Dietrich Büsselberg - Academia.edu (original) (raw)

Papers by Dietrich Büsselberg

Cancers, Jun 27, 2023

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Frontiers in Nutrition, May 12, 2023

Obesity presents a major health challenge that increases the risk of several non-communicable ill... more Obesity presents a major health challenge that increases the risk of several non-communicable illnesses, such as but not limited to diabetes, hypertension, cardiovascular diseases, musculoskeletal and neurological disorders, sleep disorders, and cancers. Accounting for nearly 8% of global deaths (4.7 million) in 2017, obesity leads to diminishing quality of life and a higher premature mortality rate among affected individuals. Although essentially dubbed as a modifiable and preventable health concern, prevention, and treatment strategies against obesity, such as calorie intake restriction and increasing calorie burning, have gained little long-term success. In this manuscript, we detail the pathophysiology of obesity as a multifactorial, oxidative stress-dependent inflammatory disease. Current anti-obesity treatment strategies, and the effect of flavonoid-based therapeutic interventions on digestion and absorption, macronutrient metabolism, inflammation and oxidative stress and gut microbiota has been evaluated. The use of several naturally occurring flavonoids to prevent and treat obesity with a long-term efficacy, is also described.

The Epma Journal, May 22, 2023

Breast cancer (BC) is the most common female malignancy reaching a pandemic scale worldwide. A co... more Breast cancer (BC) is the most common female malignancy reaching a pandemic scale worldwide. A comprehensive interplay between genetic alterations and shifted epigenetic regions synergistically leads to disease development and progression into metastatic BC. DNA and histones methylations, as the most studied epigenetic modifications, represent frequent and early events in the process of carcinogenesis. To this end, long non-coding RNAs (lncRNAs) are recognized as potent epigenetic modulators in pathomechanisms of BC by contributing to the regulation of DNA, RNA, and histones' methylation. In turn, the methylation status of DNA, RNA, and histones can affect the level of lncRNAs expression demonstrating the reciprocity of mechanisms involved. Furthermore, lncRNAs might undergo methylation in response to actual medical conditions such as tumor development and treated malignancies. The reciprocity between genome-wide methylation status and long noncoding RNA expression levels in BC remains largely unexplored. Since the bio/medical research in the area is, per evidence, strongly fragmented, the relevance of this reciprocity for BC development and progression has not yet been systematically analyzed. Contextually, the article aims at:-consolidating the accumulated knowledge on both-the genome-wide methylation status and corresponding lncRNA expression patterns in BC and-highlighting the potential benefits of this consolidated multi-professional approach for advanced BC management. Based on a big data analysis and machine learning for individualized data interpretation, the proposed approach demonstrates a great potential to promote predictive diagnostics and targeted prevention in the cost-effective primary healthcare (suboptimal health conditions and protection against the health-to-disease transition) as well as advanced treatment algorithms tailored to the individualized patient profiles in secondary BC care (effective protection against metastatic disease). Clinically relevant examples are provided, including mitochondrial health control and epigenetic regulatory mechanisms involved.

Frontiers in Pharmacology, Apr 6, 2023

Significant limitations of the reactive medical approach in breast cancer management are clearly ... more Significant limitations of the reactive medical approach in breast cancer management are clearly reflected by alarming statistics recorded worldwide. According to the WHO updates, breast malignancies become the leading cancer type. Further, the portion of premenopausal breast cancer cases is permanently increasing and demonstrates particularly aggressive patterns and poor outcomes exemplified by young patients with triple-negative breast cancer that lacks targeted therapy. Accumulating studies suggest the crucial role of stem cells in tumour biology, high metastatic activity, and therapy resistance of aggressive breast cancer. Therefore, targeting breast cancer stem cells is a promising treatment approach in secondary and tertiary breast cancer care. To this end, naturally occurring substances demonstrate high potential to target cancer stem cells which, however, require in-depth analysis to identify effective anti-cancer agents for cost-effective breast cancer management. The current article highlights the properties of flavonoids particularly relevant for targeting breast cancer stem cells to mitigate therapy resistance. The proposed approach is conformed with the principles of 3P medicine by applying predictive diagnostics, patient stratification and treatments tailored to the individualised patient profile. Expected impacts are very high, namely, to overcome limitations of reactive medical services improving individual outcomes and the healthcare economy in breast cancer management. Relevant clinical applications are exemplified in the paper.

Biomolecules, Oct 28, 2022

Biomolecules, Mar 20, 2023

Cancers, Dec 9, 2022

Cancers, Mar 29, 2021

Cancers, Aug 4, 2021

Biomolecules, Jan 27, 2020

Several phytochemicals have been identified for their role in modifying miRNA regulating tumor pr... more Several phytochemicals have been identified for their role in modifying miRNA regulating tumor progression. miRNAs modulate the expression of several oncogenes and tumor suppressor genes including the genes that regulate tumor angiogenesis. Hypoxia inducible factor-1 alpha (HIF-1α) signaling is a central axis that activates oncogenic signaling and acts as a metabolic switch in endothelial cell (EC) driven tumor angiogenesis. Tumor angiogenesis driven by metabolic reprogramming of EC is crucial for tumor progression and metastasis in many different cancers, including breast cancers, and has been linked to aberrant miRNA expression profiles. In the current article, we identify different miRNAs that regulate tumor angiogenesis in the context of oncogenic signaling and metabolic reprogramming in ECs and review how selected phytochemicals could modulate miRNA levels to induce an anti-angiogenic action in breast cancer. Studies involving genistein, epigallocatechin gallate (EGCG) and resveratrol demonstrate the regulation of miRNA-21, miRNA-221/222 and miRNA-27, which are prognostic markers in triple negative breast cancers (TNBCs). Modulating the metabolic pathway is a novel strategy for controlling tumor angiogenesis and tumor growth. Cardamonin, curcumin and resveratrol exhibit their anti-angiogenic property by targeting the miRNAs that regulate EC metabolism. Here we suggest that using phytochemicals to target miRNAs, which in turn suppresses tumor angiogenesis, should have the potential to inhibit tumor growth, progression, invasion and metastasis and may be developed into an effective therapeutic strategy for the treatment of many different cancers where tumor angiogenesis plays a significant role in tumor growth and progression.

The Epma Journal, Aug 15, 2022

Thromboembolism is the third leading vascular disease, with a high annual incidence of 1 to 2 cas... more Thromboembolism is the third leading vascular disease, with a high annual incidence of 1 to 2 cases per 1000 individuals within the general population. The broader term venous thromboembolism generally refers to deep vein thrombosis, pulmonary embolism, and/or a combination of both. Therefore, thromboembolism can affect both-the central and peripheral veins. Arterial thromboembolism causes systemic ischemia by disturbing blood flow and oxygen supply to organs, tissues, and cells causing, therefore, apoptosis and/or necrosis in the affected tissues. Currently applied antithrombotic drugs used, e.g. to protect affected individuals against ischemic stroke, demonstrate significant limitations. For example, platelet inhibitors possess only moderate efficacy. On the other hand, thrombolytics and anticoagulants significantly increase hemorrhage. Contextually, new approaches are extensively under consideration to develop next-generation antithrombotics with improved efficacy and more personalized and targeted application. To this end, phytochemicals show potent antithrombotic efficacy demonstrated in numerous in vitro, ex vivo, and in vivo models as well as in clinical evaluations conducted on healthy individuals and persons at high risk of thrombotic events, such as pregnant women (primary care), cancer, and COVID-19-affected patients (secondary and tertiary care). Here, we hypothesized that specific antithrombotic and antiplatelet effects of plant-derived compounds might be of great clinical utility in primary, secondary, and tertiary care. To increase the efficacy, precise patient stratification based on predictive diagnostics is essential for targeted protection and treatments tailored to the person in the framework of 3P medicine. Contextually, this paper aims at critical review toward the involvement of specific classes of phytochemicals in antiplatelet and anticoagulation adapted to clinical needs. The paper exemplifies selected plant-derived drugs, plant extracts, and whole plant foods/herbs demonstrating their specific antithrombotic, antiplatelet, and fibrinolytic activities relevant for primary, secondary, and tertiary care. One of the examples considered is antithrombotic and antiplatelet protection specifically relevant for COVID-19-affected patient groups.

The Epma Journal, May 18, 2021

HPVs representing the most common sexually transmitted disease are a group of carcinogenic viruse... more HPVs representing the most common sexually transmitted disease are a group of carcinogenic viruses with different oncogenic potential. The immune system and the vaginal microbiome represent the modifiable and important risk factors in HPV-induced carcinogenesis. HPV infection significantly increases vaginal microbiome diversity, leading to gradual increases in the abundance of anaerobic bacteria and consequently the severity of cervical dysplasia. Delineation of the exact composition of the vaginal microbiome and immune environment before HPV acquisition, during persistent/progressive infections and after clearance, provides insights into the complex mechanisms of cervical carcinogenesis. It gives hints regarding the prediction of malignant potential. Relative high HPV prevalence in the general population is a challenge for modern and personalized diagnostics and therapeutic guidelines. Identifying the dominant microbial biomarkers of high-grade and low-grade dysplasia could help us to triage the patients with marked chances of lesion regression or progression. Any unnecessary surgical treatment of cervical dysplasia could negatively affect obstetrical outcomes and sexual life. Therefore, understanding the effect and role of microbiome-based therapies is a breaking point in the conservative management of HPV-associated precanceroses. The detailed evaluation of HPV capabilities to evade immune mechanisms from various biofluids (vaginal swabs, cervicovaginal lavage/secretions, or blood) could promote the identification of new immunological targets for novel individualized diagnostics and therapy. Qualitative and quantitative assessment of local immune and microbial environment and associated risk factors constitutes the critical background for preventive, predictive, and personalized medicine that is essential for improving state-of-the-art medical care in patients with cervical precanceroses and cervical cancer. The review article focuses on the influence and potential diagnostic and therapeutic applications of the local innate immune system and the microbial markers in HPV-related cancers in the context of 3P medicine.

The Epma Journal, Jul 8, 2022

According to the GLOBOCAN 2020, prostate cancer (PCa) is the most often diagnosed male cancer in ... more According to the GLOBOCAN 2020, prostate cancer (PCa) is the most often diagnosed male cancer in 112 countries and the leading cancer-related death in 48 countries. Moreover, PCa incidence permanently increases in adolescents and young adults. Also, the rates of metastasising PCa continuously grow up in young populations. Corresponding socioeconomic burden is enormous: PCa treatment costs increase more rapidly than for any other cancer. In order to reverse current trends in exploding PCa cases and treatment costs, pragmatic decisions should be made, in favour of advanced populational screening programmes and effective anti-PCa protection at the level of the health-to-disease transition (sub-optimal health conditions) demonstrating the highest cost-efficacy of treatments. For doing this, the paradigm change from reactive treatments of the clinically manifested PCa to the predictive approach and personalised prevention is essential. Phytochemicals are associated with potent anti-cancer activity targeting each stage of carcinogenesis including cell apoptosis and proliferation, cancer invasiveness and metastatic disease. For example, their positive effects are demonstrated for stabilising and restoring mitochondrial health quality, which if compromised is strongly associated with sub-optimal health conditions and strong predisposition to aggressive PCa sub-types. Further, phytochemicals significantly enhance response of cancer cells to anti-cancer therapies including radio-and chemotherapy. Evident plant-based mitigation of negative sideeffects frequently observed for conventional anti-cancer therapies has been reported. Finally, dual anti-cancer and anti-viral effects of phytochemicals such as these of silibinin have been demonstrated as being highly relevant for improved PCa management at the level of secondary and tertiary care, for example, under pandemic conditions, since PCa-affected individuals per evidence are highly vulnerable towards COVID-19 infection. Here, we present a comprehensive data analysis towards clinically relevant anti-cancer effects of phytochemicals to be considered for personalised anti-PCa protection in primary care as well as for an advanced disease management at the level of secondary and tertiary care in the framework of predictive, preventive and personalised medicine.

Cancer and Metastasis Reviews

Despite tremendous medical treatment successes, colorectal cancer (CRC) remains a leading cause o... more Despite tremendous medical treatment successes, colorectal cancer (CRC) remains a leading cause of cancer deaths worldwide. Chemotherapy as monotherapy can lead to significant side effects and chemoresistance that can be linked to several resistance-activating biological processes, including an increase in inflammation, cellular plasticity, multidrug resistance (MDR), inhibition of the sentinel gene p53, and apoptosis. As a consequence, tumor cells can escape the effectiveness of chemotherapeutic agents. This underscores the need for cross-target therapeutic approaches that are not only pharmacologically safe but also modulate multiple potent signaling pathways and sensitize cancer cells to overcome resistance to standard drugs. In recent years, scientists have been searching for natural compounds that can be used as chemosensitizers in addition to conventional medications for the synergistic treatment of CRC. Resveratrol, a natural polyphenolic phytoalexin found in various fruits a...

Journal of Advanced Research

EPMA Journal

Breast cancer incidence is actually the highest one among all cancers. Overall breast cancer mana... more Breast cancer incidence is actually the highest one among all cancers. Overall breast cancer management is associated with challenges considering risk assessment and predictive diagnostics, targeted prevention of metastatic disease, appropriate treatment options, and cost-effectiveness of approaches applied. Accumulated research evidence indicates promising anti-cancer effects of phytochemicals protecting cells against malignant transformation, inhibiting carcinogenesis and metastatic spread, supporting immune system and increasing effectiveness of conventional anti-cancer therapies, among others. Molecular and sub-/cellular mechanisms are highly complex affecting several pathways considered potent targets for advanced diagnostics and cost-effective treatments. Demonstrated anti-cancer affects, therefore, are clinically relevant for improving individual outcomes and might be applicable to the primary (protection against initial cancer development), secondary (protection against pote...

Neurobiology of Sleep and Circadian Rhythms, 2020

The circadian clock, which generates the internal daily rhythm largely mediated through release o... more The circadian clock, which generates the internal daily rhythm largely mediated through release of melatonin, can be disrupted in various ways. Multiple factors result in a disruption of the circadian cycle in the clinical context, of interest are anti-cancer drugs such as cisplatin. Cisplatin modulates the circadian clock through two mechanisms: 1) the circadian clock control of DNA excision repair and 2) the effect of circadian clock disruption on apoptosis. Cisplatin can stimulate multiple classified molecules, including DNA repair factors, DNA damage recognition factors and transcription factors in drug resistance and cisplatin-induced signal transduction. These factors interact with each other and can be transformed by DNA damage. Hence, these molecular interactions are intimately involved in cell proliferation and damage-induced apoptosis. Cisplatin has a dual-effect on circadian genes: upregulation of CLOCK expression causes an increase in proliferation but upregulation of BMAL1 expression causes an increase in apoptosis. Therefore, the interference of circadian genes by cisplatin can have multiple, opposing effects on apoptosis and cell proliferation, which may have unintended pro-cancer effects. Melatonin and intracellular Ca 2+ also have a dual-effect on cell proliferation and apoptosis and can disrupt circadian rhythms.

Cancers, Jun 27, 2023

Frontiers in Nutrition, May 12, 2023

The Epma Journal, May 22, 2023

Frontiers in Pharmacology, Apr 6, 2023

Biomolecules, Oct 28, 2022

Biomolecules, Mar 20, 2023

Cancers, Dec 9, 2022

Cancers, Mar 29, 2021

Cancers, Aug 4, 2021

Biomolecules, Jan 27, 2020

The Epma Journal, Aug 15, 2022

The Epma Journal, May 18, 2021

The Epma Journal, Jul 8, 2022

Cancer and Metastasis Reviews

Journal of Advanced Research

EPMA Journal

Neurobiology of Sleep and Circadian Rhythms, 2020

Editorial Recent updates on metal compounds in our environment and their implications on human he... more Editorial
Recent updates on metal compounds in our
environment and their implications on human health
Dietrich Büsselberg
Weill Cornell Medical College in Qatar, Qatar Foundation – Education City, POB 24144, Doha, Qatar
email: dib2015@qatar-med.cornell.edu
All living organisms (including humans) depend on an intact environment. Contamination will
a!ect air, soil and water (and the food produced) not only locally but also worldwide. The QScience
Collection, entitled ‘Metal compounds in our environment and their implications on human health’
highlights recent open access publications that illustrate the current reflection of these issues. The
articles highlight how some local events might impact the health even at the other side of the globe.
Csavina and co-workers (2013)1
recapitulate how metal particles (lead, arsenic and cadmium) in the
dust, which are generated by local mining operations, travel around the world. They also review the
transport media (soil, biota, water and air) and how the particle diameter influences the distribution of
such particles worldwide.
The sources of lead exposure (e.g. air, water, food, medication) for the population in Iran are analyzed
by Karrari and co-workers (2012)2
. Their overview also defines the impact of pre- and postnatal
exposure and the special situation in children. It emphasizes some general guidelines to reduce the lead
exposure and to improve the situation. Spatial (di!erent regions of Korea) and temporal changes (over
several years) of the pollution of nine heavy metals were analyzed by Kwon and colleagues (2014)3
.
They found that the composition of the contamination was closely related to specific industries and the
changes over time did directly reflect changes in regulations and laws.
Metal pollution whether it is in soil, water or air will be taken up by plants and animals and therefore
will become part of our daily food (and might even become more concentrated at the end of the foodchain).
A study in Iran (Isfahan) looked at the content of metals in vegetables and found that the amount
of several heavy metals (cadmium, chromium and lead) in some areas was above the recommended
levels by the WHO4
.
As risk assessment of meal pollution in cultured and wild fish species in Egypt was published by Omar
and co-workers5
. Some of the fish organs showed a high metal contend and some histo-pathological
alterations were found in some of the fish organs, which were raised in polluted water. As these fishes
are grown for human consumption the authors conclude that this is an “alarming concern for customer
health”. That indeed some fishes are highly sensitive to metal pollution was underlined by the results of
Wang and his research team6
. They found that especially the respiratory activity of a specific fish (rare
minnow) was impaired at low metal concentrations in the water. They suggest utilizing these fishes as
a “sensor” for heavy metal pollution in aquatic systems.
Physicians are not always aware of the symptoms and treatment of metal toxicity. This fact is highlighted
by Orisakwe7
, who analyzed the health care situation in Nigeria. Therefore, in the author’s conclusion
they request “the recognition and inclusion of heavy metal assays in the diagnosis of metabolic
disorders…”. A statement that physicians clearly should follow worldwide!
2 Ed. Dietrich Büsselberg
Büsselberg
Not only our food and drinks might be contaminated with heavy metals but also our medicine. Two
case reports from the United States of America describe lead poisoning after the use of Ayurvedic
medicine(8,9). A similar case report from India associates the use of Ayurvedic medicine with renal
failure due to mercury contamination of the medicine10.
More specific health impairments related to heavy metals exposure are analyzed in the following
publications. The report by Kin and co-workers11 discusses the questions whether the blood brain barrier
loses its integrity in heavy metal associated stroke. The authors reviewed and analyzed the evidence for
several metals (lead, cadmium, mercury and arsenic). As the facts are not fully understood the authors
conclude that the “blood brain barrier alternation by heavy metal exposure needs to be further revisited
to understand the mechanism of heavy metal-associated ischemic stroke”.
An article by Azevedo and colleagues12 summarizes the toxic e!ects of mercury on the cardiovascular
system and the nervous system. Reviewing the facts presented in the current literature they summarize
that – even at very low concentrations – the cardiovascular- and the nervous-system are impaired by
mercury exposure and suggest that the “reference values defining the limits for the absence of danger
should be reduced”.
A study conducted in Mexico by Moran-Martinez and colleagues13 links chronic environmental lead
exposure of men who lived in close vicinity of a lead smelter to the semen quality. Not only the blood
lead levels were elevated tin those men but also concentration, motility and viability of their semen
were significantly reduced. In addition, the morphology of the sperm cells was found to be altered by
the environmental exposure to lead.
Overall, the current literature indicates local environmental contamination with metals could a!ect
soil, water and air worldwide. Furthermore, metals are taken up by living organisms and might get
concentrated in the food chain. Worldwide trading with food items will a!ect regions which have do
not have any contamination locally. It is a fact that exposure – even to very low concentrations – to
metals could result in very serious health problems. To protect our soil, water and air, as well as our food
resources, local and global measurements have to be taken to release less metals in the environment.
References:
1. Csavina J, Field J, Taylor M et al. A review on the importance of metals and metalloids in atmospheric
dust and aerosol from mining operations. Science of The Total Environment. 2012;433:58–73.
doi:10.1016/j.scitotenv.2012.06.013.
2. Karrari P, Mehrpour O, Abdollahi M. A systematic review on status of lead pollution and toxicity in
Iran; Guidance for preventive measures. DARU Journal of Pharmaceutical Sciences. 2012;20(1):2.
doi:10.1186/1560–8115–20–2. (Featured in QScience Collection)
3. Kwon Y, Bae M, Park Y. Changes of Heavy Metals in Pollutant Release and Transfer Registers (PRTRs)
in Korea. International Journal of Environmental Research and Public Health. 2014;11(3):2381–2394.
doi:10.3390/ijerph110302381. (Featured in QScience Collection)
4. Jafarian-Dehkordi A., Alehashem M. Heavy metal contamination of vegetables in Isfahan, Iran.
Research in Pharmaceutical Sciences. 2015.
5. Omar W, Zaghloul K, Abdel-Khalek A, Abo-Hegab S. Risk Assessment and Toxic E!ects of Metal
Pollution in Two Cultured and Wild Fish Species from Highly Degraded Aquatic Habitats. Arch
Environ Contam Toxicol. 2013;65(4):753–764. doi:10.1007/s00244–013–9935-z. (Featured in
QScience Collection)
6. Wang H, Liang Y, Li S, Chang J. Acute Toxicity, Respiratory Reaction, and Sensitivity of Three
Cyprinid Fish Species Caused by Exposure to Four Heavy Metals. PLoS ONE. 2013;8(6):e65282.
doi:10.1371/journal.pone.0065282. (Featured in QScience Collection)
7. Orisakwe O. Lead and cadmium in public health in Nigeria: physicians neglect and pitfall in patient
management. North American Journal of Medical Sciences. 2014;6(2):61. doi:10.4103/1947–
2714.127740.
3
Recent updates on metal compounds in our environment and their implications on human health
QScience Collections: Metal compounds in our environment and their implications on human health
8. Pierce J, Estrada C, Mathews R. Buyers Beware: Lead Poisoning due to Ayurvedic Medicine. J GEN
INTERN MED. 2012;27(10):1384–1386. doi:10.1007/s11606–012–2048-y.
9. Breeher L, Gerr F, Fuortes L. A case report of adult lead toxicity following use of Ayurvedic herbal
medication. Journal of Occupational Medicine and Toxicology. 2013;8(1):26. doi:10.1186/1745–
6673–8-26. (Featured in QScience Collection)
10. Ali U, Ohri A, Sathe K. Acute renal failure secondary to ingestion of ayurvedic medicine containing
mercury. Indian J Nephrol. 2013;23(4):301. doi:10.4103/0971–4065.114485.
11. Kim J, Byun H, Chung E, Chung H, Bae O. Toxicological Research. 2013;29(3):157–164.
doi:10.5487/tr.2013.29.3.157.
12. Fernandes Azevedo, B., Barros Furieri, L., Peçanha, F. M., Wiggers, G. A., Frizera Vassallo,
P., Ronacher Simões, M., Fiorim, J., Rossi De Batista, P., Fioresi, M., Rossoni, L., Stefanon, I.,
Alonso, M. J., Salaices, M. And Valentim Vassallo. Toxic E!ects of Mercury on the Cardiovascular
and Central Nervous Systems. Journal of Biomedicine and Biotechnology. 2012;2012:1–11.
doi:10.1155/2012/949048. (Featured in QScience Collection)
13. Morán-Martínez J, Carranza-Rosales P, Morales-Vallarta M, Heredia-Rojas J, Bassol-Mayagoitia S,
Denys Betancourt-Martínez N, Cerda-Flores R. Chronic environmental exposure to lead a!ects semen
quality in a Mexican men population. Iranian Journal of Reproductive Medicine. 2013;11(4):267.
(Featured in QScience Collection)