The clinical impact of comorbidities among patients with idiopathic pulmonary fibrosis undergoing anti-fibrotic treatment: A multicenter retrospective observational study.

BACKGROUND: Among patients with idiopathic pulmonary fibrosis (IPF), few studies have investigated the clinical impact of anti-fibrotic treatment (AFT) with and without comorbidities. The aim of the study was to determine whether Charlson Comorbidity Index score (CCIS) can predict the efficacy of AFT in patients with IPF. METHODS: We retrospectively assessed data extracted from the medical records of IPF patients who received anti-fibrotic agents between 2009 and 2019. The collected data included age, sex, CCIS, pulmonary function test, high-resolution computed tomography (HRCT) pattern, gender/age/physiology (GAP) score, and 3-year IPF-related events defined as the first acute exacerbation or death within 3 years after starting AFT. RESULTS: We assessed 130 patients (median age, 74 years) who received nintedanib (n = 70) or pirfenidone (n = 60). Median duration of AFT was 425 days. Patients were categorized into high (≥ 3 points) and low (≤ 2 points) CCIS groups. There was no significant difference between the groups in terms of age, sex, duration of AFT, GAP score, or incidence of usual interstitial pneumonia pattern on HRCT except percentage predicted diffusion capacity of lung for carbon monoxide. Also, significant difference was not seen between the groups for 3-year IPF-related events (P = 0.75). Especially, in the low CCIS group but not the high CCIS group, the longer duration of AFT had better disease outcome. CONCLUSION: In the present study, we could not show any relation between CCIS and IPF disease outcomes in patients undergoing AFT, though the longer duration of AFT might be beneficial for IPF outcomes among patients with low CCIS.

Cardiovascular Protective Effects of Polyphenols Contained in Passion Fruit Seeds Namely Piceatannol and Scirpusin B: A Review.

Cardiovascular disease is a global health problem. According to the World Health Organization, ischemic heart disease was the leading cause of death globally in 2019, followed by stroke. The French paradox, which has been known since the early 1990s, describes the lower incidence of ischemic heart disease in French people despite the consumption of a diet rich in saturated fatty acids. This phenomenon has been attributed to the high intake of red wine, which is rich in polyphenols, namely, resveratrol and piceatannol. It is becoming clear that scirpusin B, a dimer of piceatannol, has anti-atherosclerotic properties such as vasodilation, antioxidant effects, and suppression of postprandial hyperglycemia; nonetheless, the effects of scirpusin B on the cardiovascular system have not been fully elucidated. This review aimed to describe the cardiovascular effects of piceatannol and scirpusin B on aortic and coronary artery dilation and cardiac function and to outline the cardiovascular effects of prostacyclin and nitric oxide, as these substances are involved in the vasodilatory effects exerted by these polyphenols.

Acute Effects of Transdermal Administration of Jojoba Oil on Lipid Metabolism in Mice.

Background and objectives: Aroma therapy is a complementary therapy using essential oils diluted with carrier oils. Jojoba oils have been widely used as carrier oils. However, limited information is available regarding their effects on blood biochemical parameters. This study aimed to investigate the effect of transdermal administration of jojoba oil on blood biochemical parameters in mice. Materials and Methods: Eight-week-old male hairless mice were randomly divided into naïve control and treatment groups. In the treatment group, mice were topically administered 4 µL of jojoba oil, per gram of body weight, on the dorsa 30 min before euthanasia. Thereafter, serum biochemical parameters were assayed, and gene expression was analyzed in various tissues via a real-time polymerase chain reaction. Results: Serum non-esterified fatty acid (NEFA) levels increased significantly 30 min after topical application of jojoba oil (p < 0.05). Atgl was significantly upregulated in the liver (p < 0.05), and Atgl upregulation in the liver was positively correlated with serum NEFA levels (r = 0.592, p < 0.05). Furthermore, a trend of decreasing fatty acid trafficking-related gene (FABPpm, FATP-1, FATP-3, and FATP-4) expression in the skin after topical application of jojoba oil (p = 0.067, 0.074, 0.076, and 0.082, respectively) was observed. Conclusions: Serum NEFA levels were elevated 30 min after transdermal administration of jojoba oil. The mechanisms of elevated serum NEFA levels might be related to both enhanced lipolysis in the liver and reduced fatty acid trafficking in the skin.

Efficacy of Kaempferia parviflora in a mouse model of obesity-induced dermatopathy.

Obesity results from excessive energy intake and physical inactivity, and predisposes one to various diseases. One of these reasons is that enlargement of adipocytes raises the lipid metabolic abnormalities that affect various organs. The skin is one such organ, and it has been reported that subcutaneous adipocyte cells secrete various factors and these factors are involved in reduction of dermal collagen fibers and fragility of the skin in obesity. The present study explored the efficacy of Kaempferia parviflora (KP) in preventing obesity-induced dermatopathy. We used Tsumura Suzuki obese diabetes (TSOD) mice as an obesity model. TSOD mice were fed a standard diet (MF) mixed with either an ethanol extract from KP (KPE), polymethoxyflavonoid-rich extract from KP (PMF), or polymethoxyflavonoid-poor extract from KP (X). We then evaluated the effect of these three KP fractions on aging-like skin damage induced by UVB irradiation. KPE and PMF caused a significant decrease of mouse body weight, and suppressed the increase in the thickness of the subcutaneous fat layer. In addition, KPE shifted the frequency of subcutaneous adipocyte sizes towards smaller cells possibly via its polypharmacological actions. Scanning electron microscopy revealed that the stereostructure of the collagenous fibers in the dermis was better retained in the KPE and PMF groups, in that order. These results offer the first evidence that KPE can attenuate obesity-induced dermatopathy more effectively than PMF, suggesting that KPE (or KP) might be a candidate supplement for preventing obesity-related skin disorders.

[A case of lung adenocarcinoma with gradual enlargement of thin-walled cavity causing pneumothorax].

A 71-year-old man presented with a thin-walled cavity in his left lung in November 2006. A previous chest CT in 2003 showed a small thin-walled cavity in his left lingula. Although no obvious change was observed in 2004, the cavity increased its size from 11mm to 14mm in diameter and the wall became thicker in June 2006. On the first visit to our hospital in November 2006, the diameter of the cavity was 30mm and some part of the wall was thinner than on the previous CT. The patient developed pneumothorax one month later and underwent segmentectomy of the left lingula after unsuccessful thoracic drainage. Poorly differentiated adenocarcinoma was identified in both the pleura and the inner wall around the cavity. Lung adenocarcinoma with gradual enlargement of a thin-walled cavity causing pneumothorax has never been reported before. We report here the natural course of lung adenocarcinoma with a thin-walled cavity.

[Case of pneumothorax associated with pulmonary Mycobacterium fortuitum infection].

A 39-year-old man with dyspnea was revealed to have severe pneumothorax and received partial resection of the left upper lobe after unsuccessful drainage. Necrotizing epitheloid granuloma was found in the resected lung and Mycobacterium fortuitum was detected from the lesion. Chemotherapy with levofloxacin and clarithromycin was started one year after surgery because of the newly found nodular shadow near the lesion. The case experienced pyothorax due to pulmonary tuberculosis three years before and Mycobacterium avium pleuritis one year before this episode. Three-time mycobacterial pleural infection in three years seems to be uncommon. Furthermore this is the first report of pneumothorax associated with pulmonary Mycobacterium fortuitum infection.

Aryl hydrocarbon receptor plays a significant role in mediating airborne particulate-induced carcinogenesis in mice.

Urban particulate air pollution is associated with an increased incidence of cancers, and especially lung cancer. Organic extracts of airborne particulate matter (APM) cause cancer in mice, and PAHs adsorbed to APM are associated with particle-induced carcinogenesis. PAHs are agonists for AhR and are predominantly responsible for lung cancer through induction of highly carcinogenic metabolites. PAH metabolization requires CYP1A1 induction through activation of AhR, and therefore we hypothesized that carcinogenesis due to PAHs in APM would be reduced in AhR-/- mice. To examine this hypothesis, we performed a long-term continuous-application study of carcinogenesis in AhR-/- mice using airborne particulate extract (APE) of APM collected in Sapporo. Tumor development (squamous cell carcinoma) occurred in 8 of 17 AhR+/+ mice (47%), but no tumors were found in AhR-/-mice, and CYP1A1 was induced in AhR+/+ mice but not in AhR-/- mice. These results demonstrate that AhR plays a significant role in APE-induced carcinogenesis in AhR+/+ mice and CYP1A1 activation of carcinogenic PAHs is also of importance. Therefore, measurement of CYP1A1 induction in vitro may be useful for assessment of APM-induced carcinogenesis in humans. We also show that PAH-like compounds are major contributors to AhR-mediated carcinogenesis, whereas TCDD and related compounds make a smaller contribution.

Spreading of methylation within RUNX3 CpG island in gastric cancer.

RUNX3 is a novel tumor suppressor gene that is frequently silenced by promoter hypermethylation in gastric cancer. The methylation status of multiple regions within the RUNX3 promoter CpG island (3,478 bp) was examined in gastric cancer cell lines, primary gastric cancers and non-neoplastic gastric mucosa to clarify how methylation spreads within the CpG island. The critical regions for RUNX3 silencing were evaluated by analysis of cell lines. The most 5' region of the CpG island was methylated in 90% (9/10) of gastric cancer cell lines, 96% (43/45) of primary gastric cancers and in 96% (43/45) of non-neoplastic gastric mucosa. The frequencies of methylation were less near the transcription start site and were 40% (4/10) in cell lines, 53% (24/45) in primary gastric cancers and 11% (5/45) in non-neoplastic gastric mucosa, where methylation was proven to be critical for gene silencing. Thus, hypermethylation initially occurs at the most 5' region of the RUNX3 CpG island and spreads to the transcription start site before ultimately shutting down RUNX3 mRNA expression. The detection of hypermethylation at multiple regions within the RUNX3 CpG island may be useful in the diagnosis and risk assessment of gastric cancer.

Genotoxic damage in female residents exposed to environmental air pollution in Shenyang city, China.

Air pollution has been suggested to cause genetic damage from investigations of many biological markers that measure cytogenetic damage in humans. Here, we evaluated the genotoxic effects of ambient air pollution by investigating the extent of cytogenetic damage in human blood lymphocytes from rural and industrial female residents of Shenyang city, China, using micronuclei assays and polymorphic analyses of metabolic enzyme and DNA repair genes. After adjustment for potential confounding factors including DNA polymorphisms, industrial female residents were found to have a higher micronuclei frequency. These results provide evidence that micronuclei assays are a sensitive indicator to air pollution-induced genotoxic effects in humans.

[A case of hypersensitivity pneumonitis caused by inhalation of Mycobacterium avium from a home bath with a circulating water system].

A 26-year-old man presented with complaints of exertional dyspnea and cough. The patient has already been given corticosteroids at a previous hospital. Chest CT revealed small centrilobular nodules with diffuse ground-glass opacities in both lungs. Lung biopsy specimens at thoracoscopy revealed non-necrotizing granulomas, patchy foci of mononuclear cell infiltration and fibrous thickening of alveolar septa, and Masson's bodies in bronchioles. Sputum culture showed the growth of Mycobacterium avium complex (MAC). Culture of water from the bath tub of his home showed MAC. Administration of antituberculous drugs and corticosteroids, and avoidance of bathing at home resulted in the improvement of his symptoms and CT findings. We believe the case is hypersensitivity pneumonitis to MAC in an immunocompetent patient, simulating hot tub lung. Hypersensitivity pneumonitis caused by MAC is rare in Japan.

CYP1A1 inducing potential of airborne particulate extracts collected during a 25-year period (1975-2000).

Samples of airborne particles from Sapporo, the capital of Hokkaido, Japan, were collected between 1975 and 2000. Major polycyclic aromatic hydrocarbons (PAHs) included in the extracts of airborne particles were investigated for their mutagenicity and potential for inducing drug-metabolizing enzyme cytochrome P450 (CYP)1A1, which is considered to be responsible for the activation of PAHs in airborne particle extracts, as well as in cigarette smoke, to carcinogens and is associated with risk of several cancers. There was a dose-related increase in CYP1A1 activity in human lymphoblastoid cells after exposure to airborne particulates containing PAHs. The mutagenicity of the airborne particles collected in summer was lowest and for those collected in spring was lower than in autumn or winter. Likewise, the winter sample had the strongest CYP1A1 inducing potential while the summer sample had the weakest. CYP1A1 inducing potency was strongly related to the amount of benzo(k)fluorathene (Spearman's rank correlation coefficient (gamma) = 0.97), benzo[a]pyrene g = 0.96), benzo[g,h,i]perylene (gamma = 0.94), benz[a]anthracene (g = 0.93), chrysene (gamma = 0.93) in the extracts during the 25-year period, while the enzyme activity was measurably related to the amount of pyrene (gamma = 0.64) and fluorathene (gamma = 0.54). During the 25-year period, CYP1A1 inducing potential decreased every year together with a decrease in PAHs in the airborne particle extracts. CYP1A1 inducing potential may be one of the most convenient biomarkers with which to estimate the overall carcinogenicity/mutagenicity of airborne particle extracts.

A centrosomal localization signal in cyclin E required for Cdk2-independent S phase entry.

Excess cyclin E-Cdk2 accelerates entry into S phase of the cell cycle and promotes polyploidy, which may contribute to genomic instability in cancer cells. We identified 20 amino acids in cyclin E as a centrosomal localization signal (CLS) essential for both centrosomal targeting and promoting DNA synthesis. Expressed wild-type, but not mutant, CLS peptides localized on the centrosome, prevented endogenous cyclin E and cyclin A from localizing to the centrosome, and inhibited DNA synthesis. Ectopic cyclin E localized to the centrosome and accelerated S phase entry even with mutations that abolish Cdk2 binding, but not with a mutation in the CLS. These results suggest that cyclin E has a modular centrosomal-targeting domain essential for promoting S phase entry in a Cdk2-independent manner.

Multifocal granular cell tumors of the gastrointestinal tract: Immunohistochemical findings compared with those of solitary tumors.

Granular cell tumors (GCT) are infrequently found in the gastrointestinal tract (GIT), and only four previous reports have described lesions occurring simultaneously in different sites. The present case of 11 GCT, located in the esophagus, stomach, colon and pericolic adipose tissue, occurred in a 50-year-old Japanese woman. All GCT appeared histologically benign and there was no sign of recurrence at 3 years after surgery. Immunohistochemical analysis and comparison between this case of multifocal GCT and six cases of solitary benign GCT of the GIT, which were taken from the files of the Department of Pathology at Kitasato University (1986-2000), demonstrated the follow-ing: (1) all diffusely expressed S-100, DCC and bcl-2, and (2) median labeling indices for Ki-67, cyclin D1, p53 (Pab1801), and p21WAF1/CIP1 of 4%, 24%, 1% and 28%, respectively, for the multifocal tumors, and 3.5%, 23%, 1% and 29%, respectively, for the solitary lesions, with no significant difference between the two groups. Thus, the expression of cyclin D1 and p21WAF1/CIP1 may be involved in the tumorigenesis of both types of GCT. The present case emphasizes the need to evaluate the entire GIT when a single GCT is identified. Multifocal lesions should be treated conservatively by local excision because, as with the solitary tumors, they exhibit a benign biological behavior, consistent with their low Ki-67 immunoreactivity.

Neutrophil elastase inhibitor attenuates lipopolysaccharide-induced hepatic microvascular dysfunction in mice.

The present study was conducted to elucidate the role of neutrophil elastase in lipopolysaccharide (LPS)-induced hepatic microvascular injury by using in vivo microscopy. The intravenous (i.v.) injection of LPS (0.1 mg/kg) in male C3H/HeN mice caused significant hepatic microcirculatory dysfunction: leukocyte adhesion to the sinusoids as well as to the venule, and reduced sinusoidal perfusion, in comparison with vehicle-treated mice. Concomitantly, the serum alanine aminotransferase (ALT) activity at 4 h after LPS injection was significantly increased. The serum concentrations of tumor necrosis factor (TNFalpha) and interleukin-1beta (IL-1beta) at 1 h and at 4 h after LPS injection, respectively, were significantly elevated. Neutrophil elastase inhibitors, ONO-5046 (30 and 90 mg/kg, i.v., 0 and 2 h after LPS injection) or FK706 (30 and 100 mg/kg, i.v., 0 and 2 h after LPS injection) minimized the LPS-induced hepatic microcirculatory dysfunction in a dose-dependent manner. Treatment with ONO-5046 and FK706 significantly reduced the ALT level as well as the serum concentrations of TNFalpha and IL-1beta. In addition, ONO-5046 and FK706 attenuated both hepatic microcirculatory dysfunction and liver injury mediated by TNFalpha and IL-1beta (10 microg/kg i.v.). Furthermore, both ONO-5046 and FK706 improved human neutrophil elastase (10 microg/kg i.v.)-induced hepatic microcirculatory dysfunction, although neutrophil elastase did not increase the levels of TNFalpha and IL-1beta. These results suggest that neutrophil elastase aggravates the LPS-induced hepatic microvascular dysfunction. Neutrophil elastase inhibitors attenuate hepatic microvascular dysfunction in response to LPS by inhibiting TNFalpha and IL-1beta production. Neutrophil elastase inhibitors also reduce the microvascular dysfunction mediated by TNFalpha and IL-1beta as well as by neutrophil elastase.

Effect of FR167653, a novel inhibitor of tumor necrosis factor-alpha and interleukin-1beta synthesis on lipopolysaccharide-induced hepatic microvascular dysfunction in mice.

Tumor necrosis factor-alpha (TNFalpha) and interleukin-1 (IL-1) have been recognized as key proinflammatory mediators in the pathogenesis of lipopolysaccharide (LPS)-induced liver injury. In the present study we examined the effect of FR167653, a novel inhibitor of TNFalpha and IL-1 synthesis, on the hepatic microvascular response to LPS using in vivo microscopy. Significant hepatic microvascular responses comprising leukocyte adhesion to the sinusoidal wall and central venules and reduced sinusoidal perfusion appeared 2 and 4 h after LPS (0.1 mg/kg, i.v.) injection in male C3H/HeN mice (LPS sensitive) when compared with male C3H/HeJ mice (LPS resistant). The serum concentrations of TNFalpha at 1.5 h and IL-1beta at 4 h after injection of LPS, as determined by enzyme-linked immunosorbent assay, were significantly higher in C3H/HeN mice than in C3H/HeJ mice. Administration of murine TNFalpha or IL-1beta (10 microg/kg., i.v., respectively) in both C3H/HeN and C3H/HeJ mice elicited the hepatic microvascular responses that were similar to those produced by LPS injection in C3H/HeN mice. FR167653 (1 and 10 mg/kg, i.v., 0 and 2 h after LPS injection) significantly reduced leukocyte adhesion and restored sinusoidal perfusion in a dose-dependent manner in C3H/HeN mice 4 h after LPS injection. The levels of TNFalpha, IL-1beta, and alanine aminotransferase also were significantly lower in FR167653-treated endotoxemic C3H/HeN mice than those in vehicle-treated endotoxemic animals. The results suggest that the hepatic microvascular response to LPS is partly mediated by TNFalpha and IL-1beta, and that FR167653 prevents LPS-induced hepatic microcirculatory dysfunction by inhibiting the production of TNFalpha and IL-1beta.

Calcium, calmodulin, and CaMKII requirement for initiation of centrosome duplication in Xenopus egg extracts.

Aberrant centrosome duplication is observed in many tumor cells and may contribute to genomic instability through the formation of multipolar mitotic spindles. Cyclin-dependent kinase 2 (Cdk2) is required for multiple rounds of centrosome duplication in Xenopus egg extracts but not for the initial round of replication. Egg extracts undergo periodic oscillations in the level of free calcium. We show here that chelation of calcium in egg extracts or specific inactivation of calcium/calmodulin-dependent protein kinase II (CaMKII) blocks even initial centrosome duplication, whereas inactivation of Cdk2 does not. Duplication can be restored to inhibited extracts by addition of CaMKII and calmodulin. These results indicate that calcium, calmodulin, and CaMKII are required for an essential step in initiation of centrosome duplication. Our data suggest that calcium oscillations in the cell cycle may be linked to centrosome duplication.