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Polyphenols bind G4-Quadruplex structures and act as epigenetic modifiers with anti-cancer effects.

G4-quadruplexes (G4s) are non-canonical structures of nucleic acids that develop in guanine rich regions of DNA and RNA. Due to their presence in oncogenic promoters and telomeres, G4s represent attractive targets in anticancer drug designs. G4s have also been the subject of recent research regarding their role as epigenetic modulators, supporting their participation in epigenetic processes that control gene expression. The development of small compounds that preferentially target G4s have led to a better understanding of how G4s control these mechanisms. Natural products have greatly contribu

Amyloidosis in Childhood: A Review of Clinical Features and Comparison with Adult Forms.

Amyloidosis is a rare multisystem disorder characterized by extracellular accumulation of insoluble fibrils in various organs and tissues. The most common subtype in the pediatric population is systemic reactive amyloidosis, typically developing secondary to chronic inflammatory conditions and resulting in deposition of serum amyloid A protein in association with apolipoprotein HDL3. Clinical presentation is highly variable and is mostly influenced by specific organs involved, precursor protein type, and extent of amyloid deposition, often closely reflecting clinical features of the underlying

Интерферонские регулятивные факторы как потенциальная терапевтическая цель для нейроинфламмации: фокус на болезни Альцгеймера.

Регулирующие факторы интерферона (ИРФ) являются важнейшими модуляторами иммунной и подстрекательской реакции, однако их роль в болезни Альцгеймера (AD) и других нейродегенеративных расстройствах остается неполной. В то время как IRF признаются за их регулирующие функции в нейроинфламмации, микроглиальной активации и выживании нейронов, их двойная роль как факторов патологического воспаления и посредников нейрозащитных путей подчеркивает сложный нормативный парадокс в нейродегенеративных расстройствах. Цель этого обзора заключается в обобщении текущих данных о нейрофламмации в области АД и связ

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… For instance, endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR), which triggers rapid protein kinase reactions via multiple transducers, subsequently altering the expression of numerous target genes. … Abbreviations AD: Alzheimer’s disease; IRFs: Interferon Regulatory Factors; DBD: DNA-binding domain; ISGs: IFN-stimulated genes; TREM2: triggering receptor expressed on myeloid cell 2; cGAS-STING: cyclic GMP-AMP synthase-stimulator of interferon genes; ER: endoplasmic reticulum; UPR: unfolded protein …

Dying of Stress: Chemotherapy, Radiotherapy, and Small-Molecule Inhibitors in Immunogenic Cell Death and Immunogenic Modulation.

Innovative strategies to re-establish the immune-mediated destruction of malignant cells is paramount to the success of anti-cancer therapy. Accumulating evidence suggests that radiotherapy and select chemotherapeutic drugs and small molecule inhibitors induce immunogenic cell stress on tumors that results in improved immune recognition and targeting of the malignant cells. Through immunogenic cell death, which entails the release of antigens and danger signals, and immunogenic modulation, wherein the phenotype of stressed cells is altered to become more susceptible to immune attack, radiother

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… Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 2007;8:519–529. doi: 10.1038/nrm2199. 76. Panaretakis T., Kepp O., Brockmeier U., Tesniere A., Bjorklund A.-C., Chapman D.C., Durchschlag M., Joza N., Pierron G., van Endert P., et al. … The unfolded protein response in immunogenic cell death and cancer immunotherapy. Trends Cancer. 2017;3:643–658. doi: 10.1016/j.trecan.2017.07.002. 78. Galluzzi L., Humeau J., Buqué A., Zitvogel L., Kroemer G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat. …

Salvage therapies in relapsed and/or refractory myeloma: what is current and what is the future?

The treatment landscape for multiple myeloma (MM) is evolving with our understanding of its pathophysiology. However, given the inevitable cohort heterogeneity in salvage therapy, response to treatment and overall prognoses tend to vary widely, making meaningful conclusions about treatment efficacy difficult to derive. Despite the hurdles in current research, progress is underway toward more targeted therapeutic approaches. Several new drugs with novel mechanism of action and less toxic profile have been developed in the past decade, with the potential for use as single agents or in synergy wi

Proteomic and transcriptomic analyses to explain the pleiotropic effects of Ankaferd blood stopper.

Ankaferd blood stopper is a standardized mixture of the plants Thymus vulgaris, Glycyrrhiza glabra, Vitis vinifera, Alpinia officinarum, and Urtica dioica and has been used as a topical hemostatic agent and with its clinical application established in randomized controlled trials and case reports. Ankaferd has been successfully used in gastrointestinal endobronchial mucosal and cutaneous bleedings and also in abdominal, thoracic, dental and oropharyngeal, and pelvic surgeries. Ankaferd's hemostatic action is thought to form a protein complex with coagulation factors that facilitate adhesion of

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… protein response to protect against excessive protein synthesis during endoplasmic reticulum stress. 46 Hepatocyte nuclear factor (HNF)-4a is a nuclear receptor found not only in the liver but also in other tissues, which is involved in embryonic development, cellular differentiation, and hepatocyte-specific … Cell Cycle 2012 ; 11 : 3887 – 3895 . 22983008 10.4161/cc.22133 PMC3495830 46 Zhang R Rapin N Ying Z Zhangfei/CREB-ZF—a potential regulator of the unfolded protein response . …

Multiple Facets of Autophagy and the Emerging Role of Alkylphosphocholines as Autophagy Modulators.

Autophagy is a highly conserved multistep process and functions as passage for degrading and recycling protein aggregates and defective organelles in eukaryotic cells. Based on the nature of these materials, their size and degradation rate, four types of autophagy have been described, i.e. chaperone mediated autophagy, microautophagy, macroautophagy, and selective autophagy. One of the major regulators of this process is mTOR, which inhibits the downstream pathway of autophagy following the activation of its complex 1 (mTORC1). Alkylphosphocholine (APC) derivatives represent a novel class of a

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… Autophagic flux can be enhanced by endoplasmic reticulum stress and related unfolded protein response (UPR) signaling (alkylphosphocholines, sorafenib, 2-deoxyglucose), inhibition of glycolysis (2-deoxyglucose) and blockade of the cargo receptor p62/sequestome1 (p62/SQSTM1) degradation (bortezomib). … protein response; inhibition of glycolysis. | ( Stein et al., 2010 ) Clinical Development Today, published clinical data have demonstrated sufficient evidence for efficacy in various disorders. …

Diagnosis and treatment of cardiac amyloidosis: an interdisciplinary consensus statement.

The prevalence and significance of cardiac amyloidosis have been considerably underestimated in the past; however, the number of patients diagnosed with cardiac amyloidosis has increased significantly recently due to growing awareness of the disease, improved diagnostic capabilities and demographic trends. Specific therapies that improve patient prognosis have become available for certain types of cardiac amyloidosis. Thus, the earliest possible referral of patients with suspicion of cardiac amyloidosis to an experienced center is crucial to ensure rapid diagnosis, early initiation of treatmen

Mechanisms of IFNalpha-1a-Induced Apoptosis in a Laryngeal Cancer Cell Line.

BACKGROUND Interferon alpha (IFNalpha) exerts its anti-proliferative effect on many human cancers. Among the 13 subtypes of human IFNalpha, IFNalpha-1 subtype has 2 variants, named IFNalpha-1a and IFNalpha-1b, that differ from each other in only 1 amino acid, at residue 114. However, the mechanism by which IFNalpha-1a mediates growth inhibition is still unclear. MATERIAL AND METHODS Human laryngeal carcinoma HEp2 cells were treated with IFNalpha-1a by either transient transfection or exogenous delivery. Western blot and RT-PCR analysis were carried out to assess apoptotic pathways active in IF

Multiple myeloma: the (r)evolution of current therapy and a glance into future.

Over the past 20 years, the regulatory approval of several novel agents to treat multiple myeloma (MM) has prolonged median patient survival from 3 to 8-10 years. Increased understanding of MM biology has translated to advances in diagnosis, prognosis, and response assessment, as well as informed the development of targeted and immune agents. Here we provide an overview of the recent progress in MM, and highlight research areas of greatest promise to further improve patient outcome in the future.

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… PI can overwhelm the imbalance between proteasome degradative capacity and proteasome load, 34-36 leading to endoplasmic reticulum stress due to accumulation of misfolded and unfolded proteins, activation of the unfolded protein response, and cell death. … Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells . Blood . 2006 ; 107 ( 12 ): 4907 - 4916 . 16507771 10.1182/blood-2005-08-3531 PMC1895817 37. Neri P Ren L Gratton K . Bortezomibinduced "BRCAness" sensitizes multiple myeloma cells to PARP inhibitors . …

'Nelfinavir sensitizes a clinically relevant chemo-radioresistant cervical cancer in-vitro model by targeting the AKT-USP15/USP11-HPV16 E6/E7 axis.

Resistance to standard therapies is a major challenge in managing cervical cancer, often leading to systemic relapse. This study aimed to develop an in-vitro model of chemo-radioresistant cervical cancer that mimics clinical conditions and also explore the therapeutic potential of the repurposed drug nelfinavir, an HIV protease inhibitor. HPV16-positive SiHa cervical cancer cells were subjected to concurrent cisplatin and ionizing radiation, to simulate the clinical treatment regimen for locally advanced cervical cancer. The resulting chemo-radioresistant subline exhibited increased IC50-value

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… It has shown interesting in-vitro and in-vivo off-target anti-cancer effects, such as endoplasmic reticulum stress-unfolded protein response, proteasome pathway, autophagy, apoptosis, oxidative stress in different cancers including cervix [ 15 ]. … The HIV protease inhibitor nelfinavir downregulates Akt phosphorylation by inhibiting proteasomal activity and inducing the unfolded protein response. Neoplasia. 2007;9:271–278. doi: 10.1593/neo.07124. 40. Soprano M., Sorriento D., Rusciano M.R., Maione A.S., Limite G., Forestieri P., et al. …

Protein kinase CK2: a potential therapeutic target for diverse human diseases.

CK2 is a constitutively active Ser/Thr protein kinase, which phosphorylates hundreds of substrates, controls several signaling pathways, and is implicated in a plethora of human diseases. Its best documented role is in cancer, where it regulates practically all malignant hallmarks. Other well-known functions of CK2 are in human infections; in particular, several viruses exploit host cell CK2 for their life cycle. Very recently, also SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been found to enhance CK2 activity and to induce the phosphorylation of several CK2 substrates (ei

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… CK2 protects from unfolded protein response (Fig. 2c ), 43 , 44 acting both on IRE1 (activating its XBP1-mediated pro-survival function) and PERK (inhibiting its eIF2α-mediated promotion of apoptosis). … MRP1 and P-gp are also directly activated by CK2. c Major actions of CK2 on the unfolded protein response pathway. …

Нацеливание экспорта эндоплазмического ретикулума нарушает метаболическую устойчивость в множестве миэломы.

Множественная миелома (ММ) характеризуется производством и секрецией большого количества иммуноглобулинов, в результате чего эта злонамеренность в значительной степени зависит от механизмов, которые поддерживают клеточный протеостаз. Несмотря на значительный клинический прогресс, достигнутый в области деградативной ветки протеостаза, гораздо меньше внимания уделяется биосинтетической ветке. В этом исследовании мы продемонстрировали, что сдерживание экспорта эндоплазмического ретикулума (ER), зависящего от COPII, приводит к смерти клеток в нескольких линиях ММ и основных клеток, созданных пацие

Proteasome Inhibitors for the Treatment of Multiple Myeloma.

Use of proteasome inhibitors (PIs) has been the therapeutic backbone of myeloma treatment over the past decade. Many PIs are being developed and evaluated in the preclinical and clinical setting. The first-in-class PI, bortezomib, was approved by the US food and drug administration in 2003. Carfilzomib is a next-generation PI, which selectively and irreversibly inhibits proteasome enzymatic activities in a dose-dependent manner. Ixazomib was the first oral PI to be developed and has a robust efficacy and favorable safety profile in patients with multiple myeloma. These PIs, together with other

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… Ixazomib treatment of MM cells induced caspase-mediated apoptosis, accompanied by induction of the unfolded protein response. …

Therapeutic Potential of Autophagy Modulation in Cholangiocarcinoma.

Autophagy is a multistep catabolic process through which misfolded, aggregated or mutated proteins and damaged organelles are internalized in membrane vesicles called autophagosomes and ultimately fused to lysosomes for degradation of sequestered components. The multistep nature of the process offers multiple regulation points prone to be deregulated and cause different human diseases but also offers multiple targetable points for designing therapeutic strategies. Cancer cells have evolved to use autophagy as an adaptive mechanism to survive under extremely stressful conditions within the tumo

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… Additionally, other types of cell stresses promote autophagy through the UPR (Unfolded Protein Response) and mediated by PERK, IRE1α or CAMKK2 protein [ 163 ]. … Stress conditions activate the UPR (Unfolded Protein Response) mediated by PERK and IRE-1, which leads to the activation of autophagy. The ULK complex consists in ULK1, ULK2, FIP200 and ATG13. The PI3K-Beclin1 complex consists in VPS34, VPS15, Beclin1 and ATG14, or VPS34, Beclin1, UVRAG and Ambra1. …

СТАТ3 ингибирует инъекцию иммуногенной клеточной смерти в множестве миеломы.

В одном из недавних публикаций, опубликованных в журнале " Blood Science " ( < < Кровные науки > > ), Sha et al., сообщается, что STAT3 ингибирует несколько стволовых клеток, похожих на миелому, и одновременно выявляет признаки смерти иммуногенных клеток. Эти очень интригующие выводы связывают ствол, комплексную реакцию на стресс и иммунитет от антитуманков, однако для того, чтобы эта стратегия могла считаться иммуногенной, по-прежнему необходимо подтвердить в vivo.

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… Transcriptomics revealed enrichment of the unfolded protein response (UPR) in MM cells treated with napabucasin. …

Revealing G4 Structures as Drug Targets: Exploring the Potential of Novel Therapeutic Agents.

G-quadruplex (G4) structures represent noncanonical secondary formations found in DNA and RNA. Recent research reveals that G4s are abnormally enriched in various cancers, with closely linked to malignancy, metastatic potential, and prognosis. These structures have emerged as promising biomarkers for cancer with notable clinical relevance. Concurrently, investigations into compounds that selectively recognize DNA or RNA G4s as potential anticancer agents offer new avenues for early cancer diagnosis and therapeutic strategies. This review systematically analyzes the chemical structural characte

A Comparative Oncology Drug Discovery Pipeline to Identify and Validate New Treatments for Osteosarcoma.

BackgroundOsteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease.MethodsTo overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline.R

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… The proteasome regulates the turnover of thousands of proteins in the cell [ 34 ], and proteasome inhibition creates an imbalance in the levels of misfolded proteins, leading to induction of the unfolded protein response, cellular stress, and apoptosis [ 35 ]. … Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells Blood 2006 107 4907 4916 10.1182/blood-2005-08-3531 16507771 PMC1895817 36. Stade K. Ford C.S. Guthrie C. Weis K. …

A clinicopathologic study of malignancy in VCP-associated multisystem proteinopathy.

BACKGROUND: Valosin containing protein (VCP) is an important protein with many vital functions mostly related to the ubiquitin-proteasome system that provides protein quality control. VCP-associated inclusion body myopathy with Paget disease of bone and frontotemporal dementia, also termed VCP disease and multisystem proteinopathy (MSP 1), is an autosomal dominant disorder caused by monoallelic variants in the VCP gene on human chromosome 9. VCP has also been strongly involved in cancer, with over-activity of VCP found in several cancers such as prostate, pancreatic, endometrial, esophageal ca

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… One potent and specific VCP inhibitor called NMS-873 was able to activate the unfolded protein response and thus interfered with autophagy, resulting in cancer cell death [ 57 ]. …

Storage diseases with hypertrophic cardiomyopathy phenotype.

Never judge a book by its cover, nor assume hypertrophic cardiomyopathy (HCM) as sarcomeric, as appearances can deceive. HCM phenocopies account for a 5-10% of the cases, mainly represented by storage diseases, flagged by the increasing prevalence of senile cardiac amyloid in developing countries. Multisystemic and heterogeneous presentation of these entities is a challenge for clinicians, and time delay in diagnosis is a major concern. Promising drugs and gene-specific tailored therapies are under development, therefore, more than ever, appropriate understanding of these conditions is mandato