Protein misfolding, aggregation, and aberrant aggregate accumulation play a central role in neurodegenerative disease progression. The proteotoxic factors also govern the aging process to a large extent. Molecular chaperones modulate proteostasis and thereby impact aberrant-protein-induced proteotoxicity. These chaperones have a diverse functional spectrum, including nascent protein folding, misfolded protein sequestration, refolding, or degradation. Small heat shock proteins (sHsps) possess an ATP-independent chaperone-like activity that prevents protein aggregation by keeping target proteins in a folding-competent state to be refolded by ATP-dependent chaperones. Due to their near-universal upregulation and presence in sites of proteotoxic stress like diseased brains, sHsps were considered pathological. However, gene knockdown and overexpression studies have established their protective functions. This review provides an updated overview of the sHsp role in protein aggregation amelioration and highlights evidence for sHsp modulation of neurodegenerative disease-related protein aggregation and aging.

Natural products, especially secondary metabolites produced by plants under stressed conditions, are shown to have different pharmacological impacts from one to another. Aeluropus lagopoides is one of the common halophyte plants that survive under stressed conditions, and has been used for healing wounds and as a painkiller. The bioactivity and the chemical composition of this plant have been poorly investigated. Consequently, the chemical components of A. lagopoides leaves were extracted using hexane (nonpolar), ethyl acetate (semi-polar), and n-butanol (polar) to extract the most extensive variety of metabolites. The cytotoxicity and anticancer impact of extracted secondary metabolites were evaluated against breast (MCF-7), colon (HCT-116), and liver (HepG2) cancer cell lines using a SulphoRhodamine-B (SRB) test. Their mechanisms of action were verified by observing the appearance of apoptotic bodies using the fluorescent microscope, while their antiproliferative impacts were evaluated using a flow cytometer. Results revealed that secondary metabolites extracted using hexane and ethyl acetate had the highest cytotoxicity and thus the greatest anticancer activity effect on HepG2 with IC₅₀ (24.29 ± 0.85 and 11.22 ± 0.679 µg/mL, respectively). On the other hand, flow cytometer results showed that secondary metabolites could inhibit the cell cycle in the G0/G1 phase. To ascertain the chemical composition–function relationship, the extracts were analyzed using LC-MS/MS. Accordingly, A. lagopoides hexane and ethyl acetate extracts may contain agents with anticancer potential.

Purpose: To evaluate the bioactivity of hexane extract of S. fruticosa leaves against the cancer cell lines HepG2, MCF-7, and HCT-116, and to determine the chemical composition-function relationship. Methods: Using the liquid-liquid extraction method, the nonpolarL constituent compounds were isolated from the leaves. The cytotoxicity of the hexane extract was evaluated using an SRB assay. Mechanism of action was verified by observing the appearance of apoptotic bodies using fluorescence microscopy, while anti-proliferative activity was assayed via flow cytometry. Results: The results revealed that secondary metabolites in the hexane extract demonstrated the highest cytotoxicity, and thus anticancer activity, against HCT-116 cells, with an IC50 of 17.15 ± 0.78 mg/mL. The presence of apoptotic bodies indicate an ability to induce apoptosis. Flow cytometry results suggest that the secondary metabolites stalled the cell cycle at the G0/G1 phase. Conclusion: The results indicate that S. fruticosa hexane extract may be considered a potential new source of the anti-cancer compound, momilactone B. Keywords: Anticancer, Apoptosis, Colon Cancer, Liver cancer, Breast cancer, Liquid chromatography–mass spectrometry, Suaeda fruticose, Momilactone B

Heat stroke is among the most hazardous hyperthermia-related illnesses and an emerging threat to humans from climate change. Acute brain injury and long-lasting brain damage are the hallmarks of this condition. Hyperthermic neurological manifestations are remarkable for their damage correlation with stress amplitude and long-term persistence. Hyperthermia-induced protein unfolding, and nonspecific aggregation accumulation have neurotoxic effects and contribute to the pathogenesis of brain damage in heat stroke. Therefore, we generated heat-induced, dose-responsive extreme and mild proteotoxic stress models in medulloblastoma [Daoy] and neuroblastoma [SH-SY5Y] and differentiated SH-SY5Y neuronal cells. We show that heat-induced protein aggregation is associated with reduced cell proliferation and viability. Higher protein aggregation in differentiated neurons than in neuroblastoma precursors suggests a differential neuronal vulnerability to heat. We characterized the neuronal heat shock response through RT-PCR array analysis of eighty-four genes involved in protein folding and protein quality control (PQC). We identify seventeen significantly expressed genes, five of which are Hsp70 chaperones, and four of their known complementing function proteins. Protein expression analysis determined the individual differential contribution of the five Hsp70 chaperones to the proteotoxic stress response and the significance of only two members under mild conditions. The co-expression analysis reveals significantly high co-expression between the Hsp70 chaperones and their interacting partners. The findings of this study lend support to the hypothesis that hyperthermia-induced proteotoxicity may underlie the brain injury of heat stroke. Additionally, this study presents a comprehensive map of the Hsp70 network in these models with potential clinical and translational implications.

There are many molecules used as a drug carrier. TUD-1 is a newly synthesized mesoporous silica (SM) molecule possess two important features; consists of mesoporous so it is very suitable to be drug carrier in addition to that it has the ability to induce apoptosis in cancer cells. However, the effect of TUD-1 appears to act as cell death inducer, regardless of whether it is necrosis or apoptosis. Unfortunately, recent studies indicate that a proportion of cells undergo necrosis rather than apoptosis, which limits the use of TUD-1 as a secure treatment. On the other hand, lithium considered as necrosis inhibitor element. Hence, the current study based on the idea of producing a new Li-TUD-1 by incorporated mesoporous silica (TUD-1 type) with lithium in order to produce a new compound that has the ability to activate apoptosis by mesoporous silica (TUD-1 type) and at the same time can inhibit the activity of necrosis by lithium. Herein, lithium incorporated in TUD-1 mesoporous silica by using sol–gel technique in one-step synthesis procedure. Moreover, lithium incorporated in TUD-1 with different loading in order to form different active sites such as isolated lithium ions, nanoparticles of Li2O, and bulky crystals of Li2O. The ability of the new compounds to induce apoptosis and prevent necrosis was evaluated on three different types of cancer cell lines, which are; liver HepG-2, breast MCF-7, and colon HCT116. The obtained results show that Li-TUD-1 has the ability to control necrosis and thus reduce the side effects of treatments containing silica in the case of lithium added to them, especially in chronic cases. This opinion has demonstrated by the significant increase in the IC50 value and cell viability compared to control groups. Consequently, the idea is new, so it needs more develop and test with materials that have a more apoptotic impact than silica to induce apoptosis without induction of necrosis.

Heat stroke, a hazardous hyperthermia-related illness, is characterized by CNS injury, particularly long-lasting brain damage. A root cause for hyperthermic neurological damage is heat-induced proteotoxic stress through protein aggregation, a known causative agent of neurological disorders. Stress magnitude and enduring persistence are highly correlated with hyperthermia-associated neurological damage. We used an untargeted proteomic approach using liquid chromatography–tandem mass spectrometry (LC-MS/MS) to identify and characterize time-series proteome-wide changes in dose-responsive proteotoxic stress models in medulloblastoma [Daoy], neuroblastoma [SH-SY5Y], and differentiated SH-SY5Y neuron-like cells [SH(D)]. An integrated analysis of condition–time datasets identified global proteome-wide differentially expressed proteins (DEPs) as part of the heat-induced proteotoxic stress response. The condition-specific analysis detected higher DEPs and upregulated proteins in extreme heat stress with a relatively conservative and tight regulation in differentiated SH-SY5Y neuron-like cells. Functional network analysis using ingenuity pathway analysis (IPA) identified common intercellular pathways associated with the biological processes of protein, RNA, and amino acid metabolism and cellular response to stress and membrane trafficking. The condition-wise temporal pathway analysis in the differentiated neuron-like cells detects a significant pathway, functional, and disease association of DEPs with processes like protein folding and protein synthesis, Nervous System Development and Function, and Neurological Disease. An elaborate dose-dependent stress-specific and neuroprotective cellular signaling cascade is also significantly activated. Thus, our study provides a comprehensive map of the heat-induced proteotoxic stress response associating proteome-wide changes with altered biological processes. This helps to expand our understanding of the molecular basis of the heat-induced proteotoxic stress response with potential translational connotations.