Goji Berry Juice Prevents Tumor Necrosis Factor Alpha-Induced Xerostomia in Human Salivary Gland Cells.

Sjögren's syndrome (SS) is an autoimmune disorder characterized by oral dryness that is primarily attributed to tumor necrosis factor alpha (TNF-α)-mediated reduction in saliva production. In traditional Chinese medicine, goji berries are recognized for their hydrating effect and are considered suitable to address oral dryness associated with Yin deficiency. In the present study, we used goji berry juice (GBJ) to investigate the potential preventive effect of goji berries on oral dryness caused by SS. Pretreatment of human salivary gland cells with GBJ effectively prevented the decrease in aquaporin-5 (AQP-5) mRNA and protein levels induced by TNF-α. GBJ also inhibited histone H4 deacetylation and suppressed the generation of intracellular reactive oxygen species (ROS). Furthermore, GBJ pretreatment reserved mitochondrial membrane potential and suppressed the upregulation of Bax and caspase-3, indicating that GBJ exerted an antiapoptotic effect. These findings suggest that GBJ provides protection against TNF-α in human salivary gland cells and prevents the reduction of AQP-5 expression on the cell membrane. Altogether, these results highlight the potential role of GBJ in preventing oral dryness caused by SS.

Lanicepines A and B, Sesquiterpenes with Amino Acid-Derived Substituents from the Flowering Aerial Parts of Saussurea laniceps.

Two new guaianolide sesquiterpenes, lanicepines A (1) and B (2), possessing unusual amino acid-derived substituents at C-13, were isolated from the flowering aerial parts of Saussurea laniceps, a traditional herbal medicine also known as "snow lotus". The structures of 1 and 2 were elucidated based on spectroscopic analysis including applications of the modified Mosher's method and Marfey's method as well as ECD calculations. Lanicepine A (1) contains a dihydropyridinone moiety with a carbamoyl and a hydroxymethyl group. This substituent was considered to consist of asparagine and a C4 unit. In contrast, lanicepine B (2) has a substituent that seems to be derived from l-proline and a C4 unit. Lanicepines A (1) and B (2) and two related known sesquiterpenes isolated from the same plant material, 11ß,13-dihydrodesacylcynaropicrin (3) and 11ß,13-dihydrodesacylcynaropicrin 8-O-ß-d-glucoside (4), demonstrated inhibitory activity against IL-1ß production from LPS-stimulated microglial cells.

Lophachinins A-E, abietane diterpenes from a Mongolian traditional herbal medicine Lophanthus chinensis.

Five new abietane diterpenes, lophachinins A-E (1-5), and eleven known related diterpenes were isolated from a Mongolian traditional herbal medicine, the aerial parts of Lophanthus chinensis (Lamiaceae). The structures of new diterpenes were assigned by spectroscopic analyses. Lophachinins A (1) and B (2) were abietane diterpene possessing an endoperoxy bridge at C-ring. In contrast, lophachinins C-E (3-5) had an abietane skeleton with an aromatized C-ring. The absolute configuration of 1 was elucidated by application of the modified Mosher's method, while those of 2, 3, and 5 were assigned by chemical conversions. The absolute configuration of lophachinin D (4) was deduced by ECD calculation. Anti-inflammatory activity of isolated diterpenes on microglial cells were evaluated.

Linaburiosides A-D, acylated iridoid glucosides from Linaria buriatica.

Four previously undescribed acylated iridoid glucosides, linaburiosides A‒D, one undescribed iridoid, 7-deoxyiridolactonic acid, and one known acylated iridoid glucoside, iridolinarin C, were isolated from the aerial parts of a Mongolian traditional herbal medicine, Linaria buriatica. Linaburiosides A‒D had an acyl moiety corresponding to 7-deoxyiridolactonic acid. Detailed spectroscopic analyses of linaburiosides A‒D and 7-deoxyiridolactonic acid led to the assignment of their structures. The absolute configuration of 7-deoxyiridolactonic acid was elucidated by application of the PGME method; those of linaburiosides A‒D were assigned on the basis of chemical conversions, as well as application of the modified Mosher's method. The absolute configuration of iridolinarin C was also elucidated in this study. Anti-inflammatory and antiproliferative activities of isolated compounds and their derivatives were evaluated.

Novel formula using triceps skinfold thickness to revise the Cockcroft-Gault equation for estimating renal function in Japanese bedridden elderly patients.

In recumbent elderly patients, creatinine clearance (eCCr) estimated by the Cockcroft-Gault (CG) equation may not necessarily reflect renal function. We aimed to develop a novel formula to revise the CG equation using anthropometric measurements in bedridden elderly patients and evaluate its clinical utility. The subjects included 77 bedridden Japanese patients aged ≦ 65, hospitalized at Naruto Yamakami Hospital. The actual CCr (mCCr) value was measured using the 24-hour urine collection method. Anthropometric data, such as skeletal muscle mass, body fat mass (BFM), and triceps skinfold thickness (TSF), were collected. We established a novel formula to estimate CCr(BFM) or CCr(TSF) by correcting the eCCr(Enz+0.2) value with BFM or TSF. The stage of classification of renal dysfunctions in patients with eGFR(BFM) or eGFR(TSF) was equivalent to the GFR(control) based on the mCCr. Notably, the novel equation for eCCr based on TSF (eCCr(TSF)), dubbed the "Naruto" formula, can be useful to evaluate renal function in bedridden elderly patients without expensive equipment or additional costs. In this study, mCCr was considered to be the true renal function of the patient, but whether and to what extent mCCr correlates with inulin clearance is unknown. J. Med. Invest. 65:195-202, August, 2018.

Rigenolides D-H, norsecoiridoid and secoiridoids from Gentiana rigescens Franch.

Five new compounds, rigenolides D-H (1-5), were isolated from the aerial parts of Gentiana rigescens Franch. Their structures were assigned by detailed spectroscopic analyses and chemical conversions. Rigenolides D (1) and E (2) were elucidated to be a secoiridoid and a norsecoiridoid, respectively, possessing a dienone moiety in common. Rigenolides F-H (3-5) were assigned as acylated secoiridoid glucosides.

Kamishoyosan and Shakuyakukanzoto promote recovery from paclitaxel-induced neurite retraction in PC12 cells.

BACKGROUND: In chemotherapy, the full round of treatment must be completed as scheduled to achieve the strongest therapeutic effect. However, peripheral neuropathy, a severe side effect of the chemotherapeutic agent paclitaxel, can force the premature discontinuation of treatment. As some kampo practitioners have suggested that it may be possible to counteract such side effects, we analyzed the effects of Kamishoyosan, Shakuyakukanzoto, and Goshajinkigan in an in vitro model of paclitaxel-induced peripheral neuropathy. METHODS: Paclitaxel-treated PC12 cells were assessed for neurite length and performed Western blot analysis for growth-associated protein-43 (GAP-43) and light neurofilament protein (NF-L) levels in the presence of nerve growth factor (NGF); they were re-assessed, with additional testing for acetylcholinesterase levels, after application of one of the kampo. We also compared phosphorylation of extracellular signal-regulated kinase (Erk)1/2 and Akt via Western blot analysis. About effect of kampo to anticancer efficacy, we confirmed cell cytotoxicity in A549 cells using MTT assay. RESULTS: Addition of Kamishoyosan or Shakuyakukanzoto, but not Goshajinkigan, significantly improved neurite length and GAP-43 and NF-L levels from paclitaxel-treated PC12 cells, relative to those of only NGF-treated PC12 cells. The promoting effect of Kamishoyosan and Shakuyakukanzoto in neurite outgrowth is confirmed when NGF promoted neurite outgrowth, and it was inhibited partially when Erk1/2 and Akt were blocked by Erk1/2 inhibitor or Akt inhibitor alone. Furthermore, neurite outgrowth induced by TJ24 and TJ68 was inhibited more strongly when Erk1/2 inhibitor and Akt inhibitor were treated at the same time. NGF with Kamishoyosan or Shakuyakukanzoto promoted the proportion of phosphorylated Erk1/2 and phosphorylated Akt compare with NGF only. On the other hand, Kamishoyosan or Shakuyakukanzoto didn't influence cytotoxicity of paclitaxel in A549 cells. CONCLUSIONS: Kamishoyosan or Shakuyakukanzoto promotes neurite outgrowth with NGF via increasing the proportion of phosphorylated Erk1/2 and phosphorylated Akt in PC12 cells. The effect applies to recovery from paclitaxel-induced axonal involvement and might promote recovery from paclitaxel-induced neuropathy without influence of anticancer effect of paclitaxel.

Helianthus tuberosus (Jerusalem artichoke) tubers improve glucose tolerance and hepatic lipid profile in rats fed a high-fat diet.

OBJECTIVES: To analyze the effects of feeding Helianthus tuberosus (HT) tubers on glucose tolerance and lipid profile in rats fed a high-fat diet (HFD). METHODS: A normal HFD or HFD including 10 w/w% HT tubers (HFD + HT) was fed to F334/Jcl rats. After 10 weeks, organ weights, glucose tolerance, and lipid profile were analyzed. RESULTS: The body weight, liver weight, and epidermal fat content in the HFD group were higher than those of the normal group, and similar to those of the HFD + HT group. The oral glucose tolerance test at 10 weeks revealed that the blood glucose level 30 min after beginning the test in the HFD + HT group was significantly lower than that in the HFD group. Liver triglyceride and total cholesterol levels in the HFD + HT group were significantly lower than those in the HFD group. Fecal triglyceride and total cholesterol levels in the HFD + HT group were higher than those in the HFD group. Histological analyses revealed that fat and glycogen accumulation increased in the HFD group, but decreased in the HFD + HT group. CONCLUSIONS: These results indicate that HT tubers have anti-fatty liver effects based on improvements in glucose tolerance and the hepatic lipid profile.

Extracts of Immature Orange (Aurantii fructus immaturus) and Citrus Unshiu Peel (Citri unshiu pericarpium) Induce P-Glycoprotein and Cytochrome P450 3A4 Expression via Upregulation of Pregnane X Receptor.

P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) are expressed in the intestine and are associated with drug absorption and metabolism. Pregnane X receptor (PXR) is the key molecule that regulates the expression of P-gp and CYP3A4. Given that PXR activity is regulated by a variety of compounds, it is possible that unknown PXR activators exist among known medicines. Kampo is a Japanese traditional medicine composed of various natural compounds. In particular, immature orange [Aurantii fructus immaturus (IO)] and citrus unshiu peel [Citri unshiu pericarpium (CP)] are common ingredients of kampo. A previous study reported that kampo containing IO or CP decreased the blood concentration of concomitant drugs via upregulation of CYP3A4 although the mechanism was unclear. Some flavonoids are indicated to alter P-gp and CYP3A4 activity via changes in PXR activity. Because IO and CP include various flavonoids, we speculated that the activity of P-gp and CYP3A4 in the intestine may be altered via changes in PXR activity when IO or CP is administered. We tested this hypothesis by using LS180 intestinal epithelial cells. The ethanol extract of IO contained narirutin and naringin, and that of CP contained narirutin and hesperidin. Ethanol extracts of IO and CP induced P-gp, CYP3A4, and PXR expression. The increase of P-gp and CYP3A4 expression by the IO and CP ethanol extracts was inhibited by ketoconazole, an inhibitor of PXR activation. The ethanol extract of IO and CP decreased the intracellular concentration of digoxin, a P-gp substrate, and this decrease was inhibited by cyclosporine A, a P-gp inhibitor. In contrast, CP, but not IO, stimulated the metabolism of testosterone, a CYP3A4 substrate, and this was inhibited by a CYP3A4 inhibitor. These findings indicate that the ethanol extract of IO and CP increased P-gp and CYP3A4 expression via induction of PXR protein. Moreover, this induction decreased the intracellular substrate concentration.

Evaluation of effects of various drugs on platelet functions using phorbol 12-myristate 13-acetate-induced megakaryocytic human erythroid leukemia cells.

BACKGROUND: The hyperfunction and activation of platelets have been strongly implicated in the development and recurrence of arterial occlusive disease, and various antiplatelet drugs are used to treat and prevent such diseases. New antiplatelet drugs and many other drugs have been developed, but some drugs may have adverse effects on platelet functions. OBJECTIVE: The aim of this study was to establish an evaluation method for evaluating the effect and adverse effect of various drugs on platelet functions. MATERIALS AND METHODS: Human erythroid leukemia (HEL) cells were used after megakaryocytic differentiation with phorbol 12-myristate 13-acetate as an alternative to platelets. Drugs were evaluated by changes in intracellular Ca2+ concentration ([Ca2+]i) mobilization in Fura2-loaded phorbol 12-myristate 13-acetate-induced HEL cells. Aspirin and cilostazol were selected as antiplatelet drugs and ibuprofen and sodium valproate as other drugs. RESULTS: There was a positive correlation between [Ca2+]i and platelet aggregation induced by thrombin. Aspirin (5.6-560 µM) and cilostazol (5-10 µM) significantly inhibited thrombin-induced increases in [Ca2+]i in a concentration-dependent manner. On the other hand, ibuprofen (8-200 µM) and sodium valproate (50-1,000 µg/mL) also significantly inhibited thrombin-induced increases in [Ca2+]i in a concentration-dependent manner. Furthermore, the interaction effects of the simultaneous combined use of aspirin and ibuprofen or sodium valproate were evaluated. When the inhibitory effect of aspirin was higher than that of ibuprofen, the effect of aspirin was reduced, whereas when the inhibitory effect of aspirin was lower than that of ibuprofen, the effect of ibuprofen was reduced. The combination of aspirin and sodium valproate synergistically inhibited thrombin-induced [Ca2+]i. CONCLUSION: It is possible to induce HEL cells to differentiate into megakaryocytes, which are a useful model for the study of platelet functions, and the quantification of the inhibition of thrombin-induced increases in [Ca2+]i is applicable to the evaluation of the effects of various drugs on platelets.

Tetrahydroxanthones from Mongolian medicinal plant Gentianella amarella ssp. acuta.

Two tetrahydroxanthones, 1,3,5S,8S-tetrahydroxy-5,6,7,8-tetrahydroxanthone (1) and 1,3,5R,8S-tetrahydroxy-5,6,7,8-tetrahydroxanthone (2), and six new tetrahydroxanthone glycosides, amarellins A-F (3-8), were isolated from the aerial parts of a Mongolian medicinal plant Gentianella amarella ssp. acuta (Gentianaceae). The structures of 1-8 were elucidated on the basis of spectroscopic analysis, chemical conversion, and ECD calculation. Amarellins A-C (3-5) were assigned as 8-O-ß-D-glucoside, 8-O-ß-D-xyloside, and 1-O-ß-D-glucoside of 1, respectively, while amarellins D-F (6-8) were elucidated to be 8-O-ß-D-xyloside, 1-O-ß-D-glucoside, and 3-O-ß-D-glucoside of 2, respectively.

Antitumor effect of novel anti-podoplanin antibody NZ-12 against malignant pleural mesothelioma in an orthotopic xenograft model.

Podoplanin (aggrus) is highly expressed in several types of cancers, including malignant pleural mesothelioma (MPM). Previously, we developed a rat anti-human podoplanin mAb, NZ-1, and a rat-human chimeric anti-human podoplanin antibody, NZ-8, derived from NZ-1, which induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against podoplanin-positive MPM cell lines. In this study, we showed the antitumor effect of NZ-1, NZ-8, and NZ-12, a novel rat-human chimeric anti-human podoplanin antibody derived from NZ-1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ-1 and rat NK (CD161a(+) ) cells inhibited the growth of tumors and the production of pleural effusion in NCI-H290/PDPN or NCI-H226 orthotopic xenograft mouse models. NZ-8 and human natural killer (NK) (CD56(+) ) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Furthermore, NZ-12 induced potent ADCC mediated by human MNC, compared with either NZ-1 or NZ-8. Antitumor effects were observed following treatment with NZ-12 and human NK (CD56(+) ) cells in MPM orthotopic xenograft mice. In addition, combined immunotherapy using the ADCC activity of NZ-12 mediated by human NK (CD56(+) ) cells with pemetrexed, led to enhanced antitumor effects in MPM orthotopic xenograft mice. These results strongly suggest that combination therapy with podoplanin-targeting immunotherapy using both NZ-12 and pemetrexed might provide an efficacious therapeutic strategy for the treatment of MPM.

Evaluation of the risk factors associated with high-dose chemotherapy-induced dysgeusia in patients undergoing autologous hematopoietic stem cell transplantation: possible usefulness of cryotherapy in dysgeusia prevention.

PURPOSE: Dysgeusia is one of the sporadic adverse effects induced by chemotherapy, but it remains poorly understood. The aim of this study was to retrospectively identify the risk factors related with dysgeusia in patients undergoing autologous hematopoietic stem cell transplantation (AHSCT). METHODS: Forty-eight patients with myeloma or lymphoma undergoing AHSCT were enrolled in this study. Data regarding dysgeusia and symptoms were collected by interviews conducted by medical workers. Patient characteristics and unfavorable effects induced by dysgeusia were obtained from medical records and analyzed. Logistic regression analysis was performed to identify the risk factors related with dysgeusia. RESULTS: Of the 48 patients, 20 (42 %) had dysgeusia after AHSCT. The total period of parenteral nutrition (TPN) administration and period of decreased oral intake in the dysgeusia group were statistically longer than those in the non-dysgeusia group. Multivariate analyses revealed that oral mucositis (odds ratio: 30.3; p < 0.01) and the type of chemotherapy prior to AHSCT (odds ratio: 6.56; p < 0.05) were independent risk factors, while oral cryotherapy was the independent suppressive factor of dysgeusia (odds ratio: 0.14; p < 0.05). CONCLUSION: Our study showed that dysgeusia after AHSCT led to the decrease in oral intake and extended the TPN administration period. Moreover, MEAM or LEED chemotherapy and oral mucositis were independent risk factors for dysgeusia in patients undergoing AHSCT, while oral cryotherapy was an independent suppressive factor for dysgeusia. Therefore, oral cryotherapy should be implemented into the regimen of supportive care management in patients undergoing AHSCT.

Clinical Evaluation of Pharmacist Interventions in Patients Treated with Anti-methicillin-Resistant Staphylococcus aureus Agents in a Hematological Ward.

The therapeutic effects of anti-methicillin-resistant Staphylococcus aureus (MRSA) agents, vancomycin (VCM), teicoplanin (TEIC), and arbekacin (ABK), depend on their concentrations in blood. Therefore, therapeutic drug monitoring (TDM) is important when these antibiotics are used. In the hematological ward at Tokushima University Hospital, pharmacists have ordered the measurement of blood VCM, TEIC, and ABK concentrations to promote the use of TDM in accordance with an agreed protocol since 2013. Moreover, the infection control team includes several medical disciplines and has advised on the optimal treatment using VCM, TEIC, and ABK since 2013. This study aimed to investigate the clinical effectiveness of these pharmacist interventions. We retrospectively studied 145 cases in which patients were treated with VCM, TEIC, or ABK between January 2012 and December 2013 in the hematological ward at Tokushima University Hospital. The patients were divided into a control group (71 cases) and an intervention group (74 cases), and their clinical outcomes were compared. The rate of achievement of effective drug concentrations significantly increased in the intervention group (74%), compared to the rate in the control group (55%). Moreover, univariate and multivariate Cox proportional hazard regression revealed that pharmacist intervention and appropriate concentrations of anti-MRSA agents were independent factors associated with reduced hospitalization periods in patients with lymphoma. Our study revealed that proactive pharmacist intervention may improve the therapeutic effect of anti-MRSA agents in hematology ward patients.

Encapsulation in a rapid-release liposomal formulation enhances the anti-tumor efficacy of pemetrexed in a murine solid mesothelioma-xenograft model.

We recently developed a PEG-coated liposome encapsulating the anti-folate drug pemetrexed (PMX). Such liposomal formulations have shown potent cytotoxic effects against malignant pleural mesothelioma (MPM) cells in vitro. In the present study, we investigated the pharmacokinetics, bio-distribution and in vivo anti-tumor efficacy of two liposomal PMX formulations with different drug release rates in a murine mesothelioma-xenograft model. Liposomes with different PMX release rates were prepared via manipulating liposomal membrane fluidity through incorporating either a solid-phase (HSPC) or a fluid-phase (POPC) phospholipid. Both liposomal PMX formulations showed prolonged plasma pharmacokinetics and were accumulated to a similar extent in tumors and other tissues, presumably, due to surface modification with polyethylene glycol (PEG). In a murine mesothelioma-xenograft model, interestingly, PMX encapsulated in a fast-release POPC liposome produced superior tumor growth suppression compared with either free PMX or PMX encapsulated in a slow-release HSPC liposome. Such in vivo anti-tumor efficacy was accomplished mainly by a potent induction of apoptosis within tumor tissue by the released PMX from POPC liposomes. Our results clearly emphasize the therapeutic efficacy of liposomal PMX over free PMX in conquering aggressive solid tumors such as malignant mesothelioma. A guarantee of the targeted delivery of PMX to tumor cells helps overcome some of the major shortcomings encountered with the use of free PMX.

Pemetrexed-Induced Rash May Be Prevented by Supplementary Corticosteroids.

Pemetrexed, a chemotherapeutic drug, is highly active in non-small cell lung cancer and malignant pleural mesothelioma. Unfortunately, rashes are more commonly associated with pemetrexed than other chemotherapies, and it is recommended that patients receive corticosteroids (8 mg/d of dexamethasone) for 3 d, including the day of pemetrexed administration (day 1). However, the efficacy of corticosteroids in this context has not been fully verified. In this retrospective study, we evaluated the medical records of 78 patients who received pemetrexed between April 2009 and March 2014, to confirm whether supplementary corticosteroids prevented rash development. The incidence of rash was lower in the 47 patients who received supplementary corticosteroids (after day 1) compared with the incidence among the 31 patients who did not receive supplementary corticosteroids (19.1% vs. 38.7%). The average cutoff dosage of supplementary corticosteroids on day 2 and day 3 was 1.5 mg/d of dexamethasone, as calculated using the receiver operating characteristic curve, and the odds ratio was 0.33 (95% confidence interval: 0.12-0.94). Administration of ≥1.5 mg of corticosteroids on day 2 and day 3 significantly reduced the severity of the rash compared to no supplementary treatment (grades 2/3, 13.3% vs. 33.3%, p<0.05). However, increasing the dose of corticosteroids had no additional effect on rash development. These results suggest that ≥1.5 mg of supplementary dexamethasone on day 2 and day 3 (in addition to day 1) may be necessary for preventing pemetrexed-induced rash, but high doses of dexamethasone (e.g., 8 mg/d) are unnecessary.

Maackiain is a novel antiallergic compound that suppresses transcriptional upregulation of the histamine H1 receptor and interleukin-4 genes.

Kujin contains antiallergic compounds that inhibit upregulation of histamine H1 receptor (H1R) and interleukin (IL)-4 gene expression. However, the underlying mechanism remains unknown. We sought to identify a Kujin-derived antiallergic compound and investigate its mechanism of action. The H1R and IL-4 mRNA levels were determined by real-time quantitative RT-PCR. To investigate the effects of maackiain in vivo, toluene-2,4-diisocyanate (TDI)-sensitized rats were used as a nasal hypersensitivity animal model. We identified (-)-maackiain as the responsible component. Synthetic maackiain showed stereoselectivity for the suppression of IL-4 gene expression but not for H1R gene expression, suggesting distinct target proteins for transcriptional signaling. (-)-Maackiain inhibited of PKCδ translocation to the Golgi and phosphorylation of Tyr(311) on PKCδ, which led to the suppression of H1R gene transcription. However, (-)-maackiain did not show any antioxidant activity or inhibition of PKCδ enzymatic activity per se. Pretreatment with maackiain alleviated nasal symptoms and suppressed TDI-induced upregulations of H1R and IL-4 gene expressions in TDI-sensitized rats. These data suggest that (-)-maackiain is a novel antiallergic compound that alleviates nasal symptoms in TDI-sensitized allergy model rats through the inhibition of H1R and IL-4 gene expression. The molecular mechanism underlying its suppressive effect for H1R gene expression is mediated by the inhibition of PKCδ activation.

Advanced therapeutic approach for the treatment of malignant pleural mesothelioma via the intrapleural administration of liposomal pemetrexed.

Malignant pleural mesothelioma (MPM) is an aggressive cancer that proliferates in the pleural cavity. Pemetrexed (PMX) in combination with cisplatin is currently the approved standard care for MPM, but a dismal response rate persists. Recently, we prepared various liposomal PMX formulations using different lipid compositions and evaluated their in vitro cytotoxicity against human mesothelioma cells (MSTO-211H). In the present study, we investigated the in vivo therapeutic effect of our liposomal PMX formulations using an orthotopic MPM tumor mouse model. PMX encapsulated within either cholesterol-containing (PMX/Chol CL) or cholesterol-free (PMX/Non-Chol CL) cationic liposome was intrapleurally injected into tumor-bearing mice. PMX encapsulated in cholesterol-free liposomes (PMX/Non-Chol CL) drastically inhibited the tumor growth in the pleural cavity, while free PMX and PMX encapsulated in cholesterol-containing liposomes (PMX/Chol CL) barely inhibited the tumor growth. The enhanced in vivo anti-tumor efficacy of PMX/Non-Chol CL was credited, on the one hand, for prolonging the retention of cationic liposomes in the pleural cavity via their electrostatic interaction with the negatively charged membranes of tumor cells, but on the other hand, it was charged with contributing to a higher drug release from the "fluid" liposomal membrane following intrapleural administration. This therapeutic strategy of direct intrapleural administration of liposomal PMX, along with the great advances in CL-guided therapeutics, might be a promising therapeutic approach to conquering the poor prognosis for MPM.

Characteristics of and risk factors for interstitial lung disease induced by chemotherapy for lung cancer.

BACKGROUND: Drug-induced interstitial lung disease (DILD) is generally a serious adverse effect and almost always necessitates the discontinuation of the offending drug. Cancer pharmacotherapy is strongly associated with DILD, and the risk of DILD has been suggested to be higher in patients with lung cancer because of preexisting pneumonic disease. OBJECTIVE: The aim of this retrospective study was to identify the risk factors and prognostic factors for early death from interstitial lung disease (ILD) induced by chemotherapy for lung cancer. METHODS: The medical records of 459 patients who underwent chemotherapy for lung cancer between April 2007 and March 2013 were analyzed with regard to patient background and DILD development, initial symptoms, and prognosis. RESULTS: A total of 33 patients (7.2%) developed chemotherapy-induced ILD. The most frequently observed initial symptom was dyspnea (94.3%). Preexisting ILD was identified as a risk factor for DILD (odds ratio [OR] = 5.38; 95% CI = 2.47-11.73; P < 0.01). Among the 33 patients who developed DILD, 10 patients suffered an early death despite steroid therapy. Poor prognostic factors included epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) use (OR = 9.26; 95% CI = 1.05-82.0; P < 0.05) and 2 or more prior chemotherapy regimens (OR = 6.95; 95% CI = 1.14-42.3; P < 0.05). CONCLUSIONS: Many lung cancer patients have coexisting ILD, and these patients have a high risk of developing chemotherapy-induced ILD. In addition, patients with DILD who underwent EGFR-TKI therapy and 2 or more prior chemotherapy regimens had a higher risk of fatal outcome.

Spontaneously hyperactive MEK-Erk pathway mediates paradoxical facilitation of cell proliferation in mild hypoxia.

BACKGROUND: Oxygen is important for common eukaryotic cells to generate ATP. Pathophysiological conditions such as ischemic diseases cause tissue hypoxia. In addition, oxygen availability in deep tissues is supposed to be far lower than surrounding atmosphere even in healthy animals, and the oxygen partial pressures in most normal tissues are estimated to be around 40-50mmHg, so-called mild hypoxia. Recent studies have demonstrated that mild hypoxia has distinct effects on living cells from severe hypoxia. For instance, mild hypoxia was reported to promote cell reprogramming. Although severe hypoxia is known to inhibit cell proliferation, mild hypoxia has been paradoxically demonstrated to increase cell proliferation. However, it has not been clarified by which molecular mechanisms mild hypoxia evokes the discontinuous increment of cell proliferation. METHODS: We established experimental conditions showing the opposite influences of mild and severe hypoxia on cell proliferation using undifferentiated Caco2 human colon carcinoma cells in order to clarify the underlying molecular mechanism. RESULTS: The basal activity of Erk, which is a typical mediator of mitogenic signals, is spontaneously increased specifically in cells exposed to mild hypoxia, and inhibition of MEK, an upstream kinase of the Erk, completely inhibited the mild hypoxia-induced enhancement of cell proliferation. CONCLUSIONS: Spontaneous hyperactivation of the MEK-Erk pathway by mild hypoxia should be the plausible molecular mechanism of the paradoxical promotion of cell proliferation. GENERAL SIGNIFICANCE: Our findings will provide clues to the molecular basis of mild hypoxia-evoked phenomena such as cell reprogramming.