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The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy-Drug Repurposing.

p53 and p73 are critical tumor suppressors that are often inactivated in human cancers through various mechanisms. Owing to their high structural homology, the proteins have many joined functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the 'guardian of the genome' and together with p73 forms a barrier against cancer development and progression. The TP53 is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li-Fraumeni syndrome (LFS), the inherited cance

Efficacy and safety of 5-aminolevulinic acid-guided surgery versus white-light resection in newly diagnosed glioblastoma: a systematic review and meta-analysis.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumour in adults, characterized by diffuse infiltration and poor prognosis despite multimodal therapy. Maximal safe surgical resection remains the cornerstone of management, as greater extent of resection (EOR) correlates with improved survival. However, conventional white-light microscopy often fails to distinguish tumour margins from surrounding functional brain tissue. 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery enhances intraoperative visualization by selectively accumulating protoporphyrin IX in tum

Low-intensity ultrasound combined with 5-aminolevulinic acid administration in the treatment of human tongue squamous carcinoma.

We investigated the anti-tumor efficiency of sonodynamic therapy (SDT) on human tongue squamous carcinoma SAS cell line using low intensity ultrasound (LIU) of 0.6 and 0.8 W/cm(2), plus 5-aminolevulinic acid (ALA). Xenograft in vivo experiments using Balb/ca nude mice and MTT assays in vitro showed that ALA-LIU therapy significantly suppressed the proliferation of SAS cells. ALA-LIU therapy markedly enhanced SAS cell apoptosis rate compared to LIU alone. Based on TEM and fluorescence microscopy observations, there are notably morphology changes and seriously swollen mitochondria in xenograft t

Residues stabilizing the heme moiety of the nitric oxide sensor soluble guanylate cyclase.

Soluble guanylate cyclase, a heterodimer consisting of an alpha- and a heme-containing beta-subunit, is the major receptor for the biological messenger nitric oxide (NO) and is involved in various signal transduction pathways. The heme moiety of the enzyme is bound between the axial heme ligand histidine(105) and the recently identified counterparts of the heme propionic acids, tyrosine(135) and arginine(139). The latter residues together with an invariant serine(137) form the unique heme binding motif Y-x-S-x-R. In this work, we show that replacement of the serine(137) with alanine destabiliz

Активаторы Nrf2 для лечения редких заболеваний, связанных с перегрузкой железа: от скамейки до кровати.

Железная перегрузка и связанные с ней окислительные повреждения наблюдаются во многих редких болезнях в результате мутации генов, связанных с гомеостазом железа. Будучи основным регулятором реакции на клеточную антиоксидантную реакцию, Nrf2 может также снизить системный и клеточный уровень железа путем регулирования генов и путей, связанных с железом, что делает Nrf2 очень хорошими инициаторами для лечения нарушений, связанных с перегрузкой железа. К числу успешных примеров относится клиническое использование омавельоксолона для атаксии Фридрейха и диметилфумарата для повторного излучающего мн

Interaction between endogenous carbon monoxide and hydrogen sulfide in the mechanism of gastroprotection against acute aspirin-induced gastric damage.

Acetylsalicylic acid (ASA) is mainly recognized as painkiller or anti-inflammatory drug. However, ASA causes serious side effects towards gastrointestinal (GI) tract which limits its usefulness. Carbon monoxide (CO) and hydrogen sulfide (H2S) have been described to act as important endogenous messengers and mediators of gastroprotection but whether they can interact in gastroprotection against acute ASA-induced gastric damage remains unknown. In this study male Wistar rats were pretreated with 1) vehicle (saline, i.g.), 2) tricarbonyldichlororuthenium (II) dimer (CORM-2, 5mg/kg i.g.), 3) sodiu

Brg1-mediated Nrf2/HO-1 pathway activation alleviates hepatic ischemia-reperfusion injury.

Cytoprotective gene heme oxygenase 1 (HO-1) could be induced by nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. The purpose of this study was to determine the role of Brahma-related gene 1 (Brg1), a catalytic subunit of SWI2/SNF2-like chromatin remodeling complexes, in Nrf2/HO-1 pathway activation during hepatic ischemia-reperfusion (HIR). Our results showed that hepatic Brg1 was inhibited during early HIR while Brg1 overexpression reduced oxidative injury in CMV-Brg1 mice subjected to HIR. Moreover, promoter-driven luciferase assay showed that overexpression of Brg1 by adenov

Heme oxygenase-1 protects human periodontal ligament cells against substance P-induced RANKL expression.

BACKGROUND AND OBJECTIVE: Although substance P (SP) stimulates bone resorption activity and this is reported to be correlated with the degree of periodontal inflammation, it is unclear how human periodontal ligament cells regulate neuropeptide-induced osteoclastogenesis or the possible involvement of heme oxygenase-1 (HO-1) might be. This study examines how SP affects osteoprotegerin (OPG) and RANKL expression via HO-1. MATERIAL AND METHODS: Using immortalized human periodontal ligament cells, the effects of SP on the expression of HO-1, RANKL and OPG mRNA and proteins were determined by RT-P

YL-I-108, a synthetic chalcone derivative, inhibits lipopolysaccharide-stimulated nitric oxide production in RAW 264.7 murine macrophages: involvement of heme oxygenase-1 induction and blockade of activator protein-1.

Chalcones, a group of phenolic compounds, exhibit potent anti-inflammatory properties. In the present study, we synthesized chalcone derivative, YL-I-108 ((E)-1-(2-methoxy-4,6-bis(methoxymethoxy)phenyl)-3-(3-nitrophenyl)prop-2-en-1-one), and examined its effect on the production of pro-inflammatory mediators. Treatment of RAW 264.7 macrophages with YL-I-108 potently inhibited nitrite production stimulated by LPS. YL-I-108 treatment also markedly inhibited expressions of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha). Treatment of cells with YL-I-108 signific

5‑aminiolevulinic acid induces a radiodynamic effect with enhanced delayed reactive oxygen species production under hypoxic conditions in lymphoma cells: An in vitro study.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive type of intracranial tumor. However, PCNSL is radiosensitive; thus, whole-brain radiotherapy (WBRT) is often selected as an alternative consolidation therapy. WBRT-related delayed neurotoxicity can affect the quality of life of the elderly. 5-aminolevulinic acid (ALA) is a natural precursor of heme and has been widely used as a live molecular fluorescence marker in brain tumor surgery. Experimental studies have demonstrated that combination therapy with 5-ALA and ionizing irradiation (IR), denoted radiodynamic therapy (RD

Уникальные диагностические и терапевтические функции порфиринов и фтальокянинов в области фотодинамической терапии, визуализации и термостимы.

Порфиринические молекулы играют уникальную тераностическую роль в лечении болезней; они используются для отображения, обнаружения и лечения различных форм заболевших тканей, в том числе в связи с возрастной маркулярной дегенерацией и рядом различных видов рака. В настоящее время основное внимание уделяется клинической съемке опухолей; целенаправленной доставке фотосенитеров и потенциалу фотоэнцедентов в мультимодальных биомедицинских наноплатформах. В настоящем Обзоре подчеркиваются роли порфириновых молекул в области съемки и пдта, а также исследования по совершенствованию их селективного пог

[Effects of heme oxygenase-1/carbon monoxide pathway on the mitochondrial fusion in rat alveolar epithelial type II cells stimulated by lipopolysaccharide].

OBJECTIVE: To investigate the effects of heme oxygenase-1/carbon monoxide (HO-1/CO) pathway on mitochondrial fusion in rat alveolar epithelial type II cells (AEC II) stimulated by lipopolysaccharide (LPS). METHODS: Once the cultured in vitro rat AEC II cells line RLE-6TN reached confluency of 85%, they were subcultured and randomly divided into seven groups (n = 5 each). RLE-6TN cells were routinely cultured in control group. The cells in LPS group was stimulated with 10 mg/L LPS to reproduce the model of endotoxin challenge in AECII cells. The cells in carbon monoxide-releasing molecule-2 (C

Молекулярные модели, связанные с ущербом от митохондриала: нейроиммуномодуляторы в патофизиологии центральной нервной системы.

Нейроинфламмация способствует широкому спектру нейродегенеративных заболеваний, включая болезнь Альцгеймера, болезнь Паркинсона, болезнь Хантингтона и множественный склероз. Его движут неевропейские глиальные клетки, главным образом микроглии и астроциты. Микроглии являются постоянными иммунными клетками центральной нервной системы, в то время как астроциты являются основными элементами поддержки нейронных функций, но могут также участвовать в нейроиммунной реакции. Оба этих типа глиальных клеток могут стать реактивными при обнаружении определенных внутриклеточных молекул, которые появляются в

Promising Highly Targeted Therapies for Cholangiocarcinoma: A Review and Future Perspectives.

To overcome the poor prognosis of cholangiocarcinoma (CCA), highly targeted therapies, such as antibody-drug conjugates (ADCs), photodynamic therapy (PDT) with/without systemic chemotherapy, and experimental photoimmunotherapy (PIT), have been developed. Three preclinical trials have investigated the use of ADCs targeting specific antigens, namely HER2, MUC1, and glypican-1 (GPC1), for CCA. Trastuzumab emtansine demonstrated higher antiproliferative activity in CCA cells expressing higher levels of HER2. Similarly, "staphylococcal enterotoxin A-MUC1 antibody" and "anti-GPC1 antibody-monomethyl

Osteoarthritis of the knee - biochemical aspect of applied therapies: a review.

The most prevalent form of arthritis is osteoarthritis (OA) of the knee, which is characterized by a degeneration of articular cartilage resulting in the development of osteophytes, or bone spurs. Main goals of OA treatment are to reduce pain, slow the disease progression, and improve joint function and the quality of life. The purpose of this study was to verify all the therapies recommended by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) from the biochemical point of view. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesi

Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgen

Микробиота гута и метаболиты связаны с развитием болезней в множестве склерозов.

Прогрессивный множественный склероз (MS) — неврологическое заболевание с ограниченным пониманием биологии, связанной с переходом от повторного заболевания к прогрессивному. Кишечные микробы и метаболиты изменяются в MS, но отношение к прогрессии заболеваний в значительной степени неизвестно. Мы исследуем микробиоту и метаболиты в субъектах с стабильными MS, у тех, кто ухудшился, и у тех, у кого вновь появились MS, которые стали прогрессивными. 2 Годы. Мы считаем, что эубактериум-халлий, бутириккацеа, блаутия и другие короткоцепные микробы, производящие жирные кислоты, имеют благоприятные связи

The Genetics and Epigenetics of 22q11.2 Deletion Syndrome.

Chromosome 22q11.2 deletion syndrome (22q11.2del) is a complex, multi-organ disorder noted for its varying severity and penetrance among those affected. The clinical problems comprise congenital malformations; cardiac problems including outflow tract defects, hypoplasia of the thymus, hypoparathyroidism, and/or dysmorphic facial features. Additional clinical issues that can appear over time are autoimmunity, renal insufficiency, developmental delay, malignancy and neurological manifestations such as schizophrenia. The majority of individuals with 22q11.2del have a 3 Mb deletion of DNA on chrom

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… Future directions for such patients may be clinical interventions to improve DGCR8 functions, with recent experiments reporting that protoporphyrins can enhance miRNA biogenesis in DGCR8-haploinsufficient cells ( Barr et al., 2015 ; Sachar et al., 2016 ). … Protoporphyrin IX: the Good, the Bad, and the Ugly. J. Pharmacol. Exp. Ther. 356, 267–275. 10.1124/jpet.115.228130 Sacks D. A., Hadden D. R., Maresh M., Deerochanawong C., Dyer A. R., Metzger B. E., et al. (2012). …

Management of keratinocyte carcinoma - Special considerations in the elderly.

Keratinocyte carcinomas (KCs) are now an epidemic in The United States of America, especially in elderly patients. KCs, including basal cell carcinoma and squamous cell carcinoma, can lead to disfigurement and occasionally death. However, the lower mortality rate associated with KC compared with melanoma allows for increased flexibility in the selection of treatment. Flexibility in treatment is particularly important in the elderly given that this patient population often has medical comorbidities that should be considered. These patients may have multiple KCs, higher risk tolerance to recurre

NTP Toxicology and Carcinogenesis Studies of Gallium Arsenide (CAS No. 1303-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Gallium arsenide is used primarily to make light- emitting diodes, lasers, laser windows, and photodetectors and in the photoelectronic transmission of data through optical fibers. Gallium arsenide was nominated for study because of its widespread use in the microelectronics industry, the potential for worker exposure, and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to gallium arsenide particles (greater than 98% pure; mass median aerodynamic diameter = 0.8 to 1.0 &mgr;m) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology stud