Examination of the death promoting effects of Natural extracted compounds against cancer: Pathway and morphological changes Identification in respect to cellular stress

Ο καρκίνος συγκαταλέγεται στις σημαντικότερες αιτίες θανάτου παγκοσμίως. Υπολογίζεται ότι μέχρι το 2030 ο αριθμός των νέων περιστατικών θα ανέλθει στα 23.6 εκατομμύρια παγκοσμίως. Μέχρι σήμερα οι τρόποι αντιμετώπισής περιλαμβάνουν τη χορήγηση χημειοθεραπείας, μεταξύ άλλων. Οι ασθενείς μετά τη χορήγηση της χημειοθεραπείας εμφανίζουν διαφόρων ειδών παρενέργειες. Η παρούσα διδακτορική διατριβή διερευνά την αντιμετώπιση της νόσου με τη χρήση φυσικών/φυτικών ενώσεων που απαντώνται στο φυτό Γκραβιόλα. Ένα από τα πολλά μόρια που απαντώνται στο φυτό αυτό, είναι η ανονακίνη. Το συγκεκριμένο αυτό μόριο φαίνεται να έχει περιορισμένη τοξικότητα σε φυσιολογικές κυτταρικές σειρές ενώ οδηγεί το καρκινικό κύτταρο σε απόπτωση, μέσω αναστολής των αντλιών νατρίου/καλίου και ασβεστίου. Χρησιμοποιήθηκε προσέγγιση in silico για την αναγνώριση του κυτταρικού και του μοριακού στόχου της ανονακίνης. Αυτή η μελέτη αποκάλυψε ότι η ανονακίνη φαίνεται να στοχεύει στην οικογένεια του τύπου P της αντλίας της ATPάσης, η οποία περιλαμβάνει την Νάτριο/Κάλιο ΑΤΡάση (ΝΚΑ) και την σαρκοπλασματική/δικτυοενδοθηλιακή ΑΤΡάση (SERCA). Επιπρόσθετα τα δεδομένα της in silico μελέτης έδειξαν ότι η ανονακίνη είναι όντως ένας ισχυρός αναστολέας των αντλιών NKA και SERCA. Επιπλέον, η ανονακίνη μείωσε το μέγεθος του όγκου σε ζωικό μοντέλο καρκίνου. Τέλος η βιοπληροφορική ανάλυση έδειξε ισχυρή συσχέτιση μεταξύ της έκφρασης NKA ή SERCA στην επιβίωση ασθενών με καρκίνο. Ως συμπέρασμα, η μελέτη αποδεικνύει ότι η ανονακίνη στοχεύει και τις δύο αντλίες (NKA και SERCA) και αναδεικνύει νέα θεραπευτικά μονοπάτια για τη θεραπεία του καρκίνου.Cancer is a leading cause of death and mortality in the world and by 2030 the numbers of new cancer cases is expected to rise 23.6 million. Although conventional chemotherapy is still the first choice of treatment, such procedures is associated with major cytotoxic side effects. In the present study it was shown that the phyto-compound annonacin (found in the fruit Graviola / Annona muricata) promotes anti-cancer activity in cancer cell lines. In contrast, annoancin showed limited toxicity in normal and non-transformed cells. In order to identify the cellular and molecular target of annonacin an in silico approach was undertaken. Such study revealed that annonacin, seem to target P-type ATPase pump family, that include the sodium potassium ATPase (NKA) and Sarco/endoplasmic reticulum calcium ATPase (SERCA) family members. Furthermore, the in silico data was validated by showing that annonacin is indeed a potent inhibitor of NKA and SERCA pumps. Moreover, annonacin also reduced tumor growth in a xenograft cancer model. Finally, bioinformatics analysis showed strong correlation between NKA or SERCA expressions in cancer patient’s survival. Overall, this study strongly suggests that annonacin targets both the NKA and SERCA pumps as novel pathways for cancer treatmen

Adrenal Aging and Its Implications on Stress Responsiveness in Humans

Normal aging results in subtle changes both in ACTH and cortisol secretion. Most notable is the general increase in mean daily serum cortisol levels in the elderly, without a noteworthy alteration in the normal circadian rhythm pattern. Glucocorticoid excess seen in the elderly population can have serious consequences in both the structural and functional integrity of various key areas in the brain, including the hippocampus, amygdala, prefrontal cortex, with consequent impairment in normal memory, cognitive function, and sleep cycles. The chronically elevated glucocorticoid levels also impinge on the normal stress response in the elderly, leading to an impaired ability to recover from stressful stimuli. In addition to the effects on the brain, glucocorticoid excess is associated with other age-related changes, including loss of muscle mass, hypertension, osteopenia, visceral obesity, and diabetes, among others. In contrast to the increase in glucocorticoid levels, other adrenocortical hormones, particularly serum aldosterone and DHEA (the precursor to androgens and estrogens) show significant decreases in the elderly. The underlying mechanisms for their decrease remain unclear. While the adrenomedullary hormone, norephinephrine, shows an increase in plasma levels, associated with a decrease in clearance, no notable changes observed in plasma epinephrine levels in the elderly. The multiplicity and complexity of the adrenal hormone changes observed throughout the normal aging process, suggests that age-related alterations in cellular growth, differentiation, and senescence specific to the adrenal gland must also be considered

Clinical significance of P-class pumps in cancer (Review)

P-class pumps are specific ion transporters involved in maintaining intracellular/extracellular ion homeostasis, gene transcription, and cell proliferation and migration in all eukaryotic cells. The present review aimed to evaluate the role of P-Type pumps [Na+/K+ ATPase (NKA), H+/K+ ATPase (HKA) and Ca2+-ATPase] in cancer cells across three fronts, namely structure, function and genetic expression. It has been shown that administration of specific P-class pumps inhibitors can have different effects by: i) Altering pump function; ii) inhibiting cell proliferation; iii) inducing apoptosis; iv) modifying metabolic pathways; and v) induce sensitivity to chemotherapy and lead to antitumor effects. For example, the NKA β2 subunit can be downregulated by gemcitabine, resulting in increased apoptosis of cancer cells. The sarcoendoplasmic reticulum calcium ATPase can be inhibited by thapsigargin resulting in decreased prostate tumor volume, whereas the HKA α subunit can be affected by proton pump inhibitors in gastric cancer cell lines, inducing apoptosis. In conclusion, the present review highlighted the central role of P-class pumps and their possible use and role as anticancer cellular targets for novel therapeutic chemical agents

Διερεύνηση της αντικαρκινικής δράσης φυτικών εκχυλισμάτων και οι μορφολογικές αλλαγές του καρκινικού κυτταρικού θανάτου σχετιζόμενου με στρες

Cancer is a leading cause of death and mortality in the world and by 2030 the numbers of new cancer cases is expected to rise 23.6 million. Although conventional chemotherapy is still the first choice of treatment, such procedures is associated with major cytotoxic side effects. In the present study it was shown that the phyto-compound annonacin (found in the fruit Graviola / Annona muricata) promotes anti-cancer activity in cancer cell lines. In contrast, annoancin showed limited toxicity in normal and non-transformed cells. In order to identify the cellular and molecular target of annonacin an in silico approach was undertaken. Such study revealed that annonacin, seem to target P-type ATPase pump family, that include the sodium potassium ATPase (NKA) and Sarco/endoplasmic reticulum calcium ATPase (SERCA) family members. Furthermore, the in silico data was validated by showing that annonacin is indeed a potent inhibitor of NKA and SERCA pumps. Moreover, annonacin also reduced tumor growth in a xenograft cancer model. Finally, bioinformatics analysis showed strong correlation between NKA or SERCA expressions in cancer patient’s survival. Overall, this study strongly suggests that annonacin targets both the NKA and SERCA pumps as novel pathways for cancer treatment.Ο καρκίνος συγκαταλέγεται στις σημαντικότερες αιτίες θανάτου παγκοσμίως. Υπολογίζεται ότι μέχρι το 2030 ο αριθμός των νέων περιστατικών θα ανέλθει στα 23.6 εκατομμύρια παγκοσμίως. Μέχρι σήμερα οι τρόποι αντιμετώπισής περιλαμβάνουν τη χορήγηση χημειοθεραπείας, μεταξύ άλλων. Οι ασθενείς μετά τη χορήγηση της χημειοθεραπείας εμφανίζουν διαφόρων ειδών παρενέργειες. Η παρούσα διδακτορική διατριβή διερευνά την αντιμετώπιση της νόσου με τη χρήση φυσικών/φυτικών ενώσεων που απαντώνται στο φυτό Γκραβιόλα. Ένα από τα πολλά μόρια που απαντώνται στο φυτό αυτό, είναι η ανονακίνη. Το συγκεκριμένο αυτό μόριο φαίνεται να έχει περιορισμένη τοξικότητα σε φυσιολογικές κυτταρικές σειρές ενώ οδηγεί το καρκινικό κύτταρο σε απόπτωση, μέσω αναστολής των αντλιών νατρίου/καλίου και ασβεστίου. Χρησιμοποιήθηκε προσέγγιση in silico για την αναγνώριση του κυτταρικού και του μοριακού στόχου της ανονακίνης. Αυτή η μελέτη αποκάλυψε ότι η ανονακίνη φαίνεται να στοχεύει στην οικογένεια του τύπου P της αντλίας της ATPάσης, η οποία περιλαμβάνει την Νάτριο/Κάλιο ΑΤΡάση (ΝΚΑ) και την σαρκοπλασματική/δικτυοενδοθηλιακή ΑΤΡάση (SERCA). Επιπρόσθετα τα δεδομένα της in silico μελέτης έδειξαν ότι η ανονακίνη είναι όντως ένας ισχυρός αναστολέας των αντλιών NKA και SERCA. Επιπλέον, η ανονακίνη μείωσε το μέγεθος του όγκου σε ζωικό μοντέλο καρκίνου. Τέλος η βιοπληροφορική ανάλυση έδειξε ισχυρή συσχέτιση μεταξύ της έκφρασης NKA ή SERCA στην επιβίωση ασθενών με καρκίνο. Ως συμπέρασμα, η μελέτη αποδεικνύει ότι η ανονακίνη στοχεύει και τις δύο αντλίες (NKA και SERCA) και αναδεικνύει νέα θεραπευτικά μονοπάτια για τη θεραπεία του καρκίνου

Altered SERCA Expression in Breast Cancer

Background and Objectives: Calcium (Ca2+) signaling is critical for the normal functioning of various cellular activities. However, abnormal changes in cellular Ca2+ can contribute to pathological conditions, including various types of cancer. The maintenance of intracellular Ca2+ levels is achieved through tightly regulated processes that help maintain Ca2+ homeostasis. Several types of regulatory proteins are involved in controlling intracellular Ca2+ levels, including the sarco/endoplasmic reticulum (SR/ER) Ca2+ ATPase pump (SERCA), which maintains Ca2+ levels released from the SR/ER. In total, three ATPase SR/ER Ca2+-transporting (ATP2A) 1-3 genes exist, which encode for several isoforms whose expression profiles are tissue-specific. Recently, it has become clear that abnormal SERCA expression and activity are associated with various types of cancer, including breast cancer. Breast carcinomas represent 40% of all cancer types that affect women, with a wide variety of pathological and clinical conditions. Materials and methods: Using cBioPortal breast cancer patient data, Kaplan–Meier plots demonstrated that high ATP2A1 and ATP2A3 expression was associated with reduced patient survival. Results: The present study found significantly different SERCA specific-type expressions in a series of breast cancer cell lines. Moreover, bioinformatics analysis indicated that ATP2A1 and ATP2A3 expression was highly altered in patients with breast cancer. Conclusion: Overall, the present data suggest that SERCA gene-specific expressioncan possibly be considered as a crucial target for the control of breast cancer development and progression

Fungal diversity in the soil Mycobiome: Implications for ONE health

Today, over 300 million individuals worldwide are afflicted by severe fungal infections, many of whom will perish. Fungi, as a result of their plastic genomes have the ability to adapt to new environments and extreme conditions as a consequence of globalization, including urbanization, agricultural intensification, and, notably, climate change. Soils and the impact of these anthropogenic environmental factors can be the source of pathogenic and non-pathogenic fungi and subsequent fungal threats to public health. This underscores the growing understanding that not only is fungal diversity in the soil mycobiome a critical component of a functioning ecosystem, but also that soil microbial communities can significantly contribute to plant, animal, and human health, as underscored by the One Health concept. Collectively, this stresses the importance of investigating the soil microbiome in order to gain a deeper understanding of soil fungal ecology and its interplay with the rhizosphere microbiome, which carries significant implications for human health, animal health and environmental health

Perspectives of European Patient Advocacy Groups on Volunteer Registries and Vaccine Trials: VACCELERATE Survey Study

Background: The VACCELERATE Pan-European Scientific network aims to strengthen the foundation of vaccine trial research across Europe by following the principles of equity, inclusion, and diversity. The VACCELERATE Volunteer Registry network provides access to vaccine trial sites across the European region and supports a sustainable volunteer platform for identifying potential participants for forthcoming vaccine clinical research. Objective: The aim of this study was to approach members of patient advocacy groups (PAGs) across Europe to assess their willingness to register for the VACCELERATE Volunteer Registry and their perspectives related to participating in vaccine trials. Methods: In an effort to understand how to increase recruitment for the VACCELERATE Volunteer Registry, a standardized survey was developed in English and translated into 8 different languages (Dutch, English, French, German, Greek, Italian, Spanish, and Swedish) by the respective National Coordinator team. The online, anonymous survey was circulated, from March 2022 to May 2022, to PAGs across 10 European countries (Belgium, Cyprus, Denmark, France, Germany, Greece, Ireland, Italy, Spain, and Sweden) to share with their members. The questionnaire constituted of multiple choice and open-ended questions evaluating information regarding participants' perceptions on participating in vaccine trials and their willingness to become involved in the VACCELERATE Volunteer Registry. Results: In total, 520 responses were collected and analyzed. The PAG members reported that the principal criteria influencing their decision to participate in clinical trials overall are (1) the risks involved, (2) the benefits that will be gained from their potential participation, and (3) the quality and quantity of information provided regarding the trial. The survey revealed that, out of the 520 respondents, 133 individuals across all age groups were "positive" toward registering in the VACCELERATE Volunteer Registry, with an additional 47 individuals reporting being "very positive." Respondents from Northern European countries were 1.725 (95% CI 1.206-2.468) times more likely to be willing to participate in the VACCELERATE Volunteer Registry than respondents from Southern European countries. Conclusions: Factors discouraging participants from joining vaccine trial registries or clinical trials primarily include concerns of the safety of novel vaccines and a lack of trust in those involved in vaccine development. These outcomes aid in identifying issues and setbacks in present registries, providing the VACCELERATE network with feedback on how to potentially increase participation and enrollment in trials across Europe. Development of European health communication strategies among diverse public communities, especially via PAGs, is the key for increasing patients' willingness to participate in clinical studies

Perspectives of European Patient Advocacy Groups on Volunteer Registries and Vaccine Trials : VACCELERATE survey study

Abstract: Background: The VACCELERATE Pan -European Scientific network aims to strengthen the foundation of vaccine trial research across Europe by following the principles of equity, inclusion, and diversity. The VACCELERATE Volunteer Registry network provides access to vaccine trial sites across the European region and supports a sustainable volunteer platform for identifying potential participants for forthcoming vaccine clinical research. Objective: The aim of this study was to approach members of patient advocacy groups (PAGs) across Europe to assess their willingness to register for the VACCELERATE Volunteer Registry and their perspectives related to participating in vaccine trials. Methods: In an effort to understand how to increase recruitment for the VACCELERATE Volunteer Registry, a standardized survey was developed in English and translated into 8 different languages (Dutch, English, French, German, Greek, Italian, Spanish, and Swedish) by the respective National Coordinator team. The online, anonymous survey was circulated, from March 2022 to May 2022, to PAGs across 10 European countries (Belgium, Cyprus, Denmark, France, Germany, Greece, Ireland, Italy, Spain, and Sweden) to share with their members. The questionnaire constituted of multiple choice and open-ended questions evaluating information regarding participants' perceptions on participating in vaccine trials and their willingness to become involved in the VACCELERATE Volunteer Registry. Results: In total, 520 responses were collected and analyzed. The PAG members reported that the principal criteria influencing their decision to participate in clinical trials overall are (1) the risks involved, (2) the benefits that will be gained from their potential participation, and (3) the quality and quantity of information provided regarding the trial. The survey revealed that, out of the 520 respondents, 133 individuals across all age groups were "positive" toward registering in the VACCELERATE Volunteer Registry, with an additional 47 individuals reporting being "very positive." Respondents from Northern European countries were 1.725 (95% CI 1.206-2.468) times more likely to be willing to participate in the VACCELERATE Volunteer Registry than respondents from Southern European countries. Conclusions: Factors discouraging participants from joining vaccine trial registries or clinical trials primarily include concerns of the safety of novel vaccines and a lack of trust in those involved in vaccine development. These outcomes aid in identifying issues and setbacks in present registries, providing the VACCELERATE network with feedback on how to potentially increase participation and enrollment in trials across Europe. Development of European health communication strategies among diverse public communities, especially via PAGs, is the key for increasing patients' willingness to participate in clinical studies. (JMIR Public Health Surveill 2024;10:e47241) doi: 10.2196/4724