GRANT PROJECTS

PROPOLIS AND PUNICA GRANATUM PREPARATIONS FOR THE TREATMENT OF
RHEUMATOID ARTHRITIS (2020)

Prof. Nunziatina De Tommasi, Dipartimento di Farmacia, Università degli Studi di Salerno, Fisciano (SA), Italy
Prof. Alessandra Braca, Dipartimento di Farmacia, Università di Pisa, Pisa, Italy
Dr. Claudio Pisano, Biogem, Research Institute “G. Salvatore”, Ariano Irpino (AV), Italy

Rheumatoid arthritis (RA) is a very common autoimmune disorder. Patients affected by RA show a chronic systemic inflammation that can determine both articular and bone injuries as well as a progressive functional disability, with an important impact on quality of life, social and economic aspects. The discovery of safe natural products for the RA treatment is needed also because drugs long-term use can cause severe side effects.

In this context, the aims of this project are:

  • to evaluate and characterize the effect of phyto-preparations, composed by a mixture of propolis and P. granatum fruits collected in Southern Italy regions, against a model of RA induced in mice by collagen injection.
  • to characterize the in vivo mechanism of action of the combination by analyzing the levels of different cytokines involved in Collagen Induced Arthritis;
  • to study the bioactivity of this mixture in 2D and 3D cellular models, to evaluate its efficiency as anti-inflammatory agent and identify its putative molecular targets;
  • to provide the quali-quantitative chemical characterization of the phyto-preparation used in the biological assays;
  • to provide scientific evidences supporting the conservation and sustainable use of traditional knowledge from the internal areas of Italian regions.
CLINICAL AND BIOLOGICAL EFFECTS OF CITRUS-PHYTOCHEMICALS IN SUBJECTIVE COGNITIVE DECLINE:
A PILOT RANDOMIZED CONTROLLED TRIAL. (2020)

Samantha Galluzzi, Lab Alzheimer’s Neuroimaging & Epidemiology, IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Roberta Zanardini, Molecular Markers Unit, IRCCS San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Francesco Epifano, Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, Chieti, Italy

Alzheimer's disease (AD) is a neurodegenerative disorder which represents a major health issue and financial burden for health care systems around the world. In the absence of a cure for this condition, the public health priority has focused on enhancement of cognitive performance in older age and, possibly, prevention of cognitive decline.

Several nutraceuticals have displayed over the years the ability or a strong potential to prevent cognitive impairment. Among these, auraptene and naringenin are natural bioactive compounds derived from peels of Citrus fruits. They showed anti-inflammatory, antioxidant, and neuroprotective effects in preclinical studies, memory improvement in AD mouse models and preservation of cognitive function in healthy elderly, thus representing an appealing strategy for cognitive enhancement. A population of frail elderly with subjective cognitive decline (SCD), a condition at higher risk for incident AD, is an ideal target for early intervention trials.

This is a pilot randomized controlled trial to determine clinical and biological effects of Citrus- phytochemicals in 60 individuals with SCD. Participants will be randomized to receive Citrus- phytochemicals standardized in auraptene and naringenin or placebo for 9 months. Cognitive tests and blood-based biological markers will be done at baseline and at the end of treatment as outcome measures.

VIOLA TRICOLOR AS PHYTOMEDICINE FOR THE TREATMENT OF ULCERATIVE COLITIS (2019)

Assoc. Prof. Dr. Christian Gruber, Center for Physiology and Pharmacology, Medical University of Vienna
PD Dr. Carsten Gründemann, Center for Complementary Medicine, Medical Center, University of Freiburg

Inflammatory bowel disease is a chronic recurring disease of the gastrointestinal tract and can be manifested as ulcerative colitis. In Germany, Austria and Switzerland about 400,000 patients suffer from ulcerative colitis. Hereby, Europe has the highest reported prevalence worldwide with 505 per 100,000 people being affected Symptoms include diarrhea, abdominal cramps, and rectal bleeding. Considering current guidelines, anti-inflammatory and immunosuppressive drugs or biologics are used for treatment. Due to common adverse effects and lack of efficacy of standard therapies, a widespread discovery effort has been launched to identify new drugs from natural sources.

Our scientific project aims to evaluate the use of herbal extracts of Viola tricolor as treatment of chronic inflammatory bowel diseases, especially ulcerative colitis. We have teamed up to perform cell-based signaling, mechanism-of-action and toxicity studies with tea infusions (Ph. Eur.) and experimental herbal violet extracts. Further, we aim to extract, isolate and chemically characterize novel immunomodulatory molecules from these preparations. Development of standardized extract preparation, based on the bioactive compounds of V. tricolor, will be employed. Furthermore, safety and efficacy of optimized herbal violet preparation will be assessed and documented following state-of-the-art Case Reporting guidelines, in a cohort of patients suffering from ulcerative colitis.

NATURAL PRODUCTS TARGETING MITOCHONDRIAL FUNCTION AND MITOGRAPHY:
IMPACT ON AGING AND AGE-RELATED NEURODEGENERATIVE DISORDERS (2019)

Professor Dr. Anne Eckert, Dr. Imane Lejri (PhD), Anastasia Agapouda (PhD candidate) and Selina Werner (PhD candidate), Neurobiology Lab for Brain Aging and Mental Health, Transfaculty Research Platform Molecular & Cognitive Neuroscience, University of Basel and Psychiatric University Clinics Basel

Aging is the major risk factor for neurodegenerative diseases. The underlying molecular mechanisms of brain aging involve mitochondrial dysfunction and increased oxidative stress. Several studies indicate that mitochondria are a convergence point in aging as well as in neurodegenerative mechanisms. They play a pivotal role in neuronal cell survival and death as they regulate both. Accordingly, current pharmacological concepts focus on increasing mitochondrial respiration and energy (ATP) production as well as on reducing the generation of free oxygen radicals. In addition, autophagy and mitophagy are important cellular processes responsible for breaking down cellular contents therefore preventing the accumulation of damaged biomolecules. Both autophagy and mitophagy are highly impaired during aging.

Wheat germ extract is currently used as adjuvant in cancer therapy. Its polyamines, especially spermidine, are reported to prolong the lifespan of mammals, to induce autophagy and to exhibit anti-oxidant properties.

In this study, we aim at assessing the effects of these natural compounds (wheat germ extract and polyamines) on mitochondria in human aging and Alzheimer in vitro models. For that purpose, we will use sophisticated human neuronal cell models, e.g. aged human neurons (generated from fibroblasts of old donors) and human AD neurons (generated from induced pluripotent stem cells).

NATURAL PRODUCTS TARGETING LOW RESPIRATORY INFECTIONS (2018)

Prof. Dr. Judith M. Rollinger, Department of Pharmacognosy, University of Vienna
Prof. Dr. Michaela Schmidtke, Section Experimental Virology, Institute of Medical Microbiology, Jena University Hospital

One hundred years after the devastating Spanish flu, even the implementation of powerful vaccination and the invention of antivirals and antibiotics have not been able to cope with the high morbidity and mortality associated with influenza epidemics and cyclical pandemics. According to the WHO, low respiratory tract (LRT) infections remain the most deadly communicable disease, causing 3.2 million deaths worldwide in 2015. Mainly caused by influenza viruses and picornaviruses, the mortality rate is heavily boosted by bacterial coinfection (lethal synergism).

In this project, we aim at investigating and developing natural product based antimicrobial agents. In previous studies we identified natural starting materials with broad spectrum antimicrobial activities, such as the extracts from Morus root bark and from the native mushroom Gloephyllum odoratum. Within this project we will explore the full antimicrobial potential of these natural products for the development of improved multi-functional therapeutics and for the discovery of desperately needed novel antimicrobial lead structures overcoming resistances. The envisaged investigations will thereby focus on (i) optimized and standardized extract preparations, (ii) their analytical characterization, and (iii) determination of their antiviral spectrum, as prerequisites of (iv) in vivo efficacy and toxicity studies for preclinical development.

THE EFFECT OF NATURAL COMPOUNDS ON PSORIASIS KERATINOCYTES IN VITRO AND IN VIVO (2018)

Prof. Dr. Christoph Schempp & Dr. Ute Wölfle, Research Center skinital, Department of Dermatology and Venerology, University Medical Center Freiburg

Psoriasis is a chronic inflammatory skin disease that frequently affects the joints and is associated with other comorbidities such as obesity and vascular disease. In Central Europe about 2–3 % of the population suffers from psoriasis, about two million in Germany, and 125 million worldwide.

Psoriasis has an enormous negative impact on the affected subjects. Therefore, during the last decade several new biological drugs were developed for the systemic treatment of moderate to severe psoriasis and psoriatic arthritis. These immunological therapies neutralize the effect of various proinflammatory cytokines, such as TNF-α, Interleukin-17 and Interleukin-23, to name a few.

In contrast, no innovative drugs for topical application or medical skin care products, i.e. botanical compounds, have been approved for psoriasis. Because there is a high of medical skin care in the concomitant treatment of mild forms of psoriasis and childhood psoriasis we have designed a scientific project that aims at exploring the effect of natural compounds on psoriasis keratinocytes in vitro and in vivo. Botanical compounds from Centella asiatica (Madecassoide and Asiaticoside), Mahonia aquifolium (Berberin) and Whrightia tinctoria (Triterpenes und Steroles) are of special interest because they have been used in ayurvedic and traditional Chinese medicine for thousands of years.

First, the molecular mechanisms and mode of action of the compounds and plant extracts will be investigated. Subsequently, the substances will be tested in a psoriasis skin equivalent model that will be established especially for this project. Effective substances are expected to reduce keratinocyte proliferation and epidermal thickness, inhibit inflammation and the stress induced response of the endoplasmatic reticulum (UPR).

Finally, a lipophilic ointment for the topical treatment of psoriasis will be developed. The most promising plant extract or compounds from the above specified testing will be incorporated in the vehicle and will be tested for skin tolerance and effectivity, using the standardized psoriasis plaque-test.

INVESTIGATIONS ON THE THERAPEUTIC EFFICACY OF ARNICA PREPARATIONS TO TREAT
CUTANEOUS LEISHMANIASIS (2018)

Prof. Dr. Thomas J. Schmidt, Institute of Pharmaceutical Biology and Phytochemistry, University of Münster
Prof. Dr. Sara M. Robledo, 2PECET-School of Medicine, University of Antioquia, Medellin

Leishmaniasis is one of the 20 communicable diseases currently classified by WHO as neglected tropical diseases (NTDs) affecting economically disadvantaged populations in the tropics. New efficacious, safe and affordable therapies are urgently needed. We have recently shown that Arnica tincture, an approved herbal medicinal preparation, can effectively cure cutaneous Leishmaniasis (CL) caused by Leishmania braziliensis in a golden hamster model. The tested Arnica tincture, applied topically, was even somewhat more efficacious than the standard antimonial therapeutic Glucantime. Based on these very promising results, the current investigation aims at in-depth investigations on the therapeutic efficacy of Arnica preparations for the treatment of this very severe disfiguring NTD. The main aims are to find out (i) whether Arnica is also active against CL caused by other Leishmania species, (ii) to investigate whether isolated Arnica constituents are equally efficacious as the total tincture, or whether the total extract of Arnica tincture is superior to its isolated chemical constituents and (iii) to gain first evidence on the therapeutic usefulness in human patients.

This herbal medicine could become a new efficacious cure, less toxic, more convenient to administer than standard antimonial therapy and affordable for the disadvantaged population usually affected by CL.