Browsing by Author "Koyama, Sachiko"
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Item A follow-up on quantitative and qualitative olfactory dysfunction and other symptoms in patients recovering from COVID-19 smell loss(ERS, 2022-06-01) Ohla, Kathrin; Veldhuizen, Maria G.; Green, Tomer; Hannum, Mackenzie E.; Bakke, Alyssa J.; Moein, Shima T.; Tognetti, Arnaud; Postma, Elbrich M.; Pellegrino, Robert; Hwang, Daniel Liang-Dar; Albayay, Javier; Koyama, Sachiko; Nolden, Alissa A.; Thomas-Danguin, Thierry; Mucignat-Caretta, Carla; Menger, Nick S.; Croijmans, Ilja; Öztürk, Lina; Yanık, Hüseyin; Pierron, Denis; Pereda-Loth, Veronica; Nunez-Parra, Alexia; Martinez Pineda, Aldair M.; Gillespie, David; Farruggia, Michael C.; Cecchetto, Cinzia; Fornazieri, Marco A.; Philpott, Carl; Voznessenskaya, Vera; Cooper, Keiland W.; Rohlfs Dominguez, Paloma; Calcinoni, Orietta; de Groot, Jasper; Boesveldt, Sanne; Bhutani, Surabhi; Weir, Elisabeth M.; Exten, Cara; Joseph, Paule V.; Parma, Valentina; Hayes, John E.; Niv, Masha Y.; Surgery, School of MedicineBackground: Sudden smell loss is a specific early symptom of COVID-19, which, prior to the emergence of Omicron, had estimated prevalence of ~40% to 75%. Chemosensory impairments affect physical and mental health, and dietary behavior. Thus, it is critical to understand the rate and time course of smell recovery. The aim of this cohort study was to characterize smell function and recovery up to 11 months post COVID-19 infection. Methods: This longitudinal survey of individuals suffering COVID-19-related smell loss assessed disease symptoms and gustatory and olfactory function. Participants (n=12,313) who completed an initial survey (S1) about respiratory symptoms, chemosensory function and COVID-19 diagnosis between April and September 2020, were invited to complete a follow-up survey (S2). Between September 2020 and February 2021, 27.5% participants responded (n=3,386), with 1,468 being diagnosed with COVID-19 and suffering co-occurring smell and taste loss at the beginning of their illness. Results: At follow-up (median time since COVID-19 onset ~200 days), ~60% of women and ~48% of men reported less than 80% of their pre-illness smell ability. Taste typically recovered faster than smell, and taste loss rarely persisted if smell recovered. Prevalence of parosmia and phantosmia was ~10% of participants in S1 and increased substantially in S2: ~47% for parosmia and ~25% for phantosmia. Persistent smell impairment was associated with more symptoms overall, suggesting it may be a key marker of long-COVID illness. The ability to smell during COVID-19 was rated slightly lower by those who did not eventually recover their pre-illness ability to smell at S2. Conclusions: While smell ability improves for many individuals who lost it during acute COVID-19, the prevalence of parosmia and phantosmia increases substantially over time. Olfactory dysfunction is associated with broader persistent symptoms of COVID-19, and may last for many months following acute COVID-19. Taste loss in the absence of smell loss is rare. Persistent qualitative smell symptoms are emerging as common long-term sequelae; more research into treatment options is strongly warranted given that even conservative estimates suggest millions of individuals may experience parosmia following COVID-19. Healthcare providers worldwide need to be prepared to treat post COVID-19 secondary effects on physical and mental health.Item Cross-generational impact of a male murine pheromone 2-sec-butyl-4,5- dihydrothiazole in female mice(The Royal Society, 2015-07-22) Koyama, Sachiko; Soini, Helena A.; Wager-Miller, James; Alley, William R.; Pizzo, Matthew J.; Rodda, Cathleen; Alberts, Jeffrey; Crystal, Jonathon D.; Lai, Cary; Foley, John; Novotny, Milos V.; Department of Dermatology, IU School of MedicineThe current understanding of the activity of mammalian pheromones is that endocrine and behavioural effects are limited to the exposed individuals. Here, we demonstrate that the nasal exposure of female mice to a male murine pheromone stimulates expansion of mammary glands, leading to prolonged nursing of pups. Subsequent behavioural testing of the pups from pheromone-exposed dams exhibited enhanced learning. Sialic acid components in the milk are known to be involved in brain development. We hypothesized that the offspring might have received more of this key nutrient that promotes brain development. The mRNA for polysialyltransferase, which produces polysialylated neural cell adhesion molecules related to brain development,was increased in the brain of offspring of pheromone-exposed dams at post-natal day 10, while it was not different at embryonic stages, indicating possible differential brain development during early post-natal life.Item Current Perspectives of Neuroendocrine Regulation in Liver Fibrosis(MDPI, 2022-11-26) Li, Bowen; Wang, Hui; Zhang, Yudian; Liu, Ying; Zhou, Tiejun; Zhou, Bingru; Zhang, Ying; Chen, Rong; Xing, Juan; He, Longfei; Salinas, Jennifer Mata; Koyama, Sachiko; Meng, Fanyin; Wan, Ying; Medicine, School of MedicineLiver fibrosis is a complicated process that involves different cell types and pathological factors. The excessive accumulation of extracellular matrix (ECM) and the formation of fibrotic scar disrupt the tissue homeostasis of the liver, eventually leading to cirrhosis and even liver failure. Myofibroblasts derived from hepatic stellate cells (HSCs) contribute to the development of liver fibrosis by producing ECM in the area of injuries. It has been reported that the secretion of the neuroendocrine hormone in chronic liver injury is different from a healthy liver. Activated HSCs and cholangiocytes express specific receptors in response to these neuropeptides released from the neuroendocrine system and other neuroendocrine cells. Neuroendocrine hormones and their receptors form a complicated network that regulates hepatic inflammation, which controls the progression of liver fibrosis. This review summarizes neuroendocrine regulation in liver fibrosis from three aspects. The first part describes the mechanisms of liver fibrosis. The second part presents the neuroendocrine sources and neuroendocrine compartments in the liver. The third section discusses the effects of various neuroendocrine factors, such as substance P (SP), melatonin, as well as α-calcitonin gene-related peptide (α-CGRP), on liver fibrosis and the potential therapeutic interventions for liver fibrosis.Item Dysbiosis in gastrointestinal pathophysiology: Role of the gut microbiome in Gulf War Illness(Wiley, 2023) Slevin, Elise; Koyama, Sachiko; Harrison, Kelly; Wan, Ying; Klaunig, James E.; Wu, Chaodong; Shetty, Ashok K.; Meng, Fanyin; Medicine, School of MedicineGulf War Illness (GWI) has been reported in 25%-35% of veterans returned from the Gulf war. Symptoms of GWI are varied and include both neurological and gastrointestinal symptoms as well as chronic fatigue. Development of GWI has been associated with chemical exposure particularly with exposure to pyridostigmine bromide (PB) and permethrin. Recent studies have found that the pathology of GWI is connected to changes in the gut microbiota, that is the gut dysbiosis. In studies using animal models, the exposure to PB and permethrin resulted in similar changes in the gut microbiome as these found in GW veterans with GWI. Studies using animal models have also shown that phytochemicals like curcumin are beneficial in reducing the symptoms and that the extracellular vesicles (EV) released from gut bacteria and from the intestinal epithelium can both promote diseases and suppress diseases through the intercellular communication mechanisms. The intestinal epithelium cells produce EVs and these EVs of intestinal epithelium origin are found to suppress inflammatory bowel disease severity, suggesting the benefits of utilizing EV in treatments. On the contrary, EV from the plasma of septic mice enhanced the level of proinflammatory cytokines in vitro and neutrophils and macrophages in vivo, suggesting differences in the EV depending on the types of cells they were originated and/or influences of environmental changes. These studies suggest that targeting the EV that specifically have positive influences may become a new therapeutic strategy in the treatment of veterans with GWI.Item Endurance training slows breast tumor growth in mice by suppressing Treg cells recruitment to tumors(Biomed Central, 2019-06-04) Hagar, Amit; Wang, Zemin; Koyama, Sachiko; Serrano, Josua Aponte; Melo, Luma; Vargas, Stephanie; Carpenter, Richard; Foley, John; Dermatology, School of MedicineBACKGROUND: Aerobic exercise has been shown to slow tumor progression in rodents and humans, but the mechanisms behind this effect are still unclear. Here we show that aerobic exercise in the form of chronic endurance training suppresses tumor recruitment of FoxP3+ Treg cells thus enhancing antitumor immune efficiency. METHODS: Adult wild-type and athymic BALB/c female mice were endurance-trained for 8 weeks. Circulating leukocytes as well as muscle and liver mtDNA copy number were compared to aged-matched concurrent sedentary controls to establish systemic effects. 4 T1 murine mammary tumor cells were injected subcutaneously to the 4th mammary pad at the end of the training period. Tumor growth and survival rates were compared, together with antitumor immune response. RESULTS: Exercised wild-type had 17% slower growth rate, 24% longer survival, and 2-fold tumor-CD+ 8/FoxP3+ ratio than sedentary controls. Exercised athymic BALB/c females showed no difference in tumor growth or survival rates when compared to sedentary controls. CONCLUSIONS: Cytotoxic T cells are a significant factor in endurance exercise-induced suppression of tumor growth. Endurance exercise enhances antitumor immune efficacy by increasing intratumoral CD8+/FoxP3+ ratio.Item Estrogen modulates mesenchyme-epidermis interactions in the adult nipple(Company of Biologists, 2017-04-15) Wu, Hsing-Jung; Oh, Ji Won; Spandau, Dan F.; Tholpady, Sunil; Diaz, Jesus, III; Schroeder, Laura J.; Offutt, Carlos D.; Glick, Adam B.; Plikus, Maksim V.; Koyama, Sachiko; Foley, John; Medicine, School of MedicineMaintenance of specialized epidermis requires signals from the underlying mesenchyme; however, the specific pathways involved remain to be identified. By recombining cells from the ventral skin of the K14-PTHrP transgenic mice [which overexpress parathyroid hormone-related protein (PTHrP) in their developing epidermis and mammary glands] with those from wild type, we show that transgenic stroma is sufficient to reprogram wild-type keratinocytes into nipple-like epidermis. To identify candidate nipple-specific signaling factors, we compared gene expression signatures of sorted Pdgfrα-positive ventral K14-PTHrP and wild-type fibroblasts, identifying differentially expressed transcripts that are involved in WNT, HGF, TGFβ, IGF, BMP, FGF and estrogen signaling. Considering that some of the growth factor pathways are targets for estrogen regulation, we examined the upstream role of this hormone in maintaining the nipple. Ablation of estrogen signaling through ovariectomy produced nipples with abnormally thin epidermis, and we identified TGFβ as a negatively regulated target of estrogen signaling. Estrogen treatment represses Tgfβ1 at the transcript and protein levels in K14-PTHrP fibroblasts in vitro, while ovariectomy increases Tgfb1 levels in K14-PTHrP ventral skin. Moreover, ectopic delivery of Tgfβ1 protein into nipple connective tissue reduced epidermal proliferation. Taken together, these results show that specialized nipple epidermis is maintained by estrogen-induced repression of TGFβ signaling in the local fibroblasts.Item Expansion of specialized epidermis induced by hormonal state and mechanical strain(Elsevier, 2015-05) Wu, Hsin-Jung; Easwaran, Teresa; Offutt, Carlos D.; Elgar, Richard Levi; Spandau, Dan F.; Koyama, Sachiko; Foley, John; Department of Medicine, IU School of MedicineIn mammals, some sites of specialized skin such as the palms, soles, and lips grow proportionally with the animal. However, other types of specialized skin such as the nipple and anal/genital region are dramatically altered with changes of reproductive status. The specific cell types that mediate the growth of these sites have not been identified. In the mouse, we observed a dramatic expansion of the specialized epidermis of the nipple, coupled to changes in connective tissue and hair shaft density, which we designate as areola formation. During this process thymidine analog uptake was elevated in the epidermis and hair follicles. Although there were no changes in connective tissue cell proliferation, we did observe an altered expression of extracellular matrix genes. In addition, the fibroblasts of the virgin nipple areola and region showed increased transcript and protein levels for estrogen, progesterone, relaxin, and oxytocin relative to those of ventral skin. To determine the role of pregnancy, lactation hormonal milieu, and localized mechanical strain on areola formation, we created models that separated these stimuli and evaluated changes in gross structure, proliferation and protein expression. While modest increases of epidermal proliferation and remodeling of connective tissue occurred as a result of individual stimuli, areola formation required exposure to pregnancy hormones, as well as mechanical strain.Item Insight into the mechanisms of olfactory dysfunction by COVID-19(Elsevier, 2023) Koyama, Sachiko; Mori, Eri; Ueha, Rumi; Medicine, School of MedicineOne of the unique symptoms of COVID-19 is chemosensory dysfunction. Almost three years since the beginning of the pandemic of COVID-19, there have been many studies on the symptoms, progress, and possible causes, and also studies on methods that may facilitate recovery of the senses. Studies have shown that some people recover their senses even within a couple of weeks whereas there are other patients that fail to recover chemosensory functions fully for several months and some never fully recover. Here we summarize the symptoms and the progress, and then review the papers on the causation as well as the treatments that may help facilitate the recovery of the symptoms. Depending on the differences in the levels of severity and the locations where the main pathological venues are, what is most effective in facilitating recovery can vary largely across patients and thus may require individualized strategies for each patient. The goal of this paper is to provide some thoughts on these choices depending on the differences in the causes and severity.Item miR-34a regulates macrophage-associated inflammation and angiogenesis in alcohol-induced liver injury(Wolters Kluwer, 2023-04-04) Wan, Ying; Slevin, Elise; Koyama, Sachiko; Huang, Chiung-Kuei; Shetty, Ashok K.; Li, Xuedong; Harrison, Kelly; Li, Tian; Zhou, Bingru; Lorenzo, Sugeily Ramos; Zhang, Yudian; Salinas, Jennifer Mata; Xu, Wenjuan; Klaunig, James E.; Wu, Chaodong; Tsukamoto, Hidekazu; Meng, Fanyin; Medicine, School of MedicineBackground: Alcohol-associated liver disease (ALD) is a syndrome of progressive inflammatory liver injury and vascular remodeling associated with long-term heavy intake of ethanol. Elevated miR-34a expression, macrophage activation, and liver angiogenesis in ALD and their correlation with the degree of inflammation and fibrosis have been reported. The current study aims to characterize the functional role of miR-34a-regulated macrophage- associated angiogenesis during ALD. Methods results: We identified that knockout of miR-34a in 5 weeks of ethanol-fed mice significantly decreased the total liver histopathology score and miR-34a expression, along with the inhibited liver inflammation and angiogenesis by reduced macrophage infiltration and CD31/VEGF-A expression. Treatment of murine macrophages (RAW 264.7) with lipopolysaccharide (20 ng/mL) for 24 h significantly increased miR-34a expression, along with the enhanced M1/M2 phenotype changes and reduced Sirt1 expression. Silencing of miR-34a significantly increased oxygen consumption rate (OCR) in ethanol treated macrophages, and decreased lipopolysaccharide-induced activation of M1 phenotypes in cultured macrophages by upregulation of Sirt1. Furthermore, the expressions of miR-34a and its target Sirt1, macrophage polarization, and angiogenic phenotypes were significantly altered in isolated macrophages from ethanol-fed mouse liver specimens compared to controls. TLR4/miR-34a knockout mice and miR-34a Morpho/AS treated mice displayed less sensitivity to alcohol-associated injury, along with the enhanced Sirt1 and M2 markers in isolated macrophages, as well as reduced angiogenesis and hepatic expressions of inflammation markers MPO, LY6G, CXCL1, and CXCL2. Conclusion: Our results show that miR-34a-mediated Sirt1 signaling in macrophages is essential for steatohepatitis and angiogenesis during alcohol-induced liver injury. These findings provide new insight into the function of microRNA-regulated liver inflammation and angiogenesis and the implications for reversing steatohepatitis with potential therapeutic benefits in human alcohol-associated liver diseases.