Crosstalk between exosomes and autophagy: A review of molecular mechanisms and therapies

Exosomes are extracellular vesicles that primarily exist in bodily fluids such as blood. Autophagy is an intracellular degradation process, which, along with exosomes, can significantly influence human health and has therefore attracted considerable attention in recent years. Exosomes have been shown to regulate the intracellular autophagic process, which, in turn, affects the circulating exosomes. However, crosstalk between exosomal and autophagic pathways is highly complex, depends primarily on the environment, and varies greatly in different diseases. In addition, studies have demonstrated that exosomes, from specific cell, can mitigate several diseases by regulating autophagy, which can also affect the excessive release of some harmful exosomes. This phenomenon lays a theoretical foundation for the improvement of many diseases. Herein, we review the mechanisms and clinical significance of the association and regulation of exosomes and autophagy, in order to provide a new perspective for the prevention and treatment of associated diseases.     

Adverse reaction to an adrenergic herbal extract (Citrus aurantium)

We report the case of a 52 year old woman that had an adverse reaction after taking a dry herbal extract of an unripe fruit of Citrus aurantium L. var. amara, as dietary supplement for weight loosing. The fruit is also known as zhi shi (in traditional Chinese Medicine) or bitter orange in other parts of the world.     

Keratin gene mutations in disorders of human skin and its appendages

Keratins, the major structural protein of all epithelia are a diverse group of cytoskeletal scaffolding proteins that form intermediate filament networks, providing structural support to keratinocytes that maintain the integrity of the skin. Expression of keratin genes is usually regulated by differentiation of the epidermal cells within the stratifying squamous epithelium. Amongst the 54 known functional keratin genes in humans, about 22 different genes including, the cornea, hair and hair follicle-specific keratins have been implicated in a wide range of hereditary diseases. The exact phenotype of each disease usually reflects the spatial expression level and the types of mutated keratin genes, the location of the mutations and their consequences at sub-cellular levels as well as other epigenetic and/or environmental factors. The identification of specific pathogenic mutations in keratin disorders formed the basis of our understanding that led to re-classification, improved diagnosis with prognostic implications, prenatal testing and genetic counseling in severe keratin genodermatoses. Molecular defects in cutaneous keratin genes encoding for keratin intermediate filaments (KIFs) causes keratinocytes and tissue-specific fragility, accounting for a large number of genetic disorders in human skin and its appendages. These diseases are characterized by keratinocytes fragility (cytolysis), intra-epidermal blistering, hyperkeratosis, and keratin filament aggregation in severely affected tissues. Examples include epidermolysis bullosa simplex (EBS; K5, K14), keratinopathic ichthyosis (KPI; K1, K2, K10) i.e. epidermolytic ichthyosis (EI; K1, K10) and ichthyosis bullosa of Siemens (IBS; K2), pachyonychia congenita (PC; K6a, K6b, K16, K17), epidermolytic palmo-plantar keratoderma (EPPK; K9, (K1)), monilethrix (K81, K83, K86), ectodermal dysplasia (ED; K85) and steatocystoma multiplex. These keratins also have been identified to have roles in apoptosis, cell proliferation, wound healing, tissue polarity and remodeling. This review summarizes and discusses the clinical, ultrastructural, molecular genetics and biochemical characteristics of a broad spectrum of keratin-related genodermatoses, with special clinical emphasis on EBS, EI and PC. We also highlight current and emerging model tools for prognostic future therapies. Hopefully, disease modeling and in-depth understanding of the molecular pathogenesis of the diseases may lead to the development of novel therapies for several hereditary cutaneous diseases.     

Simultaneous Integrated Boost Radiotherapy in Unresectable Stage IV (M0) Head and Neck Squamous Cell Cancer Patients: Daily Clinical Practice

AimTo evaluate clinical outcome in locally-advanced stage IV (M0) head and neck cancer patients treated using intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) in daily clinical practice.BackgroundDespite SIB-IMRT has been reported as a feasible and effective advanced head and neck cancer treatment, there are few data about its concurrent use with systemic therapies.Material and MethodsWe reviewed 41 staged IV (M0) head and neck cancer patients treated in two radiotherapy units in the city of Messina (Italy) during the last six years, using intensity modulated techniques-SIB. 22/41 patients had concomitant chemotherapy or cetuximab. Acute and late toxicities, objective response (OR) rate, local control (LC) and overall survival (OS) have been evaluated.Results37/41 patients received the planned doses of radiotherapy, 2 patients died during the therapy. The major acute regional toxicities were skin reaction and mucositis. A case of mandibular osteoradionecrosis was recorded. At completion of treatment, OR was evaluated in 38 patients: 32/38 patients (84.2%) had complete (55.3%) and partial (28.9%) response. The 1- and 5-year LC rates were 73.4% and 69.73%, respectively. The 1-, 3-, and 5-year OS rates were 85.93%, 51.49% and 44.14%, respectively. No statistically significant differences in outcomes have been observed in patients treated with radiotherapy alone vs. irradiation concomitant to chemo/biotherapy. The median OS was 45 months.ConclusionSIB-IMRT is safeand can be used with concomitant chemotherapy/biotherapy in real-life daily clinical practice. SIB-IMRT alone is a valid alternative in patients unfit for systemic therapies.     

Antitussive and expectorant activities of licorice and its major compounds

Licorice has been used as an antitussive and expectorant herbal medicine for a long history. This work evaluated the activities of 14 major compounds and crude extracts of licorice, using the classical ammonia-induced cough model and phenol red secretion model in mice. Liquiritin apioside (1), liquiritin (2), and liquiritigenin (3) at 50?mg/kg (i.g.) could significantly decrease cough frequency by 30–78% (p?<?.01). The antitussive effects could be partially antagonized by the pretreatment of methysergide or glibenclamide, but not naloxone. Moreover, compounds 1–3 showed potent expectorant activities after 3?days treatment (p?<?.05). The water and ethanol extracts of licorice, which contain abundant 1 and 2, could decrease cough frequency at 200?mg/kg by 25–59% (p?<?.05), and enhance the phenol red secretion (p?<?.05), while the ethyl acetate extract showed little effect. These results indicate liquiritin apioside and liquiritin are the major antitussive and expectorant compounds of licorice. Their antitussive effects depend on both peripheral and central mechanisms.     

Chemoresistance and chemosensitization in cholangiocarcinoma

One of the main difficulties in the management of patients with advanced cholangiocarcinoma (CCA) is their poor response to available chemotherapy. This is the result of powerful mechanisms of chemoresistance (MOC) of quite diverse nature that usually act synergistically. The problem is often worsened by altered MOC gene expression in response to pharmacological treatment. Since CCA includes a heterogeneous group of cancers their genetic signature coding for MOC genes is also diverse; however, several shared traits have been defined. Some of these characteristics are shared with other types of liver cancer, namely hepatocellular carcinoma and hepatoblastoma. An important goal in modern oncologic pharmacology is to develop novel strategies to overcome CCA chemoresistance either by increasing drug specificity, such as in targeted therapies aimed to inhibit receptors with tyrosine kinase activity, or to increase the amounts of active agents inside CCA cells by enhancing drug uptake or reducing efflux through export pumps. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.     

GLP-1 receptor agonists and reduction of cardiometabolic risk: Potential underlying mechanisms

Type 2 diabetes mellitus (T2DM) is a metabolic condition with an elevated impact on cardiovascular (CV) risk. The innovative therapeutic approaches for T2DM - incretin-based therapies (IBTs), including glucagon-like peptide 1 (GLP-1) receptor agonists, have become popular and more widely used in recent years. The available scientific data from clinical studies and clinical practice highlights their beyond glucose-lowering effects, which is achieved without any increase in hypoglycaemia. The former effects include reduction in body weight, lipids, blood pressure, inflammatory markers, oxidative stress, endothelial dysfunction, and subclinical atherosclerosis, thus reducing and potentially preventing CV events. In fact, the introduction of IBTs is one of the key moments in the history of diabetes research and treatment. Such therapeutic strategies allow customization of antidiabetic treatment to each patient's need and therefore obtain better metabolic control with reduced CV risk. The aim of the present paper is to provide a comprehensive overview of the effects of GLP-1RA on various cardiometabolic markers and overall CV risk, with particular attention on recent CV outcome studies and potential mechanisms. In particular, the effects of liraglutide on formation and progression of atherosclerotic plaque and mechanisms explaining its cardioprotective effects are highlighted.     

Availability of Essential Elements in Nutrient Supplements Used as Antidiabetic Herbal Formulations

Five brands of antidiabetic herbal formulations as tablets, Diabetex, Divya Madhu Nashini, Jambrushila, Diabeticin, and Madhumeh Nashini, from different pharmacies were analyzed for six minor (Na, K, Ca, Cl, Mg, and P) and 20 trace (As, Ba, Br, Ce, Co, Cr, Cs, Cu, Fe, Hg, La, Mn, Rb, Sb, Sc, Se, Sm, Th, V, and Zn) elements by thermal neutron irradiation followed by high-resolution gamma ray spectrometry. Further Ni, Cd, and Pb were determined by atomic absorption spectrophotometry. Most elements vary in a narrow range by a factor of 2–4 while a few others vary in a wide range, e.g., Na (0.05–0.67 mg/g), Mn (26.7–250 μg/g), and V (0.26–2.50 μg/g). All the five brands contain K, Cl, Mg, P, and Ca as minor constituents along with mean trace amounts of Cr (2.11 ± 0.67 μg/g), Cu (15.7 ± 7.11 μg/g), Fe (459 ± 171 μg/g), Mn (143 ± 23 μg/g), Se (238 ± 112 ng/g), and V (0.99 ± 0.93 μg/g). Jambrushila is enriched in Na, Ca, Mg, Cl, Fe, Cu, Se, and Zn, essential nutrients responsible for curing diabetes. Dietary intake of Mn, Fe, and Cu are greater than 10% of the recommended dietary allowance, whereas that for Zn and Se is less than 2%. Mean contents of toxic elements (As, Cd, Hg, and Pb) were found below permissible limits except in Jambrushila. Cr and Zn were inversely correlated with r = −0.81, whereas Rb and Cs exhibit linear correlation (r = 0.93) in five brands. C, H, N analysis showed C ∼ 55%, H ∼ 12%, and N ∼ 2% with a total of ∼70% organic matter. However, thermal decomposition studies at 700°C suggest less than 5% nonvolatile metal oxides. Herbal formulations contain minor and trace elements in bioavailable forms that favorably influence glucose tolerance and possibly increase the body’s ability to ameliorate development of diabetes.     

Recent advances in cancer stem/progenitor cell research: therapeutic implications for overcoming resistance to the most aggressive cancers

Overcoming intrinsic and acquired resistance of cancer stem/progenitor cells to current clinical treatments represents a major challenge in treating and curing the most aggressive and metastatic cancers. This review summarizes recent advances in our understanding of the cellular origin and molecular mechanisms at the basis of cancer initiation and progression as well as the heterogeneity of cancers arising from the malignant transformation of adult stem/progenitor cells. We describe the critical functions provided by several growth factor cascades, including epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor (SCF) receptor (KIT), hedgehog and Wnt/beta-catenin signalling pathways that are frequently activated in cancer progenitor cells and are involved in their sustained growth, survival, invasion and drug resistance. Of therapeutic interest, we also discuss recent progress in the development of new drug combinations to treat the highly aggressive and metastatic cancers including refractory/relapsed leukaemias, melanoma and head and neck, brain, lung, breast, ovary, prostate, pancreas and gastrointestinal cancers which remain incurable in the clinics. The emphasis is on new therapeutic strategies consisting of molecular targeting of distinct oncogenic signalling elements activated in the cancer progenitor cells and their local microenvironment during cancer progression. These new targeted therapies should improve the efficacy of current therapeutic treatments against aggressive cancers, and thereby preventing disease relapse and enhancing patient survival.     

Current progress in use of adipose derived stem cells in peripheral nerve regeneration

Unlike central nervous system neurons; those in the peripheral nervous system have the potential for full regeneration after injury. Following injury, recovery is controlled by schwann cells which replicate and modulate the subsequent immune response. The level of nerve recovery is strongly linked to the severity of the initial injury despite the significant advancements in imaging and surgical techniques. Multiple experimental model shave been used with varying successes to augment the natural regenerative processes which occur following nerve injury. Stem cell therapy in peripheral nerve injury may be an important future intervention to improve the best attainable clinical results. In particular adipose derived stem cells(ADSCs) are multipotent mesenchymal stem cells similar to bone marrow derived stem cells, which are thought to have neurotrophic properties and the ability to differentiate into multiple lineages. They are ubiquitous within adipose tissue; they can form many structures resembling the mature adult peripheral nervous system. Following early in vitro work; multiple small and large animal in vivo models have been used in conjunction with conduits, autografts and allografts to successfully bridge the peripheral nerve gap. Some of the ADSC related neuroprotective and regenerative properties have been elucidated however much work remains before a model can be used successfully in human peripheral nerve injury(PNI). This review aims to provide a detailed overview of progress made in the use of ADSC in PNI, with discussion on the role of a tissue engineered approach for PNI repair.