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In hypoxic pulmonary hypertension (PH), pulmonary vascular remodeling is characterized by the emergence of activated adventitial fibroblasts, leading to medial smooth muscle hyperplasia. Previous studies have suggested that CD26/dipeptidyl peptidase-4 (DPP4) plays a crucial role in the pathobiological processes in lung diseases. However, its role in pulmonary fibroblasts in hypoxic PH remains unknown. Therefore, we aimed to clarify the mechanistic role of CD26/DPP4 in lung fibroblasts in hypoxic PH. Dpp4 knockout (Dpp4 KO) and wild-type (WT) mice were exposed to hypoxia for 4 weeks. The degree of PH severity and medial wall thickness was augmented in Dpp4 KO mice compared with that in WT mice, suggesting that CD26/DPP4 plays a suppressive role in the development of hypoxic PH. Transcriptome analysis of human lung fibroblasts cultured under hypoxic conditions revealed that TGFB2, TGFB3, and TGFA were all upregulated as differentially expressed genes after DPP4 knockdown with small interfering RNA treatment. These results suggest that CD26/DPP4 plays a suppressive role in TGFβ signal-regulated fibroblast activation under hypoxic conditions. Therefore, CD26/DPP4 may be a potential therapeutic target in patients with PH associated with chronic hypoxia. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension (PH) with interstitial lung diseases (ILDs) often causes intractable conditions. CD26/Dipeptidyl peptidase-4 (DPP4) is expressed in lung constituent cells and may be related to the pathogenesis of various respiratory diseases. We aimed to clarify the functional roles of CD26/DPP4 in PH-ILD, paying particular attention to vascular smooth muscle cells (SMCs). Dpp4 knockout (Dpp4KO) and wild type (WT) mice were administered bleomycin (BLM) intraperitoneally to establish a PH-ILD model. The BLM-induced increase in the right ventricular systolic pressure and the right ventricular hypertrophy observed in WT mice were attenuated in Dpp4KO mice. The BLM-induced vascular muscularization in small pulmonary vessels in Dpp4KO mice was milder than that in WT mice. The viability of TGFβ-stimulated human pulmonary artery SMCs (hPASMCs) was lowered due to the DPP4 knockdown with small interfering RNA. According to the results of the transcriptome analysis, upregulated genes in hPASMCs with TGFβ treatment were related to pulmonary vascular SMC proliferation via the Notch, PI3K-Akt, and NFκB signaling pathways. Additionally, DPP4 knockdown in hPASMCs inhibited the pathways upregulated by TGFβ treatment. These results suggest that genetic deficiency of Dpp4 protects against BLM-induced PH-ILD by alleviating vascular remodeling, potentially through the exertion of an antiproliferative effect via inhibition of the TGFβ-related pathways in PASMCs. [ABSTRACT FROM AUTHOR]

Background: Cathepsin K, which is involved in bone resorption, is a good target for treating osteoporosis, but no clinically approved medicine has been developed. Recently, allosteric inhibitors with high specificity and few side effects have been attracting attention for use in new medicines. Methods: Cathepsin K inhibitors were isolated from the methanol extract of Chamaecrista nomame (Leguminosae) using cathepsin K inhibition activity-assisted multi-step chromatography. Standard kinetic analysis was employed to examine the mechanism of cathepsin K inhibition when an isolated inhibitor and its derivative were used. The allosteric binding of these cathepsin K inhibitors was supported by a docking study using AutoDock vina. Combinations of allosteric cathepsin K inhibitors expected to bind to different allosteric sites were examined by means of cathepsin K inhibition assay. Results: Two types of cathepsin K inhibitors were identified in the methanol extract of Chamaecrista nomame. One type consisted of cassiaoccidentalin B and torachrysone 8-β-gentiobioside, and inhibited both cathepsin K and B with similar inhibitory potential, while the other type of inhibitor consisted of pheophytin a, and inhibited cathepsin K but not cathepsin B, suggesting that pheophytin a binds to an allosteric site of cathepsin K. Kinetic analysis of inhibitory activity suggested that pheophytin a and its derivative, pheophorbide b, bind allosterically to cathepsin K. This possibility was supported by a docking study on cathepsin K. The cathepsin K inhibitory activity of pheophytin a and pheophorbide b was enhanced by combining them with the allosteric inhibitors NSC 13345 and NSC94914, which bind to other allosteric sites on cathepsin K. Conclusions: Different allosteric inhibitors that bind to different sites in combination, as shown in this study, may be useful for designing new allosteric inhibitory drugs with high specificity and few side effects. [ABSTRACT FROM AUTHOR]

Orbital emphysema after nose-blowing is an uncommon condition and can appear without a trigger. Herein, we reported a case of orbital emphysema after nose-blowing and performed a literature review. A 68-year-old man fell and sustained an injury near his left orbit. No symptoms were noted. He noticed a left periorbital swelling after blowing his nose. Through computed tomography examination, he was diagnosed with subcutaneous emphysema. There are no previous reports that have reviewed the clinical features, need for surgery, and severity of symptoms of subcutaneous emphysema after nasal swallowing due to different factors. We retrospectively analyzed a cohort of 48 cases by searching PubMed to clarify these issues. Regarding the emphysema trigger, 21 cases had an injury or had previously undergone surgery. In 34 cases, conservative treatment was required, while surgery was selected in the acute phase in 6 cases and after the acute phase as a radical cure in 8 cases. Reduced visual acuity, diplopia, exophthalmos, facial hypoesthesia, and color disorders were noted and were more common among surgical cases. The literature review revealed no association between fracture location and the need for surgery; furthermore, surgery was less required in non-trauma cases, excluding osteoma, than in trauma cases (p = 0.0169). Our study reveals that a strict follow-up examination of visual symptoms is necessary for the first 2 days in cases of subcutaneous emphysema caused by nose blowing after facial trauma. [ABSTRACT FROM AUTHOR]

The use of an endoscope in exoscopic transcranial neurosurgery for skull-base lesions has not yet been investigated. Thus, this study aimed to investigate the advantages, disadvantages, and safety of "simultaneous temporary use of an endoscope during exoscopic surgery" (exo-endoscopic surgery (EES)). Consecutive exo-endoscopic surgeries performed by experienced neurosurgeons and assistants were analyzed. Surgical complications and time were compared with previous consecutive microsurgeries performed by the same surgeon. A questionnaire survey was conducted on 16 neurosurgeons with experience in both "temporary simultaneous use of endoscope during microscopic surgery" (micro-endoscopic surgery (MES)) and EES. EES was performed in 18 of 76 exoscopic surgeries, including tumor removal (n = 10), aneurysm clipping (n = 5), and others (n = 3). There were no significant differences in operative time, anesthesia time, or complications from microsurgery by the same operator. According to the questionnaire survey results, compared with MES, EES had a wider field of view due to its lack of an eyepiece, was easier when loading and unloading instruments into and out of the surgical field, and was more suitable for the simultaneous observation of two fields of view. Overall, 79.2% of surgeons indicated that EES may be better suited than MES to simultaneously observe two fields of view. [ABSTRACT FROM AUTHOR]

Lipomas of the cerebellopontine angle (CPA) and internal auditory canal (IAC) are relatively rare tumors. Acoustic neurinoma is the most common tumor in this location, which often causes hearing loss, vertigo, and tinnitus. Occasionally, this tumor compresses the brainstem, prompting surgical resection. Lipomas in this area may cause symptoms similar to neurinoma. However, they are not considered for surgical treatment because their removal may result in several additional deficits. Conservative therapy and repeated magnetic resonance imaging examinations for CPA/IAC lipomas are standard measures for preserving cranial nerve function. Herein, we report a case of acoustic neurinoma and CPA lipoma occurring in close proximity to each other ipsilaterally. The main symptom was hearing loss without facial nerve paralysis. Therefore, facial nerve injury had to be avoided. Considering the anatomical relationships among the tumors, cranial nerves, and CPA/IAC lipoma, we performed total surgical removal of the acoustic neurinoma. We intentionally left the lipoma untreated, which enabled facial nerve preservation. This report may be a useful reference for the differential diagnosis of similar cases in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of prostate cancer (PC) is statistically biased due to the increase in prostate-specific antigen (PSA) screening and the accuracy of national cancer registration systems. However, studies on latent PC provide less biased information. This comprehensive review included studies evaluating latent PC in several countries. The prevalence of latent PC has been stable since 1950 in Western countries, but it has increased over time in Asian countries. Latent PC in Asian men has increased in prevalence and is higher in grade. This increase occurred not only due to the increase in PSA screening, but also due to increasing adoption of a Westernized lifestyle. Racial differences between Caucasian and Asian men may also explain the tumor location of latent PC. The autopsy findings in patients with latent PC included a significant proportion of high grade and stage cancers, suggesting a need to reconsider the definition of clinically insignificant PC. The incidence of prostate cancer (PC) has been increasing in Asian countries, where it was previously low. Although the adoption of a Westernized lifestyle is a possible explanation, the incidence is statistically biased due to the increase in prostate-specific antigen (PSA) screening and the accuracy of national cancer registration systems. Studies on latent PC provide less biased information. This review included studies evaluating latent PC in several countries after excluding studies using random or single-section evaluations and those that did not mention section thickness. The findings showed that latent PC prevalence has been stable since 1950 in Western countries, but has increased over time in Asian countries. Latent PC in Asian men has increased in both prevalence and number of high-grade cases. Racial differences between Caucasian and Asian men may explain the tumor location of latent PC. In conclusion, the recent increase in latent PC in Asian men is consistent with an increase in clinical PC. Evidence suggests that this increase is caused not only by the increase in PSA screening, but also by the adoption of a more Westernized lifestyle. Autopsy findings suggest the need to reconsider the definition of clinically insignificant PC. [ABSTRACT FROM AUTHOR]

Melatonin is probably produced in all cells but is only secreted by the pineal gland. The pineal secretion of melatonin is determined by the light–dark cycle, and it is only released at night. Melatonin regulates biological rhythms via its receptors located in the suprachiasmatic nuclei of the hypothalamus. Melatonin also has strong antioxidant activities to scavenge free radicals such as reactive oxygen species (ROS). The direct free radical scavenging actions are receptor independent. ROS play an important role in reproductive function including in the ovulatory process. However, excessive ROS can also have an adverse effect on oocytes because of oxidative stress, thereby causing infertility. It is becoming clear that melatonin is located in the ovarian follicular fluid and in the oocytes themselves, which protects these cells from oxidative damage as well as having other beneficial actions in oocyte maturation, fertilization, and embryo development. Trials on humans have investigated the improvement of outcomes of assisted reproductive technology (ART), such as in vitro fertilization and embryo transfer (IVF-ET), by way of administering melatonin to patients suffering from infertility. In addition, clinical research has examined melatonin as an anti-aging molecule via its antioxidative actions, and its relationship with the aging diseases, e.g., Alzheimer's and Parkinson's disease, is also underway. Melatonin may also reduce ovarian aging, which is a major issue in assisted reproductive technology. This review explains the relationship between melatonin and human reproductive function, as well as the clinical applications expected to improve the outcomes of assisted reproductive technology such as IVF, while also discussing possibilities for melatonin in preventing ovarian aging. [ABSTRACT FROM AUTHOR]