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Rational treatment of chemotherapy-induced peripheral neuropathy with capsaicin 8% patch: from pain relief towards disease modification.

PurposeChemotherapy-induced peripheral neuropathy (CIPN) with associated chronic pain is a common and disabling condition. Current treatments for neuropathic pain in CIPN are largely ineffective, with unfavorable side-effects. The capsaicin 8% patch (capsaicin 179 mg patch) is approved for the treatment of neuropathic pain: a single topical cutaneous application can produce effective pain relief for up to 12 weeks. We assessed the therapeutic potential of capsaicin 8% patch in patients with painful CIPN, and its mechanism of action.Patients and methods16 patients with chronic painful CIPN (mea

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… sodium channels, 24 potassium channels, 25 transient receptor potential vanilloid receptors (TRPV), 26 Langerhans cells, 27 oxidative stress, 28 mitogen activated protein kinase (MAPK), 29 N-methyl-d-aspartate (NMDA) receptors, 30 neuropeptide Y, 31 nitric oxide, 32 5-HT2A, 33 protein kinase C, 34 calpains …

Премии победителей и резюме 32nd Ежегодный симпозиум Общества протеинов; Бостон, ОЭТ, июль 9-12, 2018.

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Bortezomib inhibits chikungunya virus replication by interfering with viral protein synthesis.

Chikungunya virus (CHIKV) is an alphavirus that causes a febrile illness accompanied by myalgia and arthralgia. Despite having re-emerged as a significant public health threat, there are no approved therapeutics or prophylactics for CHIKV infection. In this study, we explored the anti-CHIKV effects of proteasome inhibitors and their potential mechanism of antiviral action. A panel of proteasome inhibitors with different functional groups reduced CHIKV infectious titers in a dose-dependent manner. Bortezomib, which has been FDA-approved for multiple myeloma and mantle cell lymphoma, was further

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… Activities of proteasome and m-calpain are essential for Chikungunya virus replication. Virus Genes. 2016;52(5):716–21. 10.1007/s11262-016-1355-5 37. Hoy SM. Subcutaneous bortezomib: in multiple myeloma. Drugs. 2013;73(1):45–54. 10.1007/s40265-013-0006-6 38. …

Sophorolipids as anticancer agents: progress and challenges.

Sophorolipids (SLs) are considered effective biosurfactant for cancer treatment, which can efficiently inhibit the viability of various cancer types including breast, lung, liver, cervical and colon cancers. Their mechanism of action targets apoptosis and operates at the level of caspase enzymes, upregulation and downregulation of the B-cell lymphoma (Bcl)-family proteins, and changes in mitochondrial membrane permeability. The binding of SLs to the cancer cell receptors modulates the expression of Bax, APAF1, Bcl-2 and Bcl-x, and triggers the release of cytochrome c into the cytosol which fur

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… The opening of the mitochondrial calcium uniporter (MCU) and influx of Ca 2 ⁺ into the mitochondria, further initiates and amplifies the apoptotic signaling cascade through calcium-calpain pathway based activation of caspases (caspase-3, caspase-6, and caspase-7) [ 56 ]. …

Biomarkers of Chemotherapy-Induced Peripheral Neuropathy: Current Status and Future Directions.

Chemotherapy induced peripheral neuropathy (CIPN) is an often severe and debilitating complication of multiple chemotherapeutic agents that can affect patients of all ages, across cancer diagnoses. CIPN can persist post-therapy, and significantly impact the health and quality of life of cancer survivors. Identifying patients at risk for CIPN is challenging due to the lack of standardized objective measures to assess for CIPN. Furthermore, there are no approved preventative treatments for CIPN, and therapeutic options for CIPN remain limited once it develops. Biomarkers of CIPN have been studie

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… Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation . Proc Natl Acad Sci USA. ( 2007 ) 104 : 11103 – 8 . 10.1073/pnas.0701546104 17581879 PMC1904151 96. Mo M Erdelyi I Szigeti-Buck K Benbow JH Ehrlich BE . …

Evidence for reciprocal network interactions between injured hearts and cancer.

Heart failure (HF) and cancer are responsible for 50% of all deaths in middle-aged people. These diseases are tightly linked, which is supported by recent epidemiological studies and case control studies, demonstrating that HF patients have a higher risk to develop cancer such as lung and breast cancer. For HF patients, a one-size-fits-all clinical management strategy is not effective and patient management represents a major economical and clinical burden. Anti-cancer treatments-mediated cardiotoxicity, leading to HF have been extensively studied. However, recent studies showed that even befo

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… Same group has shown that the mechanisms of muscle depletion is due to increased proteasome- and calpain-dependent proteolysis in tumor bearing rats treated with TNF-alpha synthesis inhibitor, or an antiprotozoal drug blocking the IL-6 and TNF-alpha action ( 105 ). …

Targeting the proteasome in cancer therapy: development and future opportunities in natural products.

BACKGROUND: The ubiquitin-proteasome pathway is a critical therapeutic target in malignancies, particularly multiple myeloma. The development of proteasome inhibitors (PIs) has marked a milestone in multiple myeloma therapy and now constitutes the backbone of frontline treatment regimens. However, primary and acquired resistance remain a major challenge, underscoring the need to identify new PIs as well as agents that can resensitize resistant cells. METHOD: This review provides an overview of the current clinical applications of PIs and offers a comprehensive summary of natural products that

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… TMC-95A exhibited remarkable selectivity, showing no inhibition against m-calpain, cathepsin L, or trypsin ( Koguchi et al., 2000 ). Notably, this family exhibits weaker cytotoxicity than FDA-approved proteasome inhibitors. … Notably, linear aldehyde 1p achieved CT-L potency similar to CFZ but exhibited increased off-target inhibition of cathepsin B and m-calpain, suggesting that the macrocyclic architecture of TMC-95A is essential for proteasome selectivity ( Wilson et al., 2016 ). …

Targeting vascular endothelial growth receptor-2 (VEGFR-2): structural biology, functional insights, and therapeutic resistance.

Angiogenesis, the process of new blood vessel formation, is a fundamental physiological process implicated in several pathological disorders. The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are crucial for angiogenesis and vasculogenesis. Among them, the tyrosine kinase receptor VEGFR-2 is primarily expressed in endothelial cells (ECs). These cells regulate various physiological responses, including differentiation, cell proliferation, migration, and survival, by binding to VEGF mitogens. Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) is a key regulator of

Acupuncture in the treatment of chemotherapy-induced peripheral neuropathy: a meta-analysis and data mining.

BackgroundThe efficacy and acupoint selection of acupuncture in treating chemotherapy-induced peripheral neuropathy (CIPN) remain controversial. This study aims to explore the specific efficacy and acupoint selection of acupuncture in treating CIPN through a meta-analysis and data mining.MethodsSearching for clinical trials on acupuncture treatment for CIPN in 8 databases, evaluating its efficacy and safety through a meta-analysis, and exploring its acupoint selection through data mining.ResultsThe meta-analysis included 21 studies and 2,121 patients, showing that compared with the control gro

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… Electroacupuncture pre-treatment alleviates sepsis-induced cardiac inflammation and dysfunction by inhibiting the calpain-2/STAT3 pathway. Front Physiol. (2022) 13:961909. doi: 10.3389/fphys.2022.961909 43. Zhou K, Wu Q, Yue J, Yu X, Ying X, Chen X, et al. …

Progress on the Application of Bortezomib and Bortezomib-Based Nanoformulations.

Bortezomib (BTZ) is the first proteasome inhibitor approved by the Food and Drug Administration. It can bind to the amino acid residues of the 26S proteasome, thereby causing the death of tumor cells. BTZ plays an irreplaceable role in the treatment of mantle cell lymphoma and multiple myeloma. Moreover, its use in the treatment of other hematological cancers and solid tumors has been investigated in numerous clinical trials and preclinical studies. Nevertheless, the applications of BTZ are limited due to its insufficient specificity, poor permeability, and low bioavailability. Therefore, in r

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… Consequently, ERS promotes the activation of apoptosis-related proteins, such as caspase-12 and calpain, and leads to cell apoptosis [ 6 , 70 ]. 2.3.4. …

Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells.

[Figure: see text] Multiple myeloma (MM) remains an intractable hematological malignancy, despite recent advances in anti-MM drugs. Here, we show that role of PDZ binding kinase (PBK) in MM tumor growth. We identified that interleukin-6 (IL-6) readily increases PBK expression. Kaplan-Meier analysis showed that the MM patients with higher expression of PBK have a significant shorter survival time compared with those with moderate/lower expression of PBK. Knockout of PBK dramatically suppressed in vivo tumor growth in MM cells, while genome editing of PBK changing from asparagine to serine subst

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… | Hemoglobin, beta | 2.2 | 6.5 PARP9 | Poly (ADP-ribose) polymerase family, member 9 | 9.6 | 6.2 DCC | Deleted in colorectal carcinoma | 3.4 | 6.1 CYP21A2 | Cytochrome P450, family 21, subfamily A, polypeptide 2 | 6.7 | 5.8 DSCC1 | DNA replication and sister chromatid cohesion 1 | 3.1 | 5.7 CAPN5 | Calpain …

Heat shock protein 90 and role of its chemical inhibitors in treatment of hematologic malignancies.

Heat shock protein 90 (Hsp90) is a conserved and constitutively expressed molecular chaperone and it has been shown to stabilize oncoproteins and facilitate cancer development. Hsp90 has been considered as a therapeutic target for cancers and three classes of Hsp90 inhibitors have been developed: (1) benzoquinone ansamycin and its derivatives, (2) radicicol and its derivates, and (3) small synthetic inhibitors. The roles of these inhibitors in cancer treatment have been studied in laboratories and clinical trials, and some encouraging results have been obtained. Interestingly, targeting of Hsp

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… Last but not the least, CTD mediates dimerization of Hsp90 [ 13 ], as truncation of this region by digestion with the Ca 2+ -dependent protease m-calpain results in dissociation of the dimer. 2.2. …

Рецепт 1 в диабете и его хронические осложнения: механизмы сигнализации и новые терапевтические достижения.

Диабет моллюсков (DM) — системное метаболическое расстройство, характеризующееся хронической гипергликемией, которая может оказывать воздействие на почки, сетчатку, периферийные нервы и сердечно-сосудистую систему, что в конечном счете приводит к многочисленным хроническим осложнениям. 1 (PAR1) — G-белковый рецептор, приводимый в действие через каноническое декольте, например тромбинированный декольте и неканоническое декольте, например, декольте с помощью активированного белка C или матрицы Metalloproteinase-1. Эти режимы активации инициируют различные каналы подачи сигналов вниз по течению,

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… Under hyperglycemic conditions, aberrantly activated platelets release platelet-derived microparticles (PMPs) enriched in active calpain-1 (CAPN1), which directly cleaves and activates the N-terminus of PAR1. …

Pancreatic Neuroendocrine Tumors: Signaling Pathways and Epigenetic Regulation.

Pancreatic neuroendocrine tumors (PNETs) are characterized by dysregulated signaling pathways that are crucial for tumor formation and progression. The efficacy of traditional therapies is limited, particularly in the treatment of PNETs at an advanced stage. Epigenetic alterations profoundly impact the activity of signaling pathways in cancer development, offering potential opportunities for drug development. There is currently a lack of extensive research on epigenetic regulation in PNETs. To fill this gap, we first summarize major signaling events that are involved in PNET development. Then,

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… This gene has been shown to be methylated at its promoter with silenced or reduced expression in colorectal cancer (CRC), though this effect can be reversed with the calpain inhibitor calpeptin, providing possible therapeutic strategies for aggressive disease [ 40 ]. … A novel methylated cation channel TRPM4 inhibited colorectal cancer metastasis through Ca(2+)/Calpain-mediated proteolysis of FAK and suppression of PI3K/Akt/mTOR signaling pathway Int. J. Biol. Sci. 2022 18 5575 5590 10.7150/ijbs.70504 36147460 PMC9461655 41. Huang J. Li J. Tang J. Wu Y. Dai F. …

Резюме книги: ISEV2017.

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Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy.

Endoplasmic reticulum (ER) stress is a key cellular mechanism that is important in the development of many diseases, including cancer. Since the discovery of the unfolded protein response (UPR), research has greatly improved our understanding of how ER stress affects cellular functions, especially protein folding and adaptation to stress. The UPR consists of three main branches: IRE1, ATF6, and PERK, each of which is crucial for regulating stress responses, protein homeostasis, and apoptosis. These pathways normally help cells handle stress effectively; however, excessive or prolonged activati

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… playing a crucial role in calcium ion storage. 166 Following ER stress, stimulation from various signals, including PERK and eIF2α, opens inositol 1,4,5-triphosphate receptor (IP3R) channels in the ER membrane, causing a substantial release of calcium ions. 167 Elevated levels of calcium ions activate calpain … This enzyme cleaves various proteins, including B-cell lymphoma-extralarge (Bcl-xL), shifting it from being antiapoptotic to being proapoptotic. 168 Furthermore, activated calpain can move to the ER, where it cleaves and activates caspase-12 at multiple sites, playing a critical role in apoptosis. …

Targeting NETosis: nature's alarm system in cancer progression.

Neutrophils are recognized active participants in inflammatory responses and are intricately linked to cancer progression. In response to inflammatory stimuli, neutrophils become activated, releasing neutrophils extracellular traps (NETs) for the capture and eradication of pathogens, a phenomenon termed NETosis. With a deeper understanding of NETs, there is growing evidence supporting their role in cancer progression and their involvement in conferring resistance to various cancer therapies, especially concerning tumor reactions to chemotherapy, radiation therapy (RT), and immunotherapy. This

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… Granulocyte colony-stimulating factor delays neutrophil apoptosis by inhibition of calpains upstream of caspase-3 Blood 2008 112 2046 54 10.1182/blood-2008-04-149575 18524991 PMC2518906 13 Farraye FA Odze RD Eaden J Itzkowitz SH AGA technical review on the diagnosis and management of colorectal neoplasia …

Circulating biosignatures in multiple myeloma and their role in multidrug resistance.

A major obstacle to chemotherapeutic success in cancer treatment is the development of drug resistance. This occurs when a tumour fails to reduce in size after treatment or when there is clinical relapse after an initial positive response to treatment. A unique and serious type of resistance is multidrug resistance (MDR). MDR causes the simultaneous cross resistance to unrelated drugs used in chemotherapy. MDR can be acquired through genetic alterations following drug exposure, or as discovered by us, through alternative pathways mediated by the transfer of functional MDR proteins and nucleic

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… An influx of calcium ions in the cytosol activates cytosolic enzyme calpain disrupting the cytoskeleton, switches on floppase (outward phospholipid pump) and scramblase disrupting the (bidirectional) on the membrane. …

Lenalidomide, bortezomib and dexamethasone induction therapy for the treatment of newly diagnosed multiple myeloma: a practical review.

For patients with newly diagnosed multiple myeloma, survival outcomes continue to improve significantly: however, nearly all patients will relapse following induction treatment. Optimisation of induction therapy is essential to provide longer term disease control and the current standard of care for most patients incorporates an immunomodulatory agent and proteasome inhibitor, most commonly lenalidomide and bortezomib in combination with dexamethasone (RVD), with maintenance until progression. Historically there has been limited access to RVD as an induction strategy outside of the United Stat

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… Combination lenalidomide/bortezomib treatment synergistically induces calpain‐dependent ikaros cleavage and apoptosis in myeloma cells . …

Pomalidomide mitigates neuronal loss, neuroinflammation, and behavioral impairments induced by traumatic brain injury in rat.

BACKGROUND: Traumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction. Secondary pathologies following TBI may be associated with chronic neurodegenerative disorders and an enhanced likelihood of developing dementia-like disease in later life. There are currently no approved drugs for mitigating the acute or chronic effects of TBI. METHODS: The effects of the drug pomalidomide (Pom), an FDA-approved immunomodulatory agent, were evaluated in a rat model of moderate to severe TBI induced by controlled cortical impact. Post-TBI

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… Pharmacological inhibition of lipid peroxidation attenuates calpain-mediated cytoskeletal degradation after traumatic brain injury. J Neurochem. 2011;117:579–88. doi: 10.1111/j.1471-4159.2011.07228.x. 75. Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS. …