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Biomolecular condensates, membrane-less entities arising from liquid–liquid phase separation, hold dichotomous roles in health and disease. Alongside their physiological functions, these condensates can transition to a solid phase, producing amyloid-like structures implicated in degenerative diseases and cancer. This review thoroughly examines the dual nature of biomolecular condensates, spotlighting their role in cancer, particularly concerning the p53 tumor suppressor. Given that over half of the malignant tumors possess mutations in the TP53 gene, this topic carries profound implications for future cancer treatment strategies. Notably, p53 not only misfolds but also forms biomolecular condensates and aggregates analogous to other protein-based amyloids, thus significantly influencing cancer progression through loss-of-function, negative dominance, and gain-of-function pathways. The exact molecular mechanisms underpinning the gain-of-function in mutant p53 remain elusive. However, cofactors like nucleic acids and glycosaminoglycans are known to be critical players in this intersection between diseases. Importantly, we reveal that molecules capable of inhibiting mutant p53 aggregation can curtail tumor proliferation and migration. Hence, targeting phase transitions to solid-like amorphous and amyloid-like states of mutant p53 offers a promising direction for innovative cancer diagnostics and therapeutics. [ABSTRACT FROM AUTHOR]

p53 is a tumor suppressor protein that is mutated in more than 50% of cancer cases. When mutated, it frequently results in p53 oncogenic gain of function (GOF), resulting in a greater tendency to aggregate in the phase separation and phase transition pathway. GOFs related to p53 aggregation include chemoresistance, which makes therapy even more difficult. The therapies available for the treatment of cancer are still quite limited, so the study of new molecules and therapeutic targets focusing on p53 aggregates is a promising strategy against cancer. In this review, we classify anticancer molecules with antiaggregation properties into four categories: thiol alkylating agents, designed peptides, agents with chaperone-based mechanisms that inhibit p53 aggregation, and miscellaneous compounds with anti-protein aggregation properties that have been studied in neurodegenerative diseases. Furthermore, we highlight autophagy as a possible degradation pathway for aggregated p53. Here, considering cancer as a protein aggregation disease, we review strategies that have been used to disrupt p53 aggregates, leading to cancer regression. [ABSTRACT FROM AUTHOR]

In transmissible spongiform encephalopathies, the infectious material consists chiefly of a protein, the scrapie prion protein [PrP.sup.Sc], that carries no genetic coding material; however, prions are likely to have accomplices that chaperone their activity and promote the conversion of the cellular prion protein [PrP.sup.c] into the disease-causing isoform ([PrP.sup.Sc]). Recent studies from several laboratories indicate that [PrP.sup.C] recognizes many nucleic acids (NAs) with high affinities, and we correlate these findings with a possible pathophysiological role for this interaction. Thus, of the chaperones, NA is the most likely candidate for prions. The participation of NAs in prion propagation opens new avenues for developing new diagnostic tools and therapeutics to target prion diseases, as well as for understanding the function of [PrP.sup.C], probably as a NA chaperone.

Hydrostatic pressure is considered as a robust tool for studying the thermodynamics of protein folding and protein interactions, as well as the dynamics and structure of folding intermediates. The prospect of understanding protein misfolding diseases by using pressure to populate partially folded intermediates at the junction between productive and off-pathway folding, which may give rise to misfolded proteins, aggregates and amyloids is equally important.

Protein misfolding and aggregation have been linked to several human diseases, including Alzheimer's disease, Parkinson's disease, and systemic amyloidosis, by mechanisms that are not yet completely understood. The hallmark of most of these diseases is the formation of highly ordered and [beta]-sheet-rich aggregates referred to as amyloid fibrils. Fibril formation by WT transthyretin (TTR) or TTR variants has been linked to the etiology of systemic amyloidosis and familial amyloid polyneuropathy, respectively. Similarly, amyloid fibril formation by [alpha]-synuclein ([alpha]-syn) has been linked to neurodegeneration in Parkinson's disease, a movement disorder characterized by selective degeneration of dopaminergic neurons in the substantia nigra. Here we show that consecutive cycles of compression--decompression under aggregating conditions lead to reversible dissociation of TTR and [alpha]-syn fibrils. The high sensitivity of amyloid fibrils toward high hydrostatic pressure (HHP) indicates the existence of packing defects in the fibril core. In addition, through the use of HHP we are able to detect differences in stability between fibrils formed from WT TTR and the familial amyloidotic polyneuropathy-associated variant V30M. The fibrils formed by WT [alpha]-syn were less susceptible to pressure denaturation than the Parkinson's disease-linked variants, A30P and A53T. This finding implies that fibrils of [alpha]-syn formed from the variants would be more easily dissolved into small oligomers by the cellular machinery. This result has physiological importance in light of the current view that the pathogenic species are the small aggregates rather the mature fibrils. Finally, the HHP-induced formation of fibrils from TTR is relatively fast ([approximately equal to]60 min), a quality that allows screening of antiamyloidogenic drugs.

Green tea (GT) has been shown to play an important role in cancer chemoprevention. However, the related molecular mechanisms need to be further explored, especially regarding the use of GT extract (GTE) from the food matrix. For this study, epigallocatechin gallate (EGCG) and epigallocatechin (EGC) were identified in GTE, representing 42 and 40% of the total polyphenols, respectively. MDA-MB-231 (p53-p.R280K mutant) and MCF-7 (wild-type p53) breast tumor cells and MCF-10A non-tumoral cells were exposed to GTE for 24–48 h and cell viability was assessed in the presence of p53 inhibitor pifithrin-α. GTE selectively targeted breast tumor cells without cytotoxic effect on non-tumoral cells and p53 inhibition led to an increase in viable cells, especially in MCF-7, suggesting the involvement of p53 in GTE-induced cytotoxicity. GTE was also effective in reducing MCF-7 and MDA-MD-231 cell migration by 30 and 50%, respectively. An increment in p53 and p21 expression stimulated by GTE was observed in MCF-7, and the opposite phenomenon was found in MDA-MB-231 cells, with a redistribution of mutant-p53 from the nucleus and no differences in p21 levels. All these findings provide insights into the action of GTE and support its anticarcinogenic potential on breast tumor cells. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) emerged as an important infectious disease agent in Brazil in 2016. Infection usually leads to mild symptoms, but severe congenital neurological disorders and Guillain-Barré syndrome have been reported following ZIKV exposure. Creating an effective vaccine against ZIKV is a public health priority. We describe the protective effect of an already licensed attenuated yellow fever vaccine (YFV, 17DD) in type-I interferon receptor knockout mice (A129) and immunocompetent BALB/c and SV-129 (A129 background) mice infected with ZIKV. YFV vaccination provided protection against ZIKV, with decreased mortality in A129 mice, a reduction in the cerebral viral load in all mice, and weight loss prevention in BALB/c mice. The A129 mice that were challenged two and three weeks after the first dose of the vaccine were fully protected, whereas partial protection was observed five weeks after vaccination. In all cases, the YFV vaccine provoked a substantial decrease in the cerebral viral load. YFV immunization also prevented hippocampal synapse loss and microgliosis in ZIKV-infected mice. Our vaccine model is T cell-dependent, with AG129 mice being unable to tolerate immunization (vaccination is lethal in this mouse model), indicating the importance of IFN-γ in immunogenicity. To confirm the role of T cells, we immunized nude mice that we demonstrated to be very susceptible to infection. Immunization with YFV and challenge 7 days after booster did not protect nude mice in terms of weight loss and showed partial protection in the survival curve. When we evaluated the humoral response, the vaccine elicited significant antibody titers against ZIKV; however, it showed no neutralizing activity in vitro and in vivo. The data indicate that a cell-mediated response promotes protection against cerebral infection, which is crucial to vaccine protection, and it appears to not necessarily require a humoral response. This protective effect can also be attributed to innate factors, but more studies are needed to strengthen this hypothesis. Our findings open the way to using an available and inexpensive vaccine for large-scale immunization in the event of a ZIKV outbreak. Author summary: Zika virus (ZIKV) is as an important infectious that may result in severe congenital neurological disorders. Our study reports that the current attenuated yellow fever vaccine is effective in immunizing against the infection caused by the Zika virus, due to the similarity between the two viruses. To study the efficacy of the vaccine, we used different mouse strains, including both animals with a healthy immune system (immunocompetent) and animals with compromised immune systems and therefore more susceptible to viral (immunocompromised) infections. The vaccine was given subcutaneously, as it does in humans. The animals were inoculated with the Zika virus directly into the brain—a protocol normally adopted in vaccine studies to simulate a high lethality infection. In all cases, the vaccinated mice developed a high degree of protection against Zika infection. Altogether, we demonstrate that the YFV vaccine elicits an immune response that protects against cerebral infection by ZIKV. Our findings suggest the possibility of using an available and inexpensive vaccine for large-scale immunization in the event of a ZIKV outbreak. [ABSTRACT FROM AUTHOR]

Yellow fever (YF) is a life‐threatening viral disease endemic in parts of Africa and Latin America. Although there is a very efficacious vaccine since the 1930s, YF still causes 29,000–60,000 annual deaths. During recent YF outbreaks there were issues of vaccine shortage of the current egg‐derived vaccine; rare but fatal vaccine adverse effects occurred; and cases were imported to Asia, where the circulating mosquito vector could potentially start local transmission. Here we investigated the production of YF virus‐like particles (VLPs) using stably transfected HEK293 cells. Process intensification was achieved by combining sequential FACS (fluorescence‐activated cell sorting) rounds to enrich the stable cell pool in terms of high producers and the use of perfusion processes. At shaken‐tube scale, FACS enrichment of cells allowed doubling VLP production, and pseudoperfusion cultivation (with daily medium exchange) further increased VLP production by 9.3‐fold as compared to batch operation mode. At perfusion bioreactor scale, the use of an inclined settler as cell retention device showed operational advantages over an ATF system. A one‐step steric exclusion chromatography purification allowed significant removal of impurities and is a promising technique for future integration of upstream and downstream operations. Characterization by different techniques confirmed the identity and 3D‐structure of the purified VLPs. [ABSTRACT FROM AUTHOR]