G protein-coupled receptors driven intestinal glucagon-like peptide-1 reprogramming for obesity: Hope or hype?

'Globesity' is a foremost challenge to the healthcare system. The limited efficacy and adverse effects of available oral pharmacotherapies pose a significant obstacle in the fight against obesity. The biology of the leading incretin hormone glucagon-like-peptide-1 (GLP-1) has been highly captivated during the last decade owing to its multisystemic pleiotropic clinical outcomes beyond inherent glucoregulatory action. That fostered a pharmaceutical interest in synthetic GLP-1 analogues to tackle type-2 diabetes (T2D), obesity and related complications. Besides, mechanistic insights on metabolic surgeries allude to an incretin-based hormonal combination strategy for weight loss that emerged as a forerunner for the discovery of injectable 'unimolecular poly-incretin-agonist' therapies. Physiologically, intestinal enteroendocrine L-cells (EECs) are the prominent endogenous source of GLP-1 peptide. Despite comprehending the potential of various G protein-coupled receptors (GPCRs) to stimulate endogenous GLP-1 secretion, decades of translational GPCR research have failed to yield regulatory-approved endogenous GLP-1 secretagogue oral therapy. Lately, a dual/poly-GPCR agonism strategy has emerged as an alternative approach to the traditional mono-GPCR concept. This review aims to gain a comprehensive understanding by revisiting the pharmacology of a few potential GPCR-based complementary avenues that have drawn attention to the design of orally active poly-GPCR agonist therapy. The merits, challenges and recent developments that may aid future poly-GPCR drug discovery are critically discussed. Subsequently, we project the mechanism-based therapeutic potential and limitations of oral poly-GPCR agonism strategy to augment intestinal GLP-1 for weight loss. We further extend our discussion to compare the poly-GPCR agonism approach over invasive surgical and injectable GLP-1-based regimens currently in clinical practice for obesity.

Synergistic Anticancer Activity of Plumbagin and Xanthohumol Combination on Pancreatic Cancer Models.

Among diverse cancers, pancreatic cancer is one of the most aggressive types due to inadequate diagnostic options and treatments available. Therefore, there is a necessity to use combination chemotherapy options to overcome the chemoresistance of pancreatic cancer cells. Plumbagin and xanthohumol, natural compounds isolated from the Plumbaginaceae family and Humulus lupulus, respectively, have been used to treat various cancers. In this study, we investigated the anticancer effects of a combination of plumbagin and xanthohumol on pancreatic cancer models, as well as the underlying mechanism. We have screened in vitro numerous plant-derived extracts and compounds and tested in vivo the most effective combination, plumbagin and xanthohumol, using a transgenic model of pancreatic cancer KPC (KrasLSL.G12D/+; p53R172H/+; PdxCretg/+). A significant synergistic anticancer activity of plumbagin and xanthohumol combinations on different pancreatic cancer cell lines was found. The combination treatment of plumbagin and xanthohumol influences the levels of B-cell lymphoma (BCL2), which are known to be associated with apoptosis in both cell lysates and tissues. More importantly, the survival of a transgenic mouse model of pancreatic cancer KPC treated with a combination of plumbagin and xanthohumol was significantly increased, and the effect on BCL2 levels has been confirmed. These results provide a foundation for a potential new treatment for pancreatic cancer based on plumbagin and xanthohumol combinations.

Role of lipid signalling in extracellular vesicles-mediated cell-to-cell communication.

Lipid signalling plays a crucial role in extracellular vesicle (EV)-mediated cell-to-cell communication. Extracellular vesicles are small membrane-bound structures released by various cell types into the extracellular environment. They include exosomes, microvesicles, and apoptotic bodies. These vesicles contain a variety of bioactive molecules, including proteins, nucleic acids (such as miRNAs and mRNAs), and lipids. Lipids are important components of EVs and are involved in various aspects of their biogenesis, cargo sorting, and functional effects on target cells. In this review, we will discuss how lipid signalling is involved in EV-mediated cell-to-cell communication. In summary, lipid signalling is intricately involved in extracellular vesicle-mediated cell-to-cell communication. The lipid composition of EVs influences their biogenesis, cargo sorting, interactions with target cells, and functional effects on recipient cells. Understanding the role of lipids in EV-mediated communication is essential for deciphering the mechanisms underlying intercellular signalling and developing potential therapeutic strategies based on EVs.

Can the molecules carried by extracellular vesicles help to diagnose pancreatic cancer early?

BACKGROUND: Pancreatic cancer is a deadly malignancy mainly because of its asymptomatic onset which prevents the implementation of the primary tumour's resection surgery, leading to metastatic spread resistant to chemotherapy. Early-detection of this cancer in its initial stage would represent a game changer in the fight against this disease. The few currently available biomarkers detectable in patients' body fluids lack sensitivity and specificity. SCOPE OF REVIEW: The recent discovery of extracellular vesicles and their role in promoting cancer's advancement has boosted interest in researching their cargo, to find reliable early detection biological markers. This review examines the most recent discoveries in the analysis of potential extra vesicle-carried biological markers for the early detection of pancreatic cancer. MAJOR CONCLUSIONS: Despite the advantages of using extracellular vesicles for early diagnosis, and the promising findings of extracellular vesicle-carried molecules possibly functional as biomarkers, until now there are no validated markers derived from extracellular vesicles available to be used in the clinic. GENERAL SIGNIFICANCE: Further studies in this direction are urgently required to provide what would be a major asset for defeating pancreatic cancer.

Perineural Invasion in Pancreatic Ductal Adenocarcinoma: From Molecules towards Drugs of Clinical Relevance.

Pancreatic ductal adenocarcinoma is one of the most threatening solid malignancies. Molecular and cellular mediators that activate paracrine signalling also regulate the dynamic interaction between pancreatic cancer cells and nerves. This reciprocal interface leads to perineural invasion (PNI), defined as the ability of cancer cells to invade nerves, similar to vascular and lymphatic metastatic cascade. Targeting PNI in pancreatic cancer might help ameliorate prognosis and pain relief. In this review, the modern knowledge of PNI in pancreatic cancer has been analysed and critically presented. We focused on molecular pathways promoting cancer progression, with particular emphasis on neuropathic pain generation, and we reviewed the current knowledge of pharmacological inhibitors of the PNI axis. PNI represents a common hallmark of PDAC and correlates with recurrence, poor prognosis and pain in pancreatic cancer patients. The interaction among pancreatic cancer cells, immune cells and nerves is biologically relevant in each stage of the disease and stimulates great interest, but the real impact of the administration of novel agents in clinical practice is limited. It is still early days for PNI-targeted treatments, and further advanced studies are needed to understand whether they could be effective tools in the clinical setting.

Extracellular vesicles derived from pancreatic cancer cells are enriched in the growth factor Midkine.

The growth factor Midkine is a heparin-binding cytokine originally discovered during the differentiation process induced by the retinoic acid in embryonal carcinoma cells. Several studies pointed out the key role of this protein in tumour progression and its elevated expression in different malignancies, including pancreatic cancer. New diagnostic and therapeutic tools are urgently required to treat this highly aggressive and incurable disease capable of metastasising, evading diagnosis, and resisting therapy. Serum midkine promises to be a very functional tumour marker and a target for cancer treatment as an elevated concentration of serum midkine is consistently reported in patients with various tumours. Here, we identified high levels of midkine in extracellular vesicles isolated from pancreatic cancer cell lines and showed that it stimulates the growth of pancreatic cancer cells not expressing midkine.

Modulatory role of the endocannabinoidome in the pathophysiology of the gastrointestinal tract.

Originating from Eastern Asia, the plant Cannabis sativa has been used for centuries as a medicinal treatment. The unwanted psychotropic effects of one of its major components, Δ9-tetrahydrocannabinol, discouraged its therapeutic employment until, recently, the discovery of cannabinoids receptors and their endogenous ligands endocannabinoids reignited the interest. The endocannabinoid system has lately been found to play an important role in the maintenance of human health, both centrally and peripherally. However, the initial idea of the endocannabinoid system structure has been quickly understood to be too simplistic and, as new receptors, mediators, and enzymes have been discovered to participate in a complex relationship, the new, more comprehensive term "expanded endocannabinoid system" or "endocannabinoidome", has taken over. The discovery of other endocannabinoid-like receptors, such as the G protein-coupled receptor 119 and G protein-coupled receptor 55, has opened the way to the development of potential therapeutic targets for the treatment of various metabolic disorders. In addition, recent findings have also provided evidence suggesting the potential therapeutic link between the endocannabinoidome and various inflammatory-based gut diseases, such as inflammatory bowel disease and cancer. This review will provide an introduction to the endocannabinoidome, focusing on its modulatory role in the gastrointestinal tract and on the interest generated by the link between gut microbiota, the endocannabinoid system and metabolic diseases such as inflammatory bowel disease, type-2 diabetes and obesity. In addition, we will look at the potential novel aspects and benefits of drugs targeting the endocannabinoid system.

Exosomal integrins and their influence on pancreatic cancer progression and metastasis.

As one of the most lethal and untreatable types of cancer so far, pancreatic cancer is not benefitting from advancements in research. Despite all the efforts, this malignancy is still very difficult to diagnose in time, resistant to treatments, and prone to relapses. The appearance of metastasis-notoriously difficult to fight and a signal of unfortunate prognosis-is the event most dreaded by every cancer patient, especially by those with pancreatic cancer. Strategies for early detection and treatment of metastases are limited, and new action plans are desperately awaited. Recently, the importance of cell-secreted vesicles, or exosomes, in cell-cell communication and, particularly, their key role in promoting pathological conditions, such as infectious diseases and cancer, have attracted the attention of the scientific community. The discovery of some exosome membrane components, such as adhesion receptors and integrins, and their ability to influence cancer cell functions and metastasis progression, has added some important understanding of the metastatic process and will hopefully open the door to the development of new tools for identifying and targeting metastases. The aim of this review is to discuss the role played by integrins in exosomal-mediated pancreatic cancer progression and metastasis.

Dissecting lipid metabolism alterations in SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic that has infected over a hundred million people globally. There have been more than two million deaths recorded worldwide, with no end in sight until a widespread vaccination will be achieved. Current research has centred on different aspects of the virus interaction with cell surface receptors, but more needs to be done to further understand its mechanism of action in order to develop a targeted therapy and a method to control the spread of the virus. Lipids play a crucial role throughout the viral life cycle, and viruses are known to exploit lipid signalling and synthesis to affect host cell lipidome. Emerging studies using untargeted metabolomic and lipidomic approaches are providing new insight into the host response to COVID-19 infection. Indeed, metabolomic and lipidomic approaches have identified numerous circulating lipids that directly correlate to the severity of the disease, making lipid metabolism a potential therapeutic target. Circulating lipids play a key function in the pathogenesis of the virus and exert an inflammatory response. A better knowledge of lipid metabolism in the host-pathogen interaction will provide valuable insights into viral pathogenesis and to the development of novel therapeutic targets.

Therapeutic potential of cannabinoids in combination cancer therapy.

Derivatives of the plant Cannabis sativa have been used for centuries for both medical and recreational purposes, as well as industrial. The first proof of its medicinal use comes from ancient China, although there is evidence of its earlier utilization in Europe and Asia. In the 19th century, European practitioners started to employ cannabis extracts to treat tetanus, convulsions, and mental diseases and, in 1851, cannabis made its appearance in the Pharmacopoeia of the United States as an analgesic, hypnotic and anticonvulsant. It was only in 1937 that the Marijuana Tax Act prohibited the use of this drug in the USA. The general term Cannabis is commonly used by the scientific and scholar community to indicate derivatives of the plant Cannabis sativa. The word cannabinoid is a term describing chemical compounds that are either derivate of Cannabis (phytocannabinoids) or artificial analogues (synthetic) or are produced endogenously by the body (endocannabinoids). A more casual term "marijuana" or "weed", a compound derived from dried Cannabis flower tops and leaves, has progressively superseded the term cannabis when referred to its recreational use. The 2018 World health organisation (WHO) data suggest that nearly 2.5% of the global population (147 million) uses marijuana and some countries, such as Canada and Uruguay, have already legalised it. Due to its controversial history, the medicinal use of cannabinoids has always been a centre of debate. The isolation and characterisation of Δ9 tetrahydrocannabinol (THC), the major psychoactive component of cannabis and the detection of two human cannabinoid receptor (CBRs) molecules renewed interest in the medical use of cannabinoids, boosting research and commercial heed in this sector. Some cannabinoid-based drugs have been approved as medications, mainly as antiemetic, antianorexic, anti-seizure remedies and in cancer and multiple sclerosis patients' palliative care. Nevertheless, due to the stigma commonly associated with these compounds, cannabinoids' potential in the treatment of conditions such as cancer is still largely unknown and therefore underestimated.

Exosomal long non-coding RNAs in the diagnosis and oncogenesis of pancreatic cancer.

Extracellular vesicles, specifically exosomes, play a significant role as an extracellular messenger through their transporting cargo. Of particular interest are the potential roles they play in pancreatic cancer, one of the leading causes of cancer-related mortality worldwide. Pancreatic Ductal Adenocarcinoma displays high chemo-resistance and metastatic ability, which may be influenced by cancer-derived exosomes carrying proteins, lipids and RNA. To date, among the most extensively examined exosomal molecular cargo there are long non-coding RNAs (lncRNAs) that, despite the increasing interest in their role and functions, are relatively poorly understood compared to other RNA transcripts. Nevertheless, we have witnessed an increasing interest for lncRNAs roles and functions in the past decade. For example, lncRNAs have been investigated as potential biomarkers for diagnosing pancreatic cancer and may have a role as therapeutics targets for precision medicine, but may also directly intervene in tumour progression features such as metastasis, epithelial to mesenchymal transition and resistance of cancer cells towards chemotherapy agents. The function of lncRNAs within various cancer exosomes is still undefined. In this review, we summarize the current knowledge on pancreatic cancer-derived exosome specific lncRNAs having prominent roles in genome integrity, pancreatic cancer progression and in other oncogenic hallmarks.

Rhenium N-heterocyclic carbene complexes block growth of aggressive cancers by inhibiting FGFR- and SRC-mediated signalling.

BACKGROUND: Platinum-based anticancer drugs have been at the frontline of cancer therapy for the last 40 years, and are used in more than half of all treatments for different cancer types. However, they are not universally effective, and patients often suffer severe side effects because of their lack of cellular selectivity. There is therefore a compelling need to investigate the anticancer activity of alternative metal complexes. Here we describe the potential anticancer activity of rhenium-based complexes with preclinical efficacy in different types of solid malignancies. METHODS: Kinase profile assay of rhenium complexes. Toxicology studies using zebrafish. Analysis of the growth of pancreatic cancer cell line-derived xenografts generated in zebrafish and in mice upon exposure to rhenium compounds. RESULTS: We describe rhenium complexes which block cancer proliferation in vitro by inhibiting the signalling cascade induced by FGFR and Src. Initially, we tested the toxicity of rhenium complexes in vivo using a zebrafish model and identified one compound that displays anticancer activity with low toxicity even in the high micromolar range. Notably, the rhenium complex has anticancer activity in very aggressive cancers such as pancreatic ductal adenocarcinoma and neuroblastoma. We demonstrate the potential efficacy of this complex via a significant reduction in cancer growth in mouse xenografts. CONCLUSIONS: Our findings provide a basis for the development of rhenium-based chemotherapy agents with enhanced selectivity and limited side effects compared to standard platinum-based drugs.

Inhibition of the Lysophosphatidylinositol Transporter ABCC1 Reduces Prostate Cancer Cell Growth and Sensitizes to Chemotherapy.

Expression of ATP-binding cassette (ABC) transporters has long been implicated in cancer chemotherapy resistance. Increased expression of the ABCC subfamily transporters has been reported in prostate cancer, especially in androgen-resistant cases. ABCC transporters are known to efflux drugs but, recently, we have demonstrated that they can also have a more direct role in cancer progression. The pharmacological potential of targeting ABCC1, however, remained to be assessed. In this study, we investigated whether the blockade of ABCC1 affects prostate cancer cell proliferation using both in vitro and in vivo models. Our data demonstrate that pharmacological inhibition of ABCC1 reduced prostate cancer cell growth in vitro and potentiated the effects of Docetaxel in vitro and in mouse models of prostate cancer in vivo. Collectively, these data identify ABCC1 as a novel and promising target in prostate cancer therapy.

Dual PDK1/Aurora Kinase A Inhibitors Reduce Pancreatic Cancer Cell Proliferation and Colony Formation.

Deregulation of different intracellular signaling pathways is a common feature in cancer. Numerous studies indicate that persistent activation of the phosphoinositide 3-kinase (PI3K) pathway is often observed in cancer cells. 3-phosphoinositide dependent protein kinase-1 (PDK1), a transducer protein that functions downstream of PI3K, is responsible for the regulation of cell proliferation and migration and it also has been found to play a key role in different cancers, pancreatic and breast cancer amongst others. As PI3K is being described to be aberrantly expressed in several cancer types, designing inhibitors targeting various downstream molecules of PI3K has been the focus of anticancer agent development for a long time. In particular, dual inhibitory drugs targeting key signaling molecules in the PI3K pathway have attracted the attention of scientists. Several drugs have progressed to clinical trials, with limited success due to toxicity and bioavailability concerns. Very few anticancer drugs targeting the PI3K pathway have been approved for clinical use and their efficacy is particularly limited towards certain tumors such as pancreatic cancer. Here, we tested two drugs displaying dual inhibitory activity towards PDK1 and Aurora kinase A in a panel of pancreatic cancer cell lines and in two in vivo models of pancreatic cancer. Our data show that both inhibitors are able to impair cell proliferation and clonogenic potential in pancreatic cancer cells. However, the limited activity of both compounds in vivo indicates that further optimization of the pharmacokinetics properties is required.

Metal-based antitumor compounds: beyond cisplatin.

Despite improvements in the 5-year survival rate to over 80% in cancers, such as Hodgkin lymphoma and testicular cancer, more aggressive tumors including pancreatic and brain cancer still have extremely low survival rates. The establishment of chemoresistance, responsible for the reduction in treatment efficiency and cancer relapse, is one possible explanation for this setback. Metal-based compounds, a class of anticancer drugs, are largely used in the treatment of cancer. Herein, we will review the use of metal-based small molecules in chemotherapy, focusing on recent studies, and we will discuss how new nonplatinum-based agents are prompting scientists to increase drug specificity to overcome chemoresistance in cancer cells.

Oleoyl-lysophosphatidylinositol enhances glucagon-like peptide-1 secretion from enteroendocrine L-cells through GPR119.

The gastrointestinal tract is increasingly viewed as critical in controlling glucose metabolism, because of its role in secreting multiple glucoregulatory hormones, such as glucagon like peptide-1 (GLP-1). Here we investigate the molecular pathways behind the GLP-1- and insulin-secreting capabilities of a novel GPR119 agonist, Oleoyl-lysophosphatidylinositol (Oleoyl-LPI). Oleoyl-LPI is the only LPI species able to potently stimulate the release of GLP-1 in vitro, from murine and human L-cells, and ex-vivo from murine colonic primary cell preparations. Here we show that Oleoyl-LPI mediates GLP-1 secretion through GPR119 as this activity is ablated in cells lacking GPR119 and in colonic primary cell preparation from GPR119-/- mice. Similarly, Oleoyl-LPI-mediated insulin secretion is impaired in islets isolated from GPR119-/- mice. On the other hand, GLP-1 secretion is not impaired in cells lacking GPR55 in vitro or in colonic primary cell preparation from GPR55-/- mice. We therefore conclude that GPR119 is the Oleoyl-LPI receptor, upstream of ERK1/2 and cAMP/PKA/CREB pathways, where primarily ERK1/2 is required for GLP-1 secretion, while CREB activation appears dispensable.

Defining the Anti-Cancer Activity of Tricarbonyl Rhenium Complexes: Induction of G2/M Cell Cycle Arrest and Blockade of Aurora-A Kinase Phosphorylation.

Rhenium and ruthenium complexes containing N-heterocylic carbene (NHC) ligands and conjugated to indomethacin were prepared. The anticancer properties were probed against pancreatic cell lines, revealing a remarkable activity of the rhenium fragment as anticancer agent. The ruthenium complexes were found to be inactive against the same pancreatic cancer cell lines, either alone or in conjugation with indomethacin. An in-depth biological study revealed the origin of the anticancer properties of the rhenium tricarbonyl fragment, of which a complete elucidation had yet to be achieved. It was found that the rhenium complexes induce cell cycle arrest at the G2/M phase by inhibiting the phosphorylation of Aurora-A kinase. A preliminary study on the structure-activity relationship on a large family of these complexes revealed that the anticancer properties are mainly associated with the lability of the ancillary ligand, with inert complexes showing limited to no anticancer properties.

Pancreatic cancer: Current research and future directions.

Despite the survival rate advancements in different types of cancer in the last 40 years, the perspective for pancreatic cancer patients has seen no substantial changes. Indeed, the five year survival rate remains around 5%. Nevertheless, in the last decade we have witnessed an increased interest in pancreatic cancer biology and this has produced a substantial increment in our knowledge on pancreatic cancer progression. The big challenge is now to translate this knowledge in better outcomes for patients. The aim of this review is to describe the latest discoveries and advancements in pancreatic cancer research and to discuss future directions.

Diet and Pancreatic Cancer Prevention.

Pancreatic cancer is without any doubt the malignancy with the poorest prognosis and the lowest survival rate. This highly aggressive disease is rarely diagnosed at an early stage and difficult to treat due to its resistance to radiotherapy and chemotherapy. Therefore, there is an urgent need to clarify the causes responsible for pancreatic cancer and to identify preventive strategies to reduce its incidence in the population. Some circumstances, such as smoking habits, being overweight and diabetes, have been identified as potentially predisposing factors to pancreatic cancer, suggesting that diet might play a role. A diet low in fat and sugars, together with a healthy lifestyle, regular exercise, weight reduction and not smoking, may contribute to prevent pancreatic cancer and many other cancer types. In addition, increasing evidence suggests that some food may have chemo preventive properties. Indeed, a high dietary intake of fresh fruit and vegetables has been shown to reduce the risk of developing pancreatic cancer, and recent epidemiological studies have associated nut consumption with a protective effect against it. Therefore, diet could have an impact on the development of pancreatic cancer and further investigations are needed to assess the potential chemo preventive role of specific foods against this disease. This review summarizes the key evidence for the role of dietary habits and their effect on pancreatic cancer and focuses on possible mechanisms for the association between diet and risk of pancreatic cancer.

Cancer chemoprevention with nuts.

It is well established that increased nut consumption is associated with a reduced risk of major chronic diseases, such as cardiovascular disease and type 2 diabetes mellitus. On the other hand, the association between nut consumption and cancer mortality is less clear. Recent studies have suggested that nut consumption is associated with reduced cancer mortality. This evidence reinforces the interest to investigate the chemopreventive properties of nuts, and it raises questions about the specific cancer type(s) and setting that can be more affected by nut consumption, as well as the cellular mechanisms involved in this protective effect. Here we discuss recent studies on the association of nut consumption and cancer, and we propose specific cellular mechanisms by which nut components can affect cancer progression.