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The present study was conducted to investigate the inhibitory effects of the cell-free culture supernatant of L. curvatus Wikim 38 (LC38-CS) on RANKL-induced osteoclast differentiation and bone loss in a mice model of ovariectomy-induced post-menopausal osteoporosis. LC38-CS inhibited the RANKL-induced differentiation of bone marrow-derived macrophages (BMDMs) into osteoclasts in a dose-dependent manner. F-actin ring formation and bone resorption were also reduced by LC38-CS treatment of RANKL-treated BMDMs. In addition, LC38-CS decreased the RANKL-induced activation of the TRAF6/NF-κB/MAPKs axis at the early stage and the expression of osteoclastogenesis-related genes in BMDMs treated with RANKL. PRMT1 and ADMA levels, new biomarkers for osteoclastogenesis, were decreased by LC38-CS treatment. The administration of LC38-CS increased bone volume and bone mineral density (BMD) in ovariectomized (OVX) mice in μ-CT analysis. These findings suggest that LC38-CS inhibited RANKL-induced osteoclast differentiation via the downregulation of molecular mechanisms and exerted anti-osteoporotic effects.

The gut microbiome can influence the development of tumours and the efficacy of cancer therapeutics1-5; however, the multi-omics characteristics of antitumour bacterial strains have not been fully elucidated. In this study, we integrated metagenomics, genomics and transcriptomics of bacteria, and analyses of mouse intestinal transcriptome and serum metabolome data to reveal an additional mechanism by which bacteria determine the efficacy of cancer therapeutics. In gut microbiome analyses of 96 samples from patients with non-small-cell lung cancer, Bifidobacterium bifidum was abundant in patients responsive to therapy. However, when we treated syngeneic mouse tumours with commercial strains of B. bifidum to establish relevance for potential therapeutic uses, only specific B. bifidum strains reduced tumour burden synergistically with PD-1 blockade or oxaliplatin treatment by eliciting an antitumour host immune response. In mice, these strains induced tuning of the immunological background by potentiating the production of interferon-γ, probably through the enhanced biosynthesis of immune-stimulating molecules and metabolites.

Glycosylphosphatidylinositol-anchored sperm hyaluronidases (HYAL) assist sperm penetration through the cumulus–oocyte complex (COC), but their role in mammalian fertilization remains unclear. Previously, we demonstrated that sperm from HYAL 5 and 7 double-knockout (dKO) mice produced significantly less offspring than sperm from wild-type mice due to defective COC dispersal. However, the HYAL6 gene remained active in the sperm from the dKO mice, indicating that they were not entirely infertile. This study explored the role of HYAL6 in fertilization by analyzing HYAL6-mutant mice. In this mouse model, HYAL5 and HYAL7 were present in the HYAL6-knockout sperm, and they could disperse hyaluronic acid. We found that HYAL6 was present on the surface of sperm. However, male mice lacking the HYAL6 gene had normal fertility, testicular integrity, and sperm characteristics. Furthermore, in vitro fertilization assays demonstrated that HYAL6-deficient epididymal sperm functioned normally. Therefore, HYAL6 is dispensable for fertilization.

Inflammation is a multifaceted response of the immune system at the site of injury or infection caused by pathogens or stress via immune cells. Due to the adverse effects of chemical drugs, plant-based compounds are gaining interest in current research. Prunetinoside or prunetin-5-O-glucoside (PUG) is a plant-based active compound, which possesses anti-inflammatory effects on immune cells. In this study, we investigate the effect of PUG on mouse macrophage RAW264.7 cells with or without stimulation of lipopolysaccharide (LPS). Cytotoxicity results showed that PUG is non-cytotoxic to the cells and it reversed the cytotoxicity in LPS-stimulated cells. The levels of nitric oxide (NO) and interleukin-6 (IL-6) were determined using a NO detection kit and IL-6 ELISA kit, respectively, and showed a significant decrease in NO and IL-6 in PUG-treated cells. Western blot and qRT-PCR were performed for the expression of two important pro-inflammatory cytokines, COX2 and iNOS, and found that their expression was downregulated in a dose-dependent manner. Other pro-inflammatory cytokines, such as IL-1β, IL-6, and TNFα, had reduced mRNA expression after PUG treatment. Furthermore, a Western blot was performed to calculate the expression of NF-κB and MAPK pathway proteins. The results show that PUG administration dramatically reduced the phosphorylation of p-Iκbα, p-NF-κB 65, and p-JNK. Remarkably, after PUG treatment, p-P38 and p-ERK remain unchanged. Furthermore, docking studies revealed that PUG is covalently linked to NF-κB and suppresses inflammation. In conclusion, PUG exerted the anti-inflammatory mechanism by barring the NF-κB pathway and activating JNK. Thus, prunetinoside could be adopted as a therapeutic compound for inflammatory-related conditions.

The gut microbiome can influence the development of tumours and the efficacy of cancer therapeutics

Recurrent hyperhidrosis after thoracic sympathectomy is an uncomfortable condition, and compensatory hyperhidrosis (CH) is one of the most troublesome side effects. Here, we describe two patients with recurrent palmar hyperhidrosis (PH) and CH over the whole body simultaneously. They were treated with bilateral T4 sympathetic clipping and reconstruction of the sympathetic nerve from a T5 to T8 sympathetic nerve graft, which was transferred to the resected T3 sympathetic bed site. They reported improvements in sweating and were fully satisfied with the results. Our method can be considered as an alternative approach for patients with recurrent PH and CH.

We report the synthesis of a macrocyclic Gd chelate based on a 1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DO3A) coordinationn cage bearing an ethoxybenzyl (EOB) moiety and discuss its use as a T1 hepatobiliary magnetic resonance imaging (MRI) contrast agent. The new macrocyclic liver agent shows high chelation stability and high r1 relaxivity compared with linear-type Gd chelates, which are the current clinically approved liver agents. Our macrocyclic, liver-specific Gd chelate was evaluated in vivo through biodistribution analysis and liver MRI, which demonstrated its high tumor detection sensitivity and suggested that the new Gd complex is a promising contrast agent for liver cancer imaging.

A novel manganese(II) complex based on an ethylenediaminetetraacetic acid (EDTA) coordination cage bearing a benzothiazole aniline (BTA) moiety (Mn-EDTA-BTA) was designed and synthesized for use as a liver-specific MRI contrast agent with high chelation stability. In addition to forming a hydrophilic, stable complex with Mn2+, this new Mn chelate was rapidly taken up by liver hepatocytes and excreted by the kidneys and biliary system. The kinetic inertness and R1 relaxivity of the complex were much higher than those of mangafodipir trisodium (MnDPDP), a clinically approved liver-specific MRI contrast agent. The diagnostic utility of this new Mn complex in MRI was demonstrated by high-sensitivity tumor detection in an animal model of liver cancer.

A 52-year-old male patient who underwent multiple wedge resections experienced postoperative acute respiratory distress syndrome in both lungs after Viscum album pleurodesis. Despite initial rapid deterioration in clinical condition and rapid progression of bilateral lung infiltration, he exhibited a relatively smooth clinical recovery with marked response to glucocorticoid treatment. Our case report suggests that care must be taken to guard against the development of acute respiratory complications in the use of Viscum album for pleurodesis. However, in view of the clinically benign course, initial aggressive management of complications can prevent suffering and sequelae.

Persistently activated STAT3 is a promising target for a new class of anticancer drug development and cancer therapy, as it is associated with tumor initiation, progression, malignancy, drug resistance, cancer stem cell properties, and recurrence. Here, we discovered 3-(2,4-dichloro-phenoxymethyl)-5-trichloromethyl-[1,2,4]oxadiazole (ODZ10117) as a small-molecule inhibitor of STAT3 to be used in STAT3-targeted cancer therapy. ODZ10117 targeted the SH2 domain of STAT3 regardless of other STAT family proteins and upstream regulators of STAT3, leading to inhibition of the tyrosine phosphorylation, dimerization, nuclear translocation, and transcriptional activity of STAT3. The inhibitory effect of ODZ10117 on STAT3 was stronger than the known STAT3 inhibitors such as S3I-201, STA-21, and nifuroxazide. ODZ10117 suppressed the migration and invasion, induced apoptosis, reduced tumor growth and lung metastasis, and extended the survival rate in both in vitro and in vivo models of breast cancer. Overall, we demonstrated that ODZ10117 is a novel STAT3 inhibitor and may be a promising agent for the development of anticancer drugs.

Schwannomas originate from Schwann cells, and they are the most common benign neoplasms of the peripheral nerves. They can occur in most parts of the body but have a predilection for the head, the neck, and the flexor aspects of the extremities. Pancreatic schwannomas are uncommon, and only a few cases have been reported in the English literature. Approximately two-thirds of pancreatic schwannomas undergo cystic degeneration, and they should be considered in the differential diagnosis of solid pancreatic tumors with cystic changes to facilitate accurate diagnosis and optimal treatment. We report a case of a pathologically proven schwannoma in the pancreatic tail with multiple cystic and hemorrhagic changes followed by a review of relevant literature.

Methoxychlor (MXC) and vinclozolin (VIN) are well-recognized endocrine disrupting chemicals known to alter epigenetic regulations and transgenerational inheritance; however, non-endocrine disruption endpoints are also important. Thus, we determined the effects of MXC and VIN on the dysregulation of gap junctional intercellular communication (GJIC) and activation of mitogen-activated protein kinases (MAPKs) in WB-F344 rat liver epithelial cells. Both chemicals induced a rapid dysregulation of GJIC at non-cytotoxic doses, with 30 min EC50 values for GJIC inhibition being 10 µM for MXC and 126 µM for VIN. MXC inhibited GJIC for at least 24 h, while VIN effects were transient and GJIC recovered after 4 h. VIN induced rapid hyperphosphorylation and internalization of gap junction protein connexin43, and both chemicals also activated MAPK ERK1/2 and p38. Effects on GJIC were not prevented by MEK1/2 inhibitor, but by an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), resveratrol, and in the case of VIN, also, by a p38 inhibitor. Estrogen (ER) and androgen receptor (AR) modulators (estradiol, ICI 182,780, HPTE, testosterone, flutamide, VIN M2) did not attenuate MXC or VIN effects on GJIC. Our data also indicate that the effects were elicited by the parental compounds of MXC and VIN. Our study provides new evidence that MXC and VIN dysregulate GJIC via mechanisms involving rapid activation of PC-PLC occurring independently of ER- or AR-dependent genomic signaling. Such alterations of rapid intercellular and intracellular signaling events involved in regulations of gene expression, tissue development, function and homeostasis, could also contribute to transgenerational epigenetic effects of endocrine disruptors.

The objective of this study was to report on a new surgical technique, hybrid laparoscopic myomectomy that integrates the advantages of transumbilical laparoendoscopic single-site surgery and those of isobaric laparoscopy, and the initial experience with 14 cases. All of the procedures were performed by a single surgeon who has over 18 years of experience in laparoscopic surgery and 4 years of experience in laparoendoscopic single-site surgery. All cases of hybrid laparoscopic myomectomy were completed safely and effectively without conversion to conventional laparoscopic procedure. The median operative time was 75 minutes (range, 30 to 100 minutes). No postoperative complication was observed. The findings show that hybrid laparoscopic myomectomy is a safe and feasible surgical technique, and therefore can be a feasible, minimally invasive alternative to either abdominal or laparoendoscopic single-site surgery myomectomy.

Curcumin (cur) has been comprehensively studied for its various biological properties, more precisely for its antitumor potential and it has shown the promising results as well. On the other hand, Chlorin e6 (Ce6) has mostly been used as a photosensitizer in photodynamic therapy (PDT) against a variety of carcinomas. In the present study, we have synthesized a series of Chlorin e6-curcumin (Ce6-cur) conjugates and investigated their photosensitizing potential against pancreatic cancer cell lines. All the synthesized compounds were characterized by UV, 1H NMR, 13C NMR and LC-MS. These Ce6-cur conjugates showed better physicochemical properties and higher singlet oxygen generation capability. The cellular uptake was studied in AsPC-1 cells using fluorescence-activated cell sorting (FACS). Compound 17 was rapidly internalized within 30 min and sustained for 24 h. Compound 17 showed excellent PDT efficacy with IC50 of 40, 35 and 41 nM against AsPC-1, MIA PaCa-2 and PANC-1 respectively with exceptional dark/phototoxicity ratio in the range of 2371–7500. Moreover, the treatment of compound 17 upregulated the expression of BAX, Cytochrome-C and cleaved caspase 9 while downregulating the Bcl-2 expression an anti-apoptotic protein marker. These results demonstrate outstanding capability of compound 17 as a potent photosensitizer which could improve the PDT efficacy in pancreatic cancer patients.

// Joon-Suk Park 1, * , ChuHee Lee 2, * , Hyun-Kyoung Kim 3, * , Dayea Kim 3 , Jung Beom Son 3 , Eunhwa Ko 3 , Joong-Heui Cho 3 , Nam-Doo Kim 3 , Hong-Yan Nan 2 , Choong-Yong Kim 1 , Sukkyoon Yoon 3 , Sun-Hwa Lee 3 , Hwan Geun Choi 3 1 Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, South Korea 2 Department of Biochemistry and Molecular Biology, School of Medicine, Yeungnam University, Daegu, South Korea 3 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, South Korea * These authors have contributed equally to this work Correspondence to: Sun-Hwa Lee, email: sunhlee@dgmif.re.kr Hwan Geun Choi, email: hgchoi@dgmif.re.kr Keywords: breast cancer, metastasis, AXL, signal transduction, kinase inhibitor Received: April 25, 2016 Accepted: October 21, 2016 Published: November 04, 2016 ABSTRACT Breast cancer is the most common malignant disease occurring in women and represents a substantial proportion of the global cancer burden. In these patients, metastasis but not the primary tumor is the main cause of breast cancer-related deaths. Here, we report the novel finding that DN10764 (AZD7762, a selective inhibitor of checkpoint kinases 1 and 2) can suppress breast cancer metastasis. In breast cancer cells, DN10764 inhibited cell proliferation and GAS6-mediated AXL signaling, consequently resulting in suppressed migration and invasion. In addition, DN10764 induced caspase 3/7-mediated apoptosis in breast cancer cells and inhibited tube formation of human umbilical vein endothelial cells. Finally, DN10764 significantly suppressed the tumor growth and metastasis of breast cancer cells in in vivo metastasis models. Taken together, these data suggest that therapeutic strategies targeting AXL in combination with systemic therapies could improve responses to anti-cancer therapies and reduce breast cancer recurrence and metastases.

Dysregulation of gap junctional intercellular communication (GJIC) has been associated with different pathologies, including cancer; however, molecular mechanisms regulating GJIC are not fully understood. Mitogen Activated Protein Kinase (MAPK)-dependent mechanisms of GJIC-dysregulation have been well-established, however recent discoveries have implicated phosphatidylcholine-specific phospholipase C (PC-PLC) in the regulation of GJIC. What is not known is how prevalent these two signaling mechanisms are in toxicant/toxin-induced dysregulation of GJIC, and do toxicants/toxins work through either signaling mechanisms or both, or through alternative signaling mechanisms. Different chemical toxicants were used to assess whether they dysregulate GJIC via MEK or PC-PLC, or both Mek and PC-PLC, or through other signaling pathways, using a pluripotent rat liver epithelial oval-cell line, WB-F344. Epidermal growth factor, 12-O-tetradecanoylphorbol-13-acetate, thrombin receptor activating peptide-6 and lindane regulated GJIC through a MEK1/2-dependent mechanism that was independent of PC-PLC; whereas PAHs, DDT, PCB 153, dicumylperoxide and perfluorodecanoic acid inhibited GJIC through PC-PLC independent of Mek. Dysregulation of GJIC by perfluorooctanoic acid and R59022 required both MEK1/2 and PC-PLC; while benzoylperoxide, arachidonic acid, 18β-glycyrrhetinic acid, perfluorooctane sulfonic acid, 1-monolaurin, pentachlorophenol and alachlor required neither MEK1/2 nor PC-PLC. Resveratrol prevented dysregulation of GJIC by toxicants that acted either through MEK1/2 or PC-PLC. Except for alachlor, resveratrol did not prevent dysregulation of GJIC by toxicants that worked through PC-PLC-independent and MEK1/2-independent pathways, which indicated at least two other, yet unidentified, pathways that are involved in the regulation of GJIC. In conclusion: the dysregulation of GJIC is a contributing factor to the cancer process; however the underlying mechanisms by which gap junction channels are closed by toxicants vary. Thus, accurate assessments of risk posed by toxic agents, and the role of dietary phytochemicals play in preventing or reversing the effects of these agents must take into account the specific mechanisms involved in the cancer process.

Scope Indole-3-carbinol (I3C), a derivative abundant in cruciferous vegetables such as cabbage, is well known for its various health benefits such as chemo-preventive and anti-obesity effects. I3C is easily metabolized to 3,3'-diindolylmethane (DIM), a more stable form, in acidic conditions of the stomach. However, the anti-obesity effect of DIM has not been investigated clearly. We sought to investigate the effect of DIM on diet-induced obesity and to elucidate its underlying mechanisms. Methods and results High-fat diet (HFD)-fed obese mouse and MDI-induced 3T3-L1 adipogenesis models were used to study the effect of DIM. We observed that the administration of DIM (50 mg/kg BW) significantly suppressed HFD-induced obesity, associated with a decrease in adipose tissue. Additionally, we observed that DIM treatment (40 and 60 μM), but not I3C treatment, significantly inhibited MDI-induced adipogenesis by reducing the levels of several adipogenic proteins such as PPAR-γ and C/EBPα. DIM, but not I3C, suppressed cell cycle progression in the G1 phase, which occurred in the early stage of adipogenesis, inducing post-translational degradation of cyclin D1 by inhibiting ubiquitin specific peptidase 2 (USP2) activities. Conclusion Our findings indicate that cruciferous vegetables, which can produce DIM as a metabolite, have the potential to prevent or treat chronic obesity.