Influence of Adipokines on Metabolic Dysfunction and Aging.

Currently, 30% of the global population is overweight or obese, with projections from the World Obesity Federation suggesting that this figure will surpass 50% by 2035. Adipose tissue dysfunction, a primary characteristic of obesity, is closely associated with an increased risk of metabolic abnormalities, such as hypertension, hyperglycemia, and dyslipidemia, collectively termed metabolic syndrome. In particular, visceral fat accretion is considered as a hallmark of aging and is strongly linked to higher mortality rates in humans. Adipokines, bioactive peptides secreted by adipose tissue, play crucial roles in regulating appetite, satiety, adiposity, and metabolic balance, thereby rendering them key players in alleviating metabolic diseases and potentially extending health span. In this review, we elucidated the role of adipokines in the development of obesity and related metabolic disorders while also exploring the potential of certain adipokines as candidates for longevity interventions.

[Regulation of Aging Processes: A Perspective of Dietary Restriction Models].

The moderate restriction of dietary energy intake (dietary restriction: DR) extends the lifespan and health span of various laboratory animals, suggesting that it delays the aging process inherent in many animal species. Attenuated growth hormone and insulin-like growth factor-1 (IGF-1) signaling caused by mutations also increases the lifespan of mice, even those allowed to feed freely. In nematodes, the Daf16, mammalian Forkhead box O (FoxO) transcription factor, was shown to be required for lifespan extension in response to reduced IGF-1 signaling. Because DR also decreases the plasma concentration of IGF-1 in mammals, the IGF-1-FoxO axis may play a central role in the lifespan extension effect of DR and, thus, retardation of aging. Studies using knockout mice under DR conditions revealed the importance of FoxO1 and nuclear factor erythroid-derived 2-like 2 (Nrf2) in tumor suppression, and FoxO3 in lifespan extension. Human genomic studies also identified a strong association between a FOXO3 single nucleotide polymorphism and longevity. The aging mechanism is the most important risk factor for disease and frailty in aging humans. Therefore, further research on the application of DR to humans, the development of compounds and drugs that mimic the effects of DR, and mechanisms underlying FOXO3 polymorphisms for longevity is highly relevant to extending the human health span.

Mechanisms underlying retardation of aging by dietary energy restriction.

Moderate restriction of dietary energy intake, referred to here as dietary restriction (DR), delays aging and extends lifespan in experimental animals compared with a diet of ad libitum feeding (AL) control animals. Basic knowledge of the mechanisms underlying the effects of DR could be applicable to extending the healthspan in humans. This review highlights the importance of forkhead box O (FoxO) transcription factors downstream of the growth hormone-insulin-like growth factor 1 signaling in the effects of DR. Our lifespan studies in mice with heterozygous Foxo1 or Foxo3 gene knockout indicated differential roles of FoxO1 and FoxO3 in the tumor-inhibiting and life-extending effects of DR. Subsequent studies suggested a critical role of FoxO3 in metabolic and mitochondrial bioenergetic adaptation to DR. Our studies also verified hypothalamic neuropeptide Y (Npy) as a vital neuropeptide showing pleiotropic and sexually dimorphic effects for extending the healthspan in the context of nutritional availability. Npy was necessary for DR to exert its effects in male and female mice; meanwhile, under AL conditions, the loss of Npy prevented obesity and insulin resistance only in female mice. Overnutrition disrupts FoxO- and Npy-associated metabolic and mitochondrial bioenergetic adaptive processes, causing the acceleration of aging and related diseases.

Anticancer agent α-sulfoquinovosyl-acylpropanediol enhances the radiosensitivity of human malignant mesothelioma in nude mouse models.

Malignant pleural mesothelioma (MPM) is a highly malignant disease that develops after asbestos exposure. Although the number of MPM cases is predicted to increase, no effective standard therapies have been established. The novel radiosensitizer α-sulfoquinovosyl-acylpropanediol (SQAP) enhances the effects of γ-radiation in human lung and prostate cancer cell lines and in animal models. In this study, we explored the radiosensitizing effect of SQAP and its mechanisms in MPM. The human MPM cell lines MSTO-211H and MESO-4 were implanted subcutaneously into the backs and thoracic cavities of immunodeficient KSN/Slc mice, then 2 mg/kg SQAP was intravenously administered with or without irradiation with a total body dose of 8 Gy. In both the orthotopic and ectopic xenograft murine models, the combination of irradiation plus SQAP delayed the implanted human MSTO-211H tumor growth. The analysis of the changes in the relative tumor volume of the MSTO-211H indicated a statistically significant difference after 8 Gy total body combined with 2 mg/kg SQAP, compared to both the untreated control (P = 0.0127) and the radiation treatment alone (P = 0.0171). After the treatment in each case, immunostaining of the harvested tumors revealed decreased cell proliferation, increased apoptosis and normalization of tumor blood vessels in the SQAP- and irradiation-treated group. Furthermore, hypoxia-inducible factor (HIF) 1 mRNA and protein expression were decreased, indicating reoxygenation in this group. In conclusion, SQAP improved hypoxic conditions in tumor tissue and may elicit a radiosensitizing effect in malignant mesothelioma models.

The Role of Neuropeptide Y in Adipocyte-Macrophage Crosstalk during High Fat Diet-Induced Adipose Inflammation and Liver Steatosis.

Obesity is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD), which is initiated by adipocyte-macrophage crosstalk. Among the possible molecules regulating this crosstalk, we focused on neuropeptide Y (NPY), which is known to be involved in hypothalamic appetite and adipose tissue inflammation and metabolism. In this study, the NPY-/- mice showed a marked decrease in body weight and adiposity, and lower free fatty acid and adipose inflammation without food intake alteration during a high fat diet (HFD). Moreover, NPY deficiency increased the thermogenic genes expression in brown adipose tissue. Notably, NPY-mRNA expression was upregulated in macrophages from the HFD mice compared to that from the mice on a standard diet. The NPY-mRNA expression also positively correlated with the liver mass/body weight ratio. NPY deletion alleviated HFD-induced adipose inflammation and liver steatosis. Hence, our findings point toward a novel intracellular mechanism of NPY in the regulation of adipocyte-macrophage crosstalk and highlight NPY antagonism as a promising target for therapeutic approaches against obesity and NAFLD.

Primary intracranial aggressive fibromatosis arising in sella turcica: illustrative case.

BACKGROUND: Aggressive fibromatosis is a rare histologically benign but locally infiltrative myofibroblastic tumor. Primary intracranial aggressive fibromatosis (IAF) can exhibit a clinically malignant course. OBSERVATIONS: A 22-year-old otherwise healthy woman presented with left painful ophthalmoplegia. Magnetic resonance imaging (MRI) revealed a left sellar tumor with cavernous sinus invasion. Endoscopic transsphenoidal surgery was performed. The lesion could not be totally resected. An inflammatory myofibroblastic tumor was suspected, so steroid pulse therapy was introduced, but it was ineffective. The tumor recurred after a few months, and she complained of visual acuity loss, abducens nerve palsy, trigeminal neuralgia, and panhypopituitarism. The lesion was diagnosed as primary IAF by a pathological review. Gamma Knife radiosurgery was performed, and chemotherapies were introduced but ineffective. Her consciousness was disturbed, and MRI showed hypothalamic invasion of the tumor, occlusion and stenosis of carotid arteries, and cerebral stroke. Palliative care was introduced, and she died 32 months after the onset. The autopsy revealed tumor invasion to the cavernous sinus, optic nerve, hypothalamus, pituitary, and tonsillar herniation due to massive cerebral stroke. LESSONS: Radical resection can be impossible in patients with IAF. Radiotherapy and chemotherapy are not always effective for residual lesions. Adjuvant therapy for IAF remains to be explored.

Does Calorie Restriction Modulate Inflammaging via FoxO Transcription Factors?

Calorie restriction (CR) has been shown to extend lifespan and retard aging-related functional decline in animals. Previously, we found that the anti-neoplastic and lifespan-extending effects of CR in mice are regulated by forkhead box O transcription factors (FoxO1 and FoxO3), located downstream of growth hormone (GH)-insulin-like growth factor (IGF)-1 signaling, in an isoform-specific manner. Inflammaging is a term coined to represent that persistent low-level of inflammation underlies the progression of aging and related diseases. Attenuation of inflammaging in the body may underlie the effects of CR. Recent studies have also identified cellular senescence and activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin-domain-containing-3 (NLRP3) inflammasome as causative factors of inflammaging. In this paper, we reviewed the current knowledge of the molecular mechanisms linking the effects of CR with the formation of inflammasomes, particularly focusing on possible relations with FoxO3. Inflammation in the brain that affects adult neurogenesis and lifespan was also reviewed as evidence of inflammaging. A recent progress of microRNA research was described as regulatory circuits of initiation and propagation of inflammaging. Finally, we briefly introduced our preliminary results obtained from the mouse models, in which Foxo1 and Foxo3 genes were conditionally knocked out in the myeloid cell lineage.

NPY Deficiency Prevents Postmenopausal Adiposity by Augmenting Estradiol-Mediated Browning.

The orexigenic hormone neuropeptide Y (NPY) plays a pivotal role in the peripheral regulation of fat metabolism. However, the mechanisms underlying the effects of sex on NPY function have not been extensively analyzed. In this study, we examined the effects of NPY deficiency on fat metabolism in male and female mice. Body weight was slightly decreased, whereas white adipose tissue (WAT) mass was significantly decreased as the thermogenic program was upregulated in NPY-/- female mice compared with that in wild-type mice; these factors were not altered in response to NPY deficiency in male mice. Moreover, lack of NPY resulted in an increase in luteinizing hormone (LH) expression in the pituitary gland, with concomitant activation of the estradiol-mediated thermogenic program in inguinal WAT, and alleviated age-related modification of adiposity in female mice. Taken together, these data revealed a novel intracellular mechanism of NPY in the regulation of fat metabolism and highlighted the sexual dimorphism of NPY as a promising target for drug development to reduce postmenopausal adiposity.

Effects of rikkunshito supplementation on resistance to oxidative stress and lifespan in mice.

AIM: Caloric restriction (CR), which limits the caloric intake to 60-70% of ad libitum (AL) amounts in various experimental animals, delays aging and extends the lifespan. We previously showed that neuropeptide Y (NPY), an appetite-stimulating peptide, is essential for the anti-oxidative and life-extending effects of CR. Here, we investigated whether a Japanese traditional herbal medicine, rikkunshito (RKT), which induces NPY activation, has CR-like life-extending effects. METHODS: First, we evaluated the life-extending activity of RKT by examining the effect of long-term RKT administration on wild-type and NPY knockout mice. Furthermore, we tested whether RKT enhances CR-mediated beneficial effects under AL conditions with a normal diet and under mild CR conditions with a high-fat diet. We then used 3-nitropropionic acid or doxorubicin to induce oxidative stress, and analyzed the differences in survival rate, weight loss, gene expression and cellular oxidative damage among groups. RESULTS: RKT administration did not extend the lifespan of wild-type or NPY knockout mice. In the oxidative stress models, RKT treatment upregulated anti-oxidative gene expression in the liver. Furthermore, RKT administration reduced the oxidative damage in the liver compared to the CR conditions alone. However, on induction of oxidative stress by 3-nitropropionic acid or doxorubicin, RKT administration did not affect the survival rate. CONCLUSIONS: These results show that RKT administration only partially mimics the effects of CR at the cellular level, but not at the organismal level to increase the lifespan of mice. Geriatr Gerontol Int 2019; ••: ••-••.

Mechanisms of Calorie Restriction: A Review of Genes Required for the Life-Extending and Tumor-Inhibiting Effects of Calorie Restriction.

This review focuses on mechanisms of calorie restriction (CR), particularly the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis as an evolutionary conserved signal that regulates aging and lifespan, underlying the effects of CR in mammals. Topics include (1) the relation of the GH-IGF-1 signal with chronic low-level inflammation as one of the possible causative factors of aging, that is, inflammaging, (2) the isoform specificity of the forkhead box protein O (FoxO) transcription factors in CR-mediated regulation of cancer and lifespan, (3) the role for FoxO1 in the tumor-inhibiting effect of CR, (4) pleiotropic roles for FoxO1 in the regulation of disorders, and (5) sirtuin (Sirt) as a molecule upstream of FoxO. From the evolutionary view, the necessity of neuropeptide Y (Npy) for the effects of CR and the pleiotropic roles for Npy in life stages are also emphasized. Genes for mediating the effects of CR and regulating aging are context-dependent, particularly depending on nutritional states.

Targeting miR-223 in neutrophils enhances the clearance of Staphylococcus aureus in infected wounds.

Argonaute 2 bound mature microRNA (Ago2-miRNA) complexes are key regulators of the wound inflammatory response and function in the translational processing of target mRNAs. In this study, we identified four wound inflammation-related Ago2-miRNAs (miR-139-5p, miR-142-3p, miR-142-5p, and miR-223) and show that miR-223 is critical for infection control. miR-223Y/- mice exhibited delayed sterile healing with prolonged neutrophil activation and interleukin-6 expression, and markedly improved repair of Staphylococcus aureus-infected wounds. We also showed that the expression of miR-223 was regulated by CCAAT/enhancer binding protein alpha in human neutrophils after exposure to S. aureus peptides. Treatment with miR-223Y/--derived neutrophils, or miR-223 antisense oligodeoxynucleotides in S. aureus-infected wild-type wounds markedly improved the healing of these otherwise chronic, slow healing wounds. This study reveals how miR-223 regulates the bactericidal capacity of neutrophils at wound sites and indicates that targeting miR-223 might be of therapeutic benefit for infected wounds in the clinic.

Identification and functional analysis of inflammation-related miRNAs in skin wound repair.

Inflammation at a wound site is essential for preventing infection. However, misregulated inflammation leads to pathologies of the healing process, including chronic non-healing wounds and scarring. MicroRNAs (miRNAs) are key regulators of the inflammatory response and tissue repair, acting by translational processing of target mRNAs. In the final step of miRNA processing, Argonaute 2 (Ago2)-bound mature miRNA complexes bind to target mRNAs and inhibit their translation. A variety of wound healing-related miRNAs have been identified and their misregulation likely contributes to wound pathologies, including scarring and chronic healing. Recently, we have developed an Ago2-bound mature miRNA purification system that uses Ago2 antibody to analyze the expression of miRNAs from wound tissues by microarray and next generation sequencing. We have identified several wound inflammation-related miRNAs via Ago2-target immunoprecipitation assays and next generation sequencing of wound tissues from wild-type and PU.1 knockout mice, which exhibit no inflammatory response because of a lack of immune cell lineages. We demonstrated that miR-142, an identified inflammation-related miRNA, is essential role for neutrophilic chemotaxis via inhibition of small GTPase translation; its misregulation leads to susceptibility to infection against Staphylococcus aureus at skin wound sites. In this review, we summarize recent advances of miRNA studies in skin wound healing, introduce our miRNA purification system using an immunoprecipitation assay method, and discuss the function of miR-142 in skin wound healing.

GALT carcinoma: three case reports with glycoprotein 2 immunohistochemistry and electron microscopic observations.

AIMS: Gut-associated lymphoid tissue (GALT) carcinoma is a rare colorectal tumour that arises in the epithelium covering GALT. GALT carcinoma is a differentiated tubular adenocarcinoma with dense lymphoid tissue with a characteristically well-demarcated margin. To date, 26 cases of GALT carcinoma, including the three cases discussed here, have been reported. Most (24 of 26) were discovered at early stages and none of the cases have documented any metastases. This suggests that GALT carcinoma may have a favourable prognosis. It is hypothesised that GALT carcinoma originates from M cells in specialised epithelia covering GALT. However, this hypothesis has yet to be confirmed. METHODS AND RESULTS: In this study, we examined three cases of GALT carcinoma by immunohistochemistry detection of glycoprotein 2, a specific marker for M cells, and electron microscopy. Our findings showed that the tumour cells of GALT carcinoma in all three cases were negative for M cells. We thus concluded that GALT carcinoma may be a tubular adenocarcinoma arising by chance in the GALT. This unique carcinoma is a diferentiated adenocarcinoma that grows slowly with the development of GALT. CONCLUSIONS: We propose that GALT carcinoma should be classified separately because of its histological setting and good prognosis.

Comparing the Effects of Melatonin with Caloric Restriction in the Hippocampus of Aging Mice: Involvement of Sirtuin1 and the FOXOs Pathway.

It has been suggested that age-related neurodegeneration might be associated with neuropeptide Y (NPY); sirtuin1 (SIRT1) and forkhead box transcription factors O subfamily (FOXOs) pathways. Melatonin, a hormone mainly secreted by the pineal gland, is another anti-aging agent associated with the SIRT1-FOXOs pathway. This study aimed to compare the effects of melatonin (Mel) and caloric restriction (CR) on the expression of Sirt1, FoxO1, FoxO3a and FOXOs target genes in the aging mouse hippocampus. Neuropeptide Y-knockout (NpyKO) and wild-type (WT) male mice aged 19 months were previously treated either with food ad libitum or CR for 16 months. WT old animals were divided into four groups: control, CR, Mel and CR+Mel treated groups. The Mel and CR+Mel were treated with melatonin 10 mg/kg, daily, subcutaneously for 7 consecutive days. Mel treatment upregulated the mRNA expression of Sirt1, FOXOs (FoxO1 and FoxO3a) target genes that regulated the cell cycle [e.g., cyclin-dependent kinase inhibitor 1B (p27)], Wingless and INT-1 (Wnt1) and inducible signaling pathway protein 1 (Wisp1) in the aged mouse hippocampus. CR treatment also showed the similar actions. However, the mRNA expression of Sirt1, FoxO1, FoxO3a, p27 or Wisp1 did not alter in the CR+Mel group when compared with CR or Mel group. Melatonin could not produce any additive effect on the CR treatment group, suggesting that both treatments mimicked the effect, possibly via the same pathway. NPY which mediates physiological adaptations to energy deficits is an essential link between CR and longevity in mice. In order to focus on the role of Npy in mediating the effects of melatonin, the gene expression between NpyKO and WT male mice were compared. Our data showed that, in the absence of Npy, melatonin could not mediate effects on those gene expressions, suggesting that Npy was required for melatonin to mediate the effect, possibly, on life extension.

Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction.

Caloric restriction (CR) can delay onset of several age-related pathophysiologies and extend lifespan in various species, including rodents. CR also induces metabolic remodeling involved in activation of lipid metabolism, enhancement of mitochondrial biogenesis, and reduction of oxidative stress in white adipose tissue (WAT). In studies using genetically modified mice with extended lifespans, WAT characteristics influenced mammalian lifespans. However, molecular mechanisms underlying CR-associated metabolic remodeling of WAT remain unclear. Sterol regulatory element-binding protein-1c (Srebp-1c), a master transcription factor of fatty acid (FA) biosynthesis, is responsible for the pathogenesis of fatty liver (steatosis). Our study showed that, under CR conditions, Srebp-1c enhanced mitochondrial biogenesis via increased expression of peroxisome proliferator-activated receptor gamma coactivator-1α (Pgc-1α) and upregulated expression of proteins involved in FA biosynthesis within WAT. However, via Srebp-1c, most of these CR-associated metabolic alterations were not observed in other tissues, including the liver. Moreover, our data indicated that Srebp-1c may be an important factor both for CR-associated suppression of oxidative stress, through increased synthesis of glutathione in WAT, and for the prolongevity action of CR. Our results strongly suggested that Srebp-1c, the primary FA biosynthesis-promoting transcriptional factor implicated in fatty liver disease, is also the food shortage-responsive factor in WAT. This indicated that Srebp-1c is a key regulator of metabolic remodeling leading to the beneficial effects of CR.

Malignant peritoneal mesothelioma, clear cell variant, in a female and its differentiation from clear cell carcinoma.

Epithelial type malignant mesothelioma with a clear cell morphology is rare, and no case arising in the peritoneum of a female patient has been reported. Here we report a case of clear cell mesothelioma that developed in the peritoneum of a 61-year-old female. The patient died from massive ascites and respiratory failure 11days after her hospital admission. The autopsy demonstrated marked thickening of the omentum and a yellowish-whitish tumor diffusely covering the abdominal organs. The predominantly solid tumor was characterized microscopically by the growth of atypical cells with an abundant clear cytoplasm. The immunohistochemical study suggested mesothelioma rather than carcinoma. Electron microscopy showed the long and slender villi of the tumor cells, confirming the diagnosis. Primary clear cell carcinoma of the peritoneum, like clear cell mesothelioma, is rare and was also a diagnostic consideration in this patient. The differentiation between these two tumors is discussed herein.

Neuropeptide Y resists excess loss of fat by lipolysis in calorie-restricted mice: a trait potential for the life-extending effect of calorie restriction.

Neuropeptide Y (NPY) is an orexigenic peptide that plays an essential role in caloric restriction (CR)-mediated lifespan extension. However, the mechanisms underlying the NPY-mediated effects in CR are poorly defined. Here, we report that NPY deficiency in male mice during CR increases mortality in association with lipodystrophy. NPY-/- mice displayed a rapid decrease in body weight and fat mass, as well as increased lipolysis during CR. These alterations in fat regulation were inhibited by the lipolysis inhibitor, acipimox, a treatment associated with reduced mortality. The lipolytic/thermogenic signaling, ß3-adrenergic receptor/hormone sensitive lipase, was markedly activated in white adipose tissue of NPY-/- mice compared with that of NPY+/+ mice, and thermogenesis was controlled by NPY under negative energy balance. These results demonstrate the critical role of NPY in the regulation of lipid metabolic homeostasis and survival via control of lipolysis and thermogenesis in a state of negative energy balance.

MiR-142 Is Required for Staphylococcus aureus Clearance at Skin Wound Sites via Small GTPase-Mediated Regulation of the Neutrophil Actin Cytoskeleton.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate protein translation by binding to complementary target mRNAs. We previously identified two mature members of the miR-142 family, miR-142-5p and miR-142-3p, as inflammation-related miRNAs with potential roles in wound healing. Here, we demonstrated that these two miRNAs are prominently expressed in wound-infiltrated neutrophils and macrophages and play central roles in wound healing. We generated miR-142-/- mice using the exchangeable gene-trap method and showed that healing of Staphylococcus aureus-infected skin wounds was significantly delayed in miR-142-/- mice compared with that in wild-type mice. MiR-142-/- mice exhibited abnormal abscess formation at S. aureus-infected skin wound sites and were also more susceptible to horizontal transmission of wound infections. MiR-142-/- neutrophils showed altered phagocytosis as a consequence of chemotactic behavior, including enhanced F-actin assembly, disturbed cell polarity, and increased cell motility. We showed that these changes were linked to cytoskeletal regulation, and that expression of the small GTPases was markedly increased in miR-142-/- neutrophils. Collectively, our data demonstrate that the miR-142 family is indispensable for protection against S. aureus infection and its clearance at wound sites. MiR-142-3p and miR-142-5p play nonredundant roles in actin cytoskeleton regulation by controlling small GTPase translation in neutrophils at wound sites.