Investigating Biomolecules in Deep Eutectic Solvents with Molecular Dynamics Simulations: Current State, Challenges and Future Perspectives.

Deep eutectic solvents (DESs) have recently gained increased attention for their potential in biotechnological applications. DESs are binary mixtures often consisting of a hydrogen bond acceptor and a hydrogen bond donor, which allows for tailoring their properties for particular applications. If produced from sustainable resources, they can provide a greener alternative to many traditional organic solvents for usage in various applications (e.g., as reaction environment, crystallization agent, or storage medium). To navigate this large design space, it is crucial to comprehend the behavior of biomolecules (e.g., enzymes, proteins, cofactors, and DNA) in DESs and the impact of their individual components. Molecular dynamics (MD) simulations offer a powerful tool for understanding thermodynamic and transport processes at the atomic level and offer insights into their fundamental phenomena, which may not be accessible through experiments. While the experimental investigation of DESs for various biotechnological applications is well progressed, a thorough investigation of biomolecules in DESs via MD simulations has only gained popularity in recent years. Within this work, we aim to provide an overview of the current state of modeling biomolecules with MD simulations in DESs and discuss future directions with a focus for optimizing the molecular simulations and increasing our fundamental knowledge.

Sleep quality and lymphedema in breast cancer survivors: a mixed method analysis.

PURPOSE: The purpose of this convergent mixed methods study was to assess the perceptions and characteristics of sleep in breast cancer survivors (BCSs) and elucidate perceptions of sleep among BCS with lymphedema. METHODS: Participants were BCS with and without lymphedema. Both groups completed the Pittsburgh Sleep Quality Index (PSQI), PROMIS® Sleep Disturbance (8a short form), and wore an actigraph on their wrist to capture sleep/wake cycles for 7 days/nights while logging their sleep using a sleep diary. The coefficient of variation of sleep efficiency was calculated from the sleep diary to assess intraindividual variability. In addition, a subsample of BCS with lymphedema participated in a semi-structured qualitative interview. The qualitative data was analyzed separately, and the themes were applied to provide a more nuanced explanation of the quantitative outcomes. RESULTS: The BCS with lymphedema (n=23) had a significant difference in PSQI (p=0.002), PROMIS® Sleep Disturbance (p=0.084), and sleep efficiency coefficient of variation (p=0.014) compared to BCS without lymphedema (n=23). There were no statistically significant differences between groups in the actigraphy results. BCS with lymphedema perceived that lymphedema management contributed to their sleep disturbance, further exacerbating their mind/body fatigue. CONCLUSION: This study provides the foundation for future research to investigate the integration of sleep interventions with lymphedema management for holistic survivorship care for BCS with lymphedema. IMPLICATIONS FOR CANCER SURVIVORS: An innovative sleep health intervention designed to consider the unique factors contributing to sleep disturbance in BCS with lymphedema will fill a gap in their post-cancer treatment quality of life.

New Dipterocarpol-Based Molecules with α-Glucosidase Inhibitory and Hypoglycemic Activity.

Dammarane triterpenoids are affordable and bioactive natural metabolites with great structural potential, which makes them attractive sources for drug development. The aim of the study was to investigate the potency of new dipterocarpol derivatives for the treatment of diabetes. Two dammaranes (dipterocarpol and its 20(24)-diene derivative) were modified by a Claisen-Schmidt aldol condensation to afford C2(E)-arylidenes in good yields. The majority of the synthesized compounds exhibited an excellent-to-moderate inhibitory effect toward α-glucosidase (from S. saccharomyces), among them eight compounds showed IC50 values less than 10 µM. 3-Oxo-dammarane-2(E)-benzylidenes (holding p-hydroxy- 3 l and p-carbonyl- 3 m substituents) demonstrated the most potent α-glucosidase inhibition with IC50 0.753 and 0.204 µM, being 232- and 857-times more active than acarbose (IC50 174.90 µM), and a high level of NO inhibition in Raw 264.7 cells with IC50 of 1.75 and 4.57 µM, respectively. An in vivo testing of compound 3 m (in a dose of 20 mg/kg) on a model of streptozotocin-induced T1DM in rats showed a pronounced hypoglycemic activity, the ability to reduce effectively the processes of lipid peroxidation in liver tissue and decrease the excretion of glucose and pyruvic acid in the urine. Compound 3 m reduced the death of diabetic rats and preserved their motor activity.

Evaluation of A-ring hydroxymethylene-amino- triterpenoids as inhibitors of SARS-CoV-2 spike pseudovirus and influenza H1N1.

A set of triterpene A-ring hydroxymethylene-amino-derivatives was synthesized and their antiviral activity was studied. The synthesized compounds were tested for their potential inhibition of SARS-CoV-2 pseudovirus in BHK-21-hACE2 cells and influenza A/PuertoRico/8/34 (H1N1) virus in MDCK cell culture. Compounds 6, 8 and 19 showed significant anti-SARS-CoV-2 pseudovirus activity with EC50 value of 3.20-11.13 µM, which is comparable to the positive control amodiaquine (EC50 3.17 µM). Among them, 28-O-imidazolyl-azepano-betulin 6 and C3-hydroxymethylene-amino-glycyrrhetol-11,13-diene 19 were identified as the lead compounds with SI values of 7 and 10. The binding mode of compound 6 into the RBD domain of SARS-CoV-2 spike glycoprotein (PDB code: 7DK3) by docking and molecular dynamics simulation was investigated.

Myopia management algorithm. Annexe to the article titled Update and guidance on management of myopia. European Society of Ophthalmology in cooperation with International Myopia Institute.

Myopia is becoming increasingly common in young generations all over the world, and it is predicted to become the most common cause of blindness and visual impairment in later life in the near future. Because myopia can cause serious complications and vision loss, it is critical to create and prescribe effective myopia treatment solutions that can help prevent or delay the onset and progression of myopia. The scientific understanding of myopia's causes, genetic background, environmental conditions, and various management techniques, including therapies to prevent or postpone its development and slow its progression, is rapidly expanding. However, some significant information gaps exist on this subject, making it difficult to develop an effective intervention plan. As with the creation of this present algorithm, a compromise is to work on best practices and reach consensus among a wide number of specialists. The quick rise in information regarding myopia management may be difficult for the busy eye care provider, but it necessitates a continuing need to evaluate new research and implement it into daily practice. To assist eye care providers in developing these strategies, an algorithm has been proposed that covers all aspects of myopia mitigation and management. The algorithm aims to provide practical assistance in choosing and developing an effective myopia management strategy tailored to the individual child. It incorporates the latest research findings and covers a wide range of modalities, from primary, secondary, and tertiary myopia prevention to interventions that reduce the progression of myopia.

A greener approach for synthesizing metal-decorated carbogels from alginate for emerging technologies.

In the present work, a series of metal nanoparticle-decorated carbogels (M-DCs) was synthesized starting from beads of parent metal-crosslinked alginate aerogels (M-CAs). M-CAs contained Ca(ii), Ni(ii), Cu(ii), Pd(ii) and Pt(iv) ions and were converted to M-DCs by pyrolysis under a N2 atmosphere up to pyrolysis temperatures of TP = 600 °C. The textural properties of M-CAs are found to depend on the crosslinking ion, yielding fibrous pore networks with a high specific mesoporous volume and specific surface area SV (SV ∼ 480-687 m2 g-1) for M-CAs crosslinked with hard cations, Ca(ii), Ni(ii) and Cu(ii), and comparably loose networks with increased macroporosity and lower specific surface (SV ∼ 240-270 m2 g-1) for Pd(ii) and Pt(iv) crosslinked aerogels. The pyrolysis of M-CAs resulted in two simultaneously occurring processes: changes in the solid backbone and the growth of metal/metal oxide nanoparticles (NPs). The thermogravimetric analysis (TGA) showed a significant influence of the crosslinking cation on the decomposition mechanism and associated change in textural properties. Scanning electron microscopy-backscattered electron imaging (SEM-BSE) and X-ray diffraction revealed that metal ions (molecularly dispersed in the parent aerogels) formed nanoparticles composed of elementary metals and metal oxides in varying ratios over the course of pyrolytic treatment. Increasing the TP led to generally larger nanoparticles. The pyrolysis of the nickel-crosslinked aerogel (Ni-CA) preserved, to a large extent, the mesoporous structure and resulted in the evolution of fine (∼14 nm) homogeneously dispersed Ni/NiO nanoparticles. Overall, this work presents a green approach for synthesizing metal-nanoparticle containing carbon materials, useful in emerging technologies related to heterogeneous catalysis and electrocatalysis, among others.

Rehabilitation for non-motor symptoms for patients with Parkinson's disease from an α-synuclein perspective: a narrative review.

Parkinson's disease (PD) is a common neurodegenerative disorder affecting aged population around the world. PD is characterized by neuronal Lewy bodies present in the substantia nigra of the midbrain and the loss of dopaminergic neurons with various motor and non-motor symptoms associated with the disease. The protein α-synuclein has been extensively studied for its contribution to PD pathology, as α-synuclein aggregates form the major component of Lewy bodies, a hallmark of PD. In this narrative review, the authors first focus on a brief explanation of α-synuclein aggregation and circumstances under which aggregation can occur, then present a hypothesis for PD pathogenesis in the peripheral nervous system (PNS) and how PD can spread to the central nervous system from the PNS via the transport of α-synuclein aggregates. This article presents arguments both for and against this hypothesis. It also presents various non-pharmacological rehabilitation approaches and management techniques for both motor and non-motor symptoms of PD and the related pathology. This review seeks to examine a possible hypothesis of PD pathogenesis and points to a new research direction focus on rehabilitation therapy for patients with PD. As various non-motor symptoms of PD appear to occur earlier than motor symptoms, more focus on the treatment of non-motor symptoms as well as a better understanding of the biochemical mechanisms behind those non-motor symptoms may lead to better long-term outcomes for patients with PD.

IMI-Management and Investigation of High Myopia in Infants and Young Children.

Purpose: The purpose of this study was to evaluate the epidemiology, etiology, clinical assessment, investigation, management, and visual consequences of high myopia (≤-6 diopters [D]) in infants and young children. Findings: High myopia is rare in pre-school children with a prevalence less than 1%. The etiology of myopia in such children is different than in older children, with a high rate of secondary myopia associated with prematurity or genetic causes. The priority following the diagnosis of high myopia in childhood is to determine whether there is an associated medical diagnosis that may be of greater overall importance to the health of the child through a clinical evaluation that targets the commonest features associated with syndromic forms of myopia. Biometric evaluation (including axial length and corneal curvature) is important to distinguishing axial myopia from refractive myopia associated with abnormal development of the anterior segment. Additional investigation includes ocular imaging, electrophysiological tests, genetic testing, and involvement of pediatricians and clinical geneticists is often warranted. Following investigation, optical correction is essential, but this may be more challenging and complex than in older children. Application of myopia control interventions in this group of children requires a case-by-case approach due to the lack of evidence of efficacy and clinical heterogeneity of high myopia in young children. Conclusions: High myopia in infants and young children is a rare condition with a different pattern of etiology to that seen in older children. The clinical management of such children, in terms of investigation, optical correction, and use of myopia control treatments, is a complex and often multidisciplinary process.

24-Nor-allobetulins possess strong α-glucosidase inhibitory activity.

A series of 24-nor-allobetulin derivatives holding 3ß-hydroxy-, oxime, methoxyoxime, lactame and 4-bromobenzylidene substituents have been synthesized and their differences in the NMR spectra were studied in detail. It was revealed that 3-oxo-24-nor-allobetulin loses selectivity in the reaction of oximation and forms a mixture of Z/E oximes (and methoxyoximes) in contract to the related derivatives of native scaffold (that forms only E-isomers). The screening of α-glucosidase inhibitory activity revealed that 24-nor-allobetulins are more active than allobetulins. The lead 3-oxo-24-nor-allobetulin with IC50 0.49 µM was more than 60-fold and 500-fold active than acarbose and 3-oxo-allobetulin, respectively. We can conclude that the removal of the C-24 methyl group significantly increased the antidiabetic effect and 24-nor-allobetulins should be identified as the new and promising scaffolds as α-glucosidase inhibitors on the basis of triterpenoids.

Synthetic modifications of abietane diterpene acids to potent antimicrobial agents.

Among abietane type semisynthetic diterpenoids, a series of quinopimaric and maleopimaric acid derivatives modified at the carboxyl and carbonyl groups, and in ring E were synthesised to obtain new compounds with antimicrobial potency against Mycobacterium tuberculosis H37Rv and key ESKAPE pathogens. It was found that compound 8 exhibited low toxicity to human embryonic kidney cell line HEK-293 (> 32 µg/mL) and showed significant bacteriostatic activity against methicillin-resistant Staphylococcus aureus (MRSA) (MIC ≤ 0.25 µg/mL) and excellent antifungal activity against Cryptococcus neoformans var. grubii (MICs ≤0.25 µg/mL) being ≈4 and ≈30 fold more active than vancomycin and fluconazole. It also showed moderate activity against fungus Candida albicans (MIC ≤ 0.25 µg/mL). Compound 9 inhibited M. tuberculosis H37Rv with MIC of 1.25 µg/mL. The docking studies suggest possible interactions of the leading compounds with the molecular targets.

Neutrophils and macrophages drive TNF-induced lethality via TRIF/CD14-mediated responses.

TNF mediates a variety of biological processes including cellular proliferation, inflammatory responses, and cell death and is therefore associated with numerous pathologies including autoinflammatory diseases and septic shock. The inflammatory and cell death responses to TNF have been studied extensively downstream of TNF-R1 and are believed to rely on the formation of proinflammatory complex I and prodeath complex II, respectively. We recently identified a similar multimeric complex downstream of TLR4, termed the TRIFosome, that regulates inflammation and cell death in response to LPS or Yersinia pseudotuberculosis. We present evidence of a role for the TRIFosome downstream of TNF-R1, independent of TLR3 or TLR4 engagement. Specifically, TNF-induced cell death and inflammation in murine macrophages were driven by the TLR4 adaptor TRIF and the LPS co-receptor CD14, highlighting an important role for these proteins beyond TLR-mediated immune responses. Via immunoprecipitation and visualization of TRIF-specific puncta, we demonstrated TRIF- and CD14-dependent formation of prodeath and proinflammatory complexes in response to TNF. Extending these findings, in a murine TNF-induced sepsis model, TRIF and CD14 deficiency decreased systemic inflammation, reduced organ pathology, and improved survival. The outcome of TRIF activation was cell specific, because TNF-induced lethality was mediated by neutrophils and macrophages responding to TNF in a TRIF-dependent manner. Our findings suggest that in addition to their crucial role in TNF production, myeloid cells are central to TNF toxicity and position TRIF and CD14 as universal components of receptor-mediated immune responses.

Antimicrobial and Antibiotic-Resistance Reversal Activity of Some Medicinal Plants from Cameroon against Selected Resistant and Non-Resistant Uropathogenic Bacteria.

BACKGROUND AND AIM: Antibiotics' resistance is the leading cause of complications in the treatment of urinary tract infections. This study aimed to screen the antimicrobial potential of 8 plants from Cameroon against multi-resistant uropathogenic (MRU) bacteria and to investigate their antibioresistance reversal properties. METHOD: Bioactive compounds were extracted from leaves of Leucanthemum vulgare, Cymbopogon citratus, Moringa oleifera and Vernonia amygdalina; barks of Cinchona officinalis and Enantia chlorantha barks and seeds of Garcinia lucida and leaves and seeds of Azadirachta indica using water and ethanol as solvents. The extracts were tested against Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 6538 and Candida albicans 10231 using the well diffusion and the broth microdilution methods. The antibiotic-resistance reversal activity was assessed against selected MRU bacteria. The phytochemical composition and the elemental composition of the most active extracts were assessed respectively using HPLC-MS/MS and X-ray fluorescence (XRF) spectrometry. RESULTS: Among the most active plants, in decreasing order of antimicrobial activity we found ethanolic (EE) and aqueous extracts (AE) of E. chloranta bark (ECB), EE of L. vulgare leaves and G. lucida seeds. The best synergies between common antibiotics and extracts were found with EE-ECB which well-modulated kanamycin nitrofurantoin and ampicillin. All the compounds identified in EE-ECB were alkaloids and the major constituents were palmatine (51.63%), columbamine+7,8-dihydro-8-hydroxypalmatine (19.21%), jatrorrhizine (11.02%) and pseudocolumbamine (6.33%). Among the minerals found in EE-ECB (S, Si, Cl, K, Ca, Mn, Fe, Zn and Br), Br, Fe and Cl were the most abundant with mean fluorescence intensities of 4.6529, 3.4854 and 2.5942 cps/uA respectively. CONCLUSIONS: The ethanol extract of the bark of E. chlorantha has remarkable, broad-spectrum antimicrobial and contains several palmatine derivatives.

Synthesis, Anti-Influenza H1N1 and Anti-Dengue Activity of A-Ring Modified Oleanonic Acid Polyamine Derivatives.

A series of sixteen A-ring modified (2,3-indolo-, 2-benzylidene) oleanonic acid derivatives, holding some cyclic amines, linear polyamines and benzylaminocarboxamides at C28, has been synthesized and screened for antiviral activity against influenza A/PuertoRico/8/34 (H1N1) and Dengue virus serotypes of DENV-1, -2, -3, -4. It was found that 28-homopiperazine 2 and 3-N-phthalyl 22 amides of oleanonic acid demonstrated high potency with selectivity index SI 27 (IC50 21 µM) and 42 (IC50 12 µM). Oleanonic acid aminoethylpiperazine amide 6 and C-azepano-erythrodiol 23 appeared to be the most effective compounds against DENV-1 (IC50's 67 and 107 µM) and -2 (IC50's 86 and 68 µM correspondingly) serotypes.

New Molecules of Diterpene Origin with Inhibitory Properties toward α-Glucosidase.

The incidence of diabetes mellitus (DM), one of the most common chronic metabolic disorders, has increased dramatically over the past decade and has resulted in higher rates of morbidity and mortality worldwide. The enzyme, α-Glucosidase (α-GLy), is considered a therapeutic target for the treatment of type 2 DM. Herein, we synthesized arylidene, heterocyclic, cyanoetoxy- and propargylated derivatives of quinopimaric acid (levopimaric acid diene adduct with p-benzoquinone) 1-50 and, first, evaluated their ability to inhibit α-GLy. Among the tested compounds, quinopimaric acid 1, 2,3-dihydroquinopimaric acid 8 and its amide and heterocyclic derivatives 9, 30, 33, 39, 44, with IC50 values of 35.57-65.98 µM, emerged as being good inhibitors of α-GLy. Arylidene 1ß-hydroxy and 1ß,13α-epoxy methyl dihydroquinopimarate derivatives 6, 7, 26-29, thiadiazole 32, 1a,4a-dehydroquinopimaric acid 40 and its indole, nitrile and propargyl hybrids 35-38, 42, 45, 48, and 50 showed excellent inhibitory activities. The most active compounds 38, 45, 48, and 50 displayed IC50 values of 0.15 to 0.68 µM, being 1206 to 266 more active than acarbose (IC50 of 181.02 µM). Kinetic analysis revealed the most active diterpene indole with an alkyne substituent 45 as a competitive inhibitor with Ki of 50.45 µM. Molecular modeling supported this finding and suggested that the indole core plays a key role in the binding. Compound 45 also has favorable pharmacokinetic and safety properties, according to the computational ADMET profiling. The results suggested that quinopimaric acid derivatives should be considered as potential candidates for novel alternative therapies in the treatment of type 2 diabetes.

Antibacterial Activity of Medicinal Plants against Uropathogenic Escherichia coli.

Urinary tract infections (UTIs) are one of the most common bacterial infections with uropathogenic Escherichia coli (UPEC) being the most prevalent causative agent in both complicated and uncomplicated UTIs. Antibiotic resistance among UPEC has been already demonstrated against a wide variety of antibiotics and the situation is continuing to deteriorate increasing the rate of recurrence and the difficulty of treatment and prophylaxis. Recently, a big attention has been paid to non-antibiotic approaches as an alternative to conventional antibiotics. Among many strategies, phytotherapy has gained a special attention worldwide. Herbal remedies have been used in traditional medicine since ancient times and they are well known for their effectiveness in treating many health conditions including UTIs. Researches are conducted continuously to validate the use of many medicinal plants against UPEC, investigate their mechanisms of action, and determine their active constituents. Our extensive review of the recent literature revealed that many phytochemicals are shown to target and inhibit a wide variety of bioprocesses in UPEC, such as adhesion, motility, biofilm formation, and quorum sensing. Such natural approaches are very promising in confronting the antibiotic resistance of UPEC and can be further used to develop plant-based strategies and pharmaceutical products to treat and prevent UTIs caused by UPEC.

ZBP1 promotes inflammatory responses downstream of TLR3/TLR4 via timely delivery of RIPK1 to TRIF.

ZBP1 is widely recognized as a mediator of cell death for its role in initiating necroptotic, apoptotic, and pyroptotic cell death pathways in response to diverse pathogenic infection. Herein, we characterize an unanticipated role for ZBP1 in promoting inflammatory responses to bacterial lipopolysaccharide (LPS) or double-stranded RNA (dsRNA). In response to both stimuli, ZBP1 promotes the timely delivery of RIPK1 to the Toll-like receptor (TLR)3/4 adaptor TRIF and M1-ubiquitination of RIPK1, which sustains activation of inflammatory signaling cascades downstream of RIPK1. Strikingly, ZBP1-mediated regulation of these pathways is important in vivo, as Zbp1−/− mice exhibited resistance to LPS-induced septic shock, revealed by prolonged survival and delayed onset of hypothermia due to decreased inflammatory responses and subsequent cell death. Further findings revealed that ZBP1 promotes sustained inflammatory responses by mediating the kinetics of proinflammatory "TRIFosome" complex formation, thus having a profound impact downstream of TLR activation. Given the well-characterized role of ZBP1 as a viral sensor, our results exemplify previously unappreciated crosstalk between the pathways that regulate host responses to bacteria and viruses, with ZBP1 acting as a crucial bridge between the two.

Azepanodipterocarpol is potential candidate for inhibits influenza H1N1 type among other lupane, oleanane, and dammarane A-ring amino-triterpenoids.

A series of lupane-, oleanane- and dammarane-based triterpenoids with 3ß-amino, A-ring azepano- and 3,4-seco-fragments has been synthesized and evaluated for antiviral activity against influenza A(H1N1) virus. It was found that azepanodipterocarpol 8 and 3ß-amino-28-oxoallobetulin 11 showed antiviral activity with IC50 1.1 and 2.6 µg ml-1, and selectivity index of 19 and 10, respectively.

Effects of walking training on risk markers of cardiovascular disease in individuals with chronic spinal cord injury.

OBJECTIVE: To investigate the effects of an 8-week walking training program on glycemic control, lipid profile, and inflammatory markers in individuals with chronic spinal cord injury (SCI). DESIGN: A pilot, single-group, pretest-posttest study. SETTING: A neuromuscular research laboratory. PARTICIPANTS: Eleven participants with chronic SCI. INTERVENTION: An 8-week walking training program using a treadmill, a body weight-supported system, and an assistive gait training device. OUTCOME MEASURES: Levels of glycated hemoglobin (HbA1c), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP), and interleukin-6 were assessed before and after the walking training. RESULTS: Following the walking training, there was a statistically significant decrease in HbA1c level (P<0.01) of uncertain clinical significance. The lipid profile improved after training, as shown by a statistically and clinically significant increase in HDL-C level (P<0.01) and a statistically significant decrease in LDL-C level (P<0.1) of no clinical significance. The ratio of LDL-C to HDL-C was significantly reduced (P<0.01). In regard to inflammatory markers, concentrations of IL-6 showed a significant reduction after training (P=0.05) of unknown clinical significance, while those of CRP trended to decrease (P=0.13). CONCLUSION: The findings of this pilot study suggest that an 8-week walking training program may produce favorable changes in risk markers of cardiovascular disease in individuals with chronic SCI as shown by clinically meaningful improvements in HDL-C, and small changes in the right direction, but uncertain clinical significance, in HbA1c, LDL-C and IL-6. A randomized controlled trial is needed to compare the effects of walking training on these outcome measures with those of other exercise modalities suitable for this population, and to see if more prolonged exercise exposure leads to favorable parameters of significant size to justify the exercise modality.

Hollongdione arylidene derivatives induce antiproliferative activity against melanoma and breast cancer through pro-apoptotic and antiangiogenic mechanisms.

The use of natural compounds as starting point for semisynthetic derivatives has already been proven as a valuable source of active anticancer agents. Hollongdione (4,4,8,14-tetramethyl-18-norpregnan-3,20-dion), obtained by few steps from dammarane type triterpenoid dipterocarpol, was chemically modified at C2 and C21 carbon atoms by the Claisen-Schmidt aldol condensation to give a series of arylidene derivatives. The anticancer activity of the obtained compounds was assessed on NCI-60 cancer cell panel, revealing strong antiproliferative effects against a large variety of cancer cells. 2,21-Bis-[3-pyridinyl]-methylidenohollongdione 9 emerged as the most active derivative as indicated by its GI50 values in the micromolar range which, combined with its high selectivity index values, indicated its suitability for deeper biological investigation. The mechanisms involved in compound 9 antiproliferative activity, were investigated through in vitro (DAPI staining) and ex vivo (CAM assay) tests, which exhibited its apoptotic and antiangiogenic activities. In addition, compound 9 showed an overall inhibition of mitochondrial respiration. rtPCR analysis identified the more intimate activity at pro-survival/pro-apoptotic gene level. Collectively, the hollongdione derivative stand as a promising therapeutic option against melanoma and breast cancer provided that future in vivo analysis will certify its clinical efficacy.