality and morbidity rates were 4.2% and 15%, respectively. The 5-year event-free rate was 76%, whereas the postoperative HCM-related mortality rate was 4.2%. CONCLUSIONS: This study suggests that noncardiac surgery in patients with HCM is safe in terms of both short- and long-term outcomes. To confirm the findings, additional studies, such as prospective, multicenter, observational studies, should be conducted.

Glucose control using a closed-loop device decreases inflammation after cardiovascular surgery without increasing hypoglycemia risk.

Although tight glucose control might reduce inflammation after cardiac surgery, it remains unclear whether inflammation can be controlled by maintaining glucose levels within 110-180 mg/dL. We hypothesized that a glucose target range of 110-180 mg/dL decreases inflammation after cardiovascular surgery. This retrospective study included 72 cardiovascular surgery patients divided into two groups according to the glucose control approach. Patients allocated to the closed-loop group received closed-loop glucose control (target glucose levels at 110-180 mg/dL) from admission to the intensive care unit until 9 a.m. on postoperative day (POD) 1. Patients allocated to the conventional group received conventional glucose control using a sliding scale method to maintain blood glucose levels < 200 mg/dL. Primary outcomes were C-reactive protein (CRP) levels on PODs 1, 2, and 7. Data were reported as mean ± standard deviation. Comparisons were performed using the chi-squared test and unpaired t test, with p < 0.05 indicating statistical significance. The closed-loop group had significantly lower average glucose levels (169 ± 24 vs. 201 ± 36 mg/dL, p < 0.001) and standard deviation of glucose levels (22 ± 13 vs. 44 ± 20 mg/dL; p < 0.001). The CRP levels on PODs 2 and 7 were significantly lower in the closed-loop group than in the conventional group (10.8 ± 5.6 vs. 14.1 ± 5.7 mg/dL, p = 0.02; 4.6 ± 2.5 vs. 7.3 ± 4.0 mg/dL, p < 0.001; respectively). Our findings suggest that glucose control using a closed-loop device might decrease inflammation after cardiovascular surgery without increasing hypoglycemia risk.

Additional benefit of local infiltration of analgesia to femoral nerve block in total knee arthroplasty: double-blind randomized control study.

PURPOSE: Multimodal analgesia has become an important concept in current pain management following total knee arthroplasty (TKA). However, controversy remains over what is the most accepted combination. In this study, the additional benefits of local infiltration of analgesia to femoral nerve block were evaluated. METHODS: Forty patients were randomly allocated into a combined local infiltration of analgesia and femoral nerve block or femoral nerve block alone group. In the former, analgesic drugs consisting of ropivacaine and dexamethasone were injected into the peri-articular tissues, while the same amount of saline was injected into the femoral nerve block group. The primary outcome measure was the total amount of fentanyl consumption by the patient-controlled analgesia pump during the 48-h post-operative period. RESULTS: A combination of local infiltration of analgesia and femoral nerve block had less total fentanyl consumption and a larger knee ROM at post-operative day 2 than femoral nerve block alone (p < 0.05). C-reactive protein levels in the combined treatment group were significantly lower than the femoral nerve block group at post-operative day 3 (p < 0.01). There was no difference between the two groups, post-operatively, on the visual analogue scale for pain at rest or while walking, quadriceps strength, timed up and go test, circumference of thigh, Knee Society Score, and Western Ontario and McMaster Universities Osteoarthritis Index. CONCLUSION: The addition of local infiltration of analgesia to femoral nerve block promoted post-operative pain relief and the recovery of knee ROM in the early post-operative period. This combination is an effective method for post-operative pain management after TKA. LEVEL OF EVIDENCE: Randomized controlled trial, Level I.

Role of neurosteroid allopregnanolone on age-related differences in exercise-induced hypoalgesia in rats.

The beneficial effects of physical activity for pain are denominated exercise-induced hypoalgesia (EIH). Here, we examined the age-related change and potential role of the neurosteroid allopregnanolone (ALLO) on EIH in rats. Adult and aged rats were randomly divided into one of three groups; non-exercise control, Low-exercise, and High-exercise. The animals in the Low- and High-exercise groups were subjected to a 10-minute treadmill workout at 40% and 80% maximum oxygen intake intensity, respectively. In the Low-exercise groups, a significant EIH response was observed in aged but not in adult rats. The pre-treatment with ALLO synthesis inhibitor finasteride, but not opioid-receptor antagonist naloxone, inhibited the Low-exercise induced EIH response in aged rats. Furthermore, the Low-exercise increased brain ALLO levels in aged animals compared with controls, which was correlated with the mechanical pain sensitivity. On the other hand, High-exercise could induce EIH response in both adult and aged animals, but it was more effective in adult rats. The pre-treatment with naloxone, but not finasteride, reduced the EIH observed after High-exercise in both adult and aged rats. Our findings demonstrated that effective EIH can be achieved even by mild-intensity exercise in aged animals via an increase of the brain ALLO levels.

5-Aminolevulinic acid-induced severe hypotension during transurethral resection of a bladder tumor: a case report.

BACKGROUND: Although 5-aminolevulinic acid (5-ALA) is used for the photodynamic diagnosis of bladder tumors, hypotension is the most commonly observed adverse effect. We present a case of 5-ALA-induced severe hypotension during transurethral resection of a bladder tumor. CASE PRESENTATION: A 68-year-old man underwent transurethral resection of a bladder tumor using 5-ALA under general anesthesia. Three hours before anesthesia induction, ALA 20 mg/kg was administered orally. After anesthesia induction, his blood pressure decreased to 47/32 mmHg. Although we used phenylephrine and ephedrine, hypotension persisted at 50/33 mmHg. Bolus administration of noradrenaline slightly increased his blood pressure to 65/39 mmHg. Following this, bolus administration of adrenaline elevated his blood pressure. We decided to perform surgery under continuous administration of adrenaline. CONCLUSIONS: Our case report suggests that anesthesiologists should consider 5-ALA-induced hypotension as a differential diagnosis for hypotension occurring after anesthesia induction. Moreover, ephedrine and phenylephrine might be less effective in treating this condition.

Therapeutic experience with tramadol for opioid dependence in a patient with chronic low back pain: a case report.

BACKGROUND: Long-term opioid treatment for chronic non-cancer pain has become controversial, given the increasing prevalence of opioid dependence. However, there is little information on therapeutic strategies for this condition in Japanese patients. Here, we present a case of successful management of iatrogenic opioid dependence with tramadol in a patient with chronic low back pain. CASE PRESENTATION: A 68-year-old male suffering from intractable low back pain was referred to our pain clinic. He was previously treated in another hospital with transdermal fentanyl patches 6 mg/day and fentanyl sublingual tablets (100 µg as required) for this condition. On the basis of medical examination, including a review of the patient's medical history, physical examination, X-ray, and his family statement, we diagnosed him with iatrogenic opioid dependence due to inadequate fentanyl use. Then, we developed a treatment plan consisting in fentanyl detoxification with a weak opioid, tramadol. At first, the use of fentanyl sublingual tablets was interrupted after obtaining informed consent. Then, we reduced the dose of transdermal fentanyl 1 mg per 4-5 days replacing with oral sustained-release tramadol. The patient developed mild to moderate withdrawal symptoms during this period, which could be effectively managed by supportive treatments. The hospital psychiatry liaison team continuously provided the patient and his wife with information, counseling, and education regarding the treatment of opioid dependence. Throughout the detoxification process, his reported pain did not exacerbate, even slightly improved over time. The final prescription was sustained-release tramadol 300 mg/day without fentanyl, and his activities of daily living drastically improved. However, unfortunately, he died due to an aortic dissection of stent-graft edge 65 days after surgery. CONCLUSIONS: Our case highlighted that sustained-release tramadol could be effectively applied as a detoxification agent for iatrogenic opioid dependence in patients with chronic non-cancer pain.

Resveratrol-loaded nanoemulsion prevents cognitive decline after abdominal surgery in aged rats.

The maladaptive response of aged microglia to surgery and consequent neuroinflammation plays a key pathogenic role in postoperative cognitive dysfunction (POCD). Here, we assessed the preventive effect of resveratrol (RESV) for POCD in aged rats. The emulsified form of RESV (e-RESV) was selected to improve its oral and brain bioavailability. Animals were assigned to one of four groups: e-RESV (80 mg/kg) versus vehicle treatment by abdominal surgery versus isoflurane anesthesia alone (n = 8 in each group). The dose-dependent effects of e-RESV were also assessed in dose range of 0-60 mg/kg. Either vehicle or e-RESV was administered intragastrically 24 h before surgery. Seven days after procedure, cognitive function was evaluated using a novel object recognition test, followed by measurement of hippocampal pro-inflammatory cytokine levels. Our results showed that pre-treatment with e-RESV attenuated the surgery-induced cognitive impairment and related hippocampal neuroinflammation at 40 mg/kg or higher doses. Additionally, the ex-vivo experiments revealed that the preemptive e-RESV regimen reduced the hippocampal microglial immune reactivity to lipopolysaccharide. Furthermore, e-RESV induced neuroprotective benefits were inhibited by the concomitant administration of sirtinol, a specific SIRT1 inhibitor. Our findings imply the preventive potential of e-RESV for POCD via the SIRT1 signaling pathway.

p53-inducible DPYSL4 associates with mitochondrial supercomplexes and regulates energy metabolism in adipocytes and cancer cells.

The tumor suppressor p53 regulates multiple cellular functions, including energy metabolism. Metabolic deregulation is implicated in the pathogenesis of some cancers and in metabolic disorders and may result from the inactivation of p53 functions. Using RNA sequencing and ChIP sequencing of cancer cells and preadipocytes, we demonstrate that p53 modulates several metabolic processes via the transactivation of energy metabolism genes including dihydropyrimidinase-like 4 (DPYSL4). DPYSL4 is a member of the collapsin response mediator protein family, which is involved in cancer invasion and progression. Intriguingly, DPYSL4 overexpression in cancer cells and preadipocytes up-regulated ATP production and oxygen consumption, while DPYSL4 knockdown using siRNA or CRISPR/Cas9 down-regulated energy production. Furthermore, DPYSL4 was associated with mitochondrial supercomplexes, and deletion of its dihydropyrimidinase-like domain abolished its association and its ability to stimulate ATP production and suppress the cancer cell invasion. Mouse-xenograft and lung-metastasis models indicated that DPYSL4 expression compromised tumor growth and metastasis in vivo. Consistently, database analyses demonstrated that low DPYSL4 expression was significantly associated with poor survival of breast and ovarian cancers in accordance with its reduced expression in certain types of cancer tissues. Moreover, immunohistochemical analysis using the adipose tissue of obese patients revealed that DPYSL4 expression was positively correlated with INFg and body mass index in accordance with p53 activation. Together, these results suggest that DPYSL4 plays a key role in the tumor-suppressor function of p53 by regulating oxidative phosphorylation and the cellular energy supply via its association with mitochondrial supercomplexes, possibly linking to the pathophysiology of both cancer and obesity.