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The immunomodulatory effects of α-melanocyte stimulating hormone (α-MSH) in the central nervous system (CNS) have been investigated for forty years. The clinical applications of α-MSH are limited due to its short half-life. Our previous study has indicated that the short half-life of α-MSH can be extended by fusion with carrier human serum albumin (HSA) and this fusion protein has also retained the anti-inflammatory effect on the CNS. This improvement is still far from the clinical requirements. Thus, we expected to enhance the half-life and activity of the fusion protein by optimizing the linker peptide to get closer to clinical requirements. In a previous study, we screened out two candidates in vitro experiments with a flexible linker peptide (fusion protein with flexible linker peptide, FPFL) and a rigid linker peptide (fusion protein with rigid linker peptide, FPRL), respectively. However, it was not sure whether the anti-inflammatory effects in vitro could be reproduced in vivo. Our results show that FPRL is the best candidate with a longer half-life compared to the traditional flexible linker peptides. Meanwhile, the ability of FPRL to penetrate the blood-brain barrier (BBB) was enhanced, and the inhibition of TNF-α and IL-6 was improved. We also found that the toxicity of FPRL was decreased. All of the results suggested that trying to choose the rigid linker peptide in some fusion proteins may be a potential choice for improving the unsatisfactory characteristics. [ABSTRACT FROM AUTHOR]

Many stresses induce the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum, a phenomenon known as ER stress. In response to ER stress, cells initiate a protective response, known as unfolded protein response (UPR), to maintain cellular homeostasis. The UPR sensor, inositol-requiring enzyme 1 (IRE1), catalyzes the cytoplasmic splicing of bZIP transcription factor-encoding mRNAs to activate the UPR signaling pathway. Recently, we reported that pretreatment of Arabidopsis thaliana plants with tunicamycin, an ER stress inducer, increased their susceptibility to bacterial pathogens; on the other hand, IRE1 deficient mutants were susceptible to Pseudomonas syringae pv. maculicola (Psm) and failed to induce salicylic acid (SA)-mediated systemic acquired resistance. However, the functional relationship of IRE1 with the pathogen and TM treatment remains unknown. In the present study, we showed that bacterial pathogen-associated molecular patterns (PAMPs) induced IRE1 expression; however, PAMP-triggered immunity (PTI) response such as callose deposition, PR1 protein accumulation, or Pst DC3000 hrcC growth was not altered in ire1 mutants. We observed that IRE1 enhanced plant immunity against the bacterial pathogen P. syringae pv. tomato DC3000 (Pst DC3000) under ER stress. Moreover, TM-pretreated ire1 mutants were more susceptible to the avirulent strain Pst DC3000 (AvrRpt2) and showed greater cell death than wild-type plants during effector-triggered immunity (ETI). Additionally, Pst DC3000 (AvrRpt2)-mediated RIN4 degradation was reduced in ire1 mutants under TM-induced ER stress. Collectively, our results reveal that IRE1 plays a pivotal role in the immune signaling pathway to activate plant immunity against virulent and avirulent bacterial strains under ER stress. • Inositol-requiring enzyme 1 (IRE1) acts as an unfolded protein response (UPR) sensor in plants. • IRE1 is required for bacterial-induced plant immunity under endoplasmic reticulum (ER) stress in Arabidopsis thaliana by utilizing the N-glycosylation inhibitor, tunicamycin (TM), which induces ER stress. • Plants failed to defend themselves against bacterial pathogens in the absence of the IRE1 gene under ER stress. • Our results also suggest that the two copies of IRE1 , including IRE1a and IRE1b , are directly or indirectly involved in AvrRpt2-induced RIN4 degradation under ER stress. [ABSTRACT FROM AUTHOR]

The tomato (Solanum lycopersicum) is widely consumed globally and renowned for its health benefits, including the reduction of cardiovascular disease and prostate cancer risk. However, tomato production faces significant challenges, particularly due to various biotic stresses such as fungi, bacteria, and viruses. To address this challenges, we employed the CRISPR/Cas9 system to modify the tomato NUCLEOREDOXIN (SlNRX) genes (SlNRX1 and SlNRX2) belonging to the nucleocytoplasmic THIOREDOXIN subfamily. CRISPR/Cas9-mediated mutations in SlNRX1 (slnrx1) plants exhibited resistance against bacterial leaf pathogen Pseudomonas syringae pv. maculicola (Psm) ES4326, as well as the fungal pathogen Alternaria brassicicola. However, the slnrx2 plants did not display resistance. Notably, the slnrx1 demonstrated elevated levels of endogenous salicylic acid (SA) and reduced levels of jasmonic acid after Psm infection, in comparison to both wild-type (WT) and slnrx2 plants. Furthermore, transcriptional analysis revealed that genes involved in SA biosynthesis, such as ISOCHORISMATE SYNTHASE 1 (SlICS1) and ENHANCED DISEASE SUSCEPTIBILITY 5 (SlEDS5), were upregulated in slnrx1 compared to WT plants. In addition, a key regulator of systemic acquired resistance, PATHOGENESIS-RELATED 1 (PR1), exhibited increased expression in slnrx1 compared to WT. These findings suggest that SlNRX1 acts as a negative regulator of plant immunity, facilitating infection by the Psm pathogen through interference with the phytohormone SA signaling pathway. Thus, targeted mutagenesis of SlNRX1 is a promising genetic means to enhance biotic stress resistance in crop breeding. • slnrx1 mutant, not slnrx2 , is resistant to the bacterial pathogen Psm. • slnrx1 mutant is resistant to the fungal pathogen A. brassicicola. • SlNRX1 negatively regulates the salicylic acid-dependent immune pathway. • SlNRX1 inhibits the transcription of salicylic acid biosynthetic genes. • SlNRX1 negatively activates the transcription of PR1 against Psm infection. [ABSTRACT FROM AUTHOR]

Summary: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults, accounting for nearly 40% of all non-Hodgkin''s lymphomas. As cell proliferation is essential for tumor growth, analysis of the cell cycle might give additional information on tumor progression. Although markers distinctive for cell-cycle regulation in DLBCL have been addressed, less attention has been paid to cyclin H in DLBCL with respect to its prognostic and potential therapeutic implications. Cyclin H occurs as a component of the cyclin H/Cdk 7/Mat 1 complex. Cyclin H is also a substrate of protein kinase 2, a ubiquitously expressed serine/threonine protein kinase required for cell viability and cell-cycle progression. We evaluated the expression of cyclin H by immunohistochemistry in 301 DLBCLs in a tissue microarray format. Validation was done by performing quantitative real-time polymerase chain reaction and Western blotting experiments for cyclin H. We studied the relationship between cyclin H expression in comparison to other cyclins (A, B1, D1, D3, and E) and the proliferation marker Ki-67. Reduced or absent cyclin H expression was seen in 14.5% of the DLBCL cases. Interestingly, reduced or absent cyclin H expression was correlated with lower expression of proliferation marker Ki-67 (P < .0001), cyclin B1 (P = .0001), cyclin D3 (P = .0007), and cyclin E (P < .0001). Reduced or absent cyclin H expression was significantly associated with poor overall survival, in both the univariate (P = .0286) and multivariate analysis with International Prognostic Index (P = .0180). Our study demonstrates the independent prognostic value of cyclin H expression in DLBCL and proposes its use as a prognostic marker. [Copyright &y& Elsevier]

The Type I IFN receptor-generated signals required for initiation of mRNA translation and, ultimately, induction of protein products that mediate IFN responses, remain unknown. We have previously shown that IFNα and IFNβ induce phosphorylation of insulin receptor substrate proteins and downstream engagement of the phosphatidylinositol (PI) 3'-kinase pathway. In the present study we provide evidence for the existence of a Type I IFN-dependent signaling cascade activated downstream of PI 3'-kinase, involving p70 S6 kinase. Our data demonstrate that p70 S6K is rapidly phosphorylated on threonine 421 and serine 424 and is activated during treatment of cells with IFNα or IFNβ. Such activation of p70 S6K is blocked by pharmacological inhibitors of the PI 3'-kinase or the FKBP 12-rapamycin-associated protein/mammalian target of rapamycin (FRAP/ mTOR). Consistent with this, the Type I IFN-dependent phosphorylation/activation of p70 S6K is defective in embryonic fibroblasts from mice with targeted disruption of the p85α and p85β subunits of the PI 3'-kinase (p85α-/-β-/-). Treatment of sensitive cell lines with IFNα or IFNfi also results in phosphorylation/inactivation of the 4E-BP-1 repressor of mRNA translation. Such 4E-BP1 phosphorylation is also PI3'-kinase-dependent and rapamycin-sensitive, indicating that the Type I IFNinducible activation of PI3'-kinase and FRAP/mTOR resuits in dissociation of 4E-BP1 from the eukaryotic initiation factor-4E (eIF4E) complex. Altogether, our data establish that the Type I IFN receptor-activated PI 3'kinase pathway mediates activation of the p70 S6 kinase and inactivation of 4E-BP1, to regulate mRNA translation and induction of Type I IFN responses. [ABSTRACT FROM AUTHOR]

• Cancer stemness occur due to dysregulation of regulatory proteins. • Cancer stemness leads to poor clinical outcomes, recurrence, and drug resistance. • F-box proteins are vital for multiple cellular and biological processes. • Deregulated F-box proteins are the main oncogenic drivers with poor clinical outcomes. • Aberrant F-box protein orchestrate cancer stemness features with poor clinical outcome. Cancer is a complex heterogenic disease with significant therapeutic challenges. The presence of cancer stem cells (CSCs) in cancer tissue orchestrates tumor growth, progression, and metastasis, the tumor heterogeneity, disease relapse, and therapeutic resistance. Hence, it is imperative to explore how progenitor or cancer-initiating cells acquire stemness features and reprogram different biological mechanisms to maintain their sustained oncogenicity. Interestingly, deregulation of F-box proteins (FBPs) is crucial for cancer stemness features, including drug resistance and disease relapse. In this review, we highlight recent updates on the clinical significance of targeting FBPs in cancer therapy, with emphasis on eliminating CSCs and associated therapeutic challenges. Moreover, we also discuss novel strategies for the selective elimination of CSCs by targeting FBPs. [ABSTRACT FROM AUTHOR]

Fatty acid synthase (FASN) is a critical enzyme essential for the production of fats in the body. The abnormal expression of FASN is associated with different types of malignancies, including ovarian cancer. FASN plays a crucial role in cell growth and survival as a metabolic oncogene, although the specific processes that cause its dysregulation are still unknown. FASN interacts with signaling pathways linked to the progression of cancer. Pharmacologically inhibiting or inactivating the FASN gene has shown potential in causing the death of cancer cells, offering a possible treatment approach. This review examines the function of FASN in ovarian cancer, namely its level of expression, influence on the advancement of the disease, and its potential as a target for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Cancer is caused by a complex interaction of factors that interrupt the normal growth and division of cells. At the center of this process is the intricate relationship between DNA damage and the cellular mechanisms responsible for maintaining genomic stability. When DNA damage is not repaired, it can cause genetic mutations that contribute to the initiation and progression of cancer. On the other hand, the DNA damage response system, which involves the phosphorylation of the histone variant H2AX (γH2AX), is crucial in preserving genomic integrity by signaling and facilitating the repair of DNA double-strand breaks. This review provides an explanation of the molecular dynamics of H2AX in the context of DNA damage response. It emphasizes the crucial role of H2AX in recruiting and localizing repair machinery at sites of chromatin damage. The review explains how H2AX phosphorylation, facilitated by the master kinases ATM and ATR, acts as a signal for DNA damage, triggering downstream pathways that govern cell cycle checkpoints, apoptosis, and the cellular fate decision between repair and cell death. The phosphorylation of H2AX is a critical regulatory point, ensuring cell survival by promoting repair or steering cells towards apoptosis in cases of catastrophic genomic damage. Moreover, we explore the therapeutic potential of targeting H2AX in cancer treatment, leveraging its dual function as a biomarker of DNA integrity and a therapeutic target. By delineating the pathways that lead to H2AX phosphorylation and its roles in apoptosis and cell cycle control, we highlight the significance of H2AX as both a prognostic tool and a focal point for therapeutic intervention, offering insights into its utility in enhancing the efficacy of cancer treatments. • The histone variation H2AX is essential to the DNA damage response and offers a potential cancer therapeutic target. • H2AX is a well-known chromatin modification event in DNA damage response and human malignancies. • H2AX phosphorylation (γ-H2AX) is necessary for DNA repair protein assembly at damaged chromatin regions. • Detecting double strand breaks with phosphorylated histone H2AX may help in cancer treatment. [ABSTRACT FROM AUTHOR]

• Resorcylic acid lactones (RALs) are fungal polyketides. • RALs consist of a β-resorcylic acid residue embedded in a macrolactone ring. • RALs exhibit a broad range of biological activities, including anticancer activities. • Radicicol, a RAL, selectively inhibits Hsp90. • Several RALs inhibit protein kinases and nuclear factor kappa B (NF-κB). Resorcylic acid lactones (RALs) are fungal polyketides that consist of a β-resorcylic acid residue (2,4-dihydroxybenzoic acid) embedded in a macrolactone ring. RALs exhibit a broad range of biological activities, including anticancer activities. Following discovery of the selective Hsp90 inhibition activity of radicicol, the kinase inhibition activity of hypothemycin, monocillin II, 5Z-7-oxo-zeaenol, and L-783,277 RALs, and the nuclear factor kappa B (NF-κB) inhibition activity of the RAL zearalenone, have attracted great attention as potential therapeutics for cancer treatment. In this minireview, we focus on natural RALs that possess cytotoxic activities [IC 50 values < 10 μM (or 4–5 μg/ml)], discussing their structures, isolation, occurrence, biological activities, and anticancer molecular mechanisms. [ABSTRACT FROM AUTHOR]

Head and neck cancer (HNC) is the sixth most common cancer type, accounting for approximately 277,597 deaths worldwide. Recently, the Food and Drug Administration (FDA) has approved immune checkpoint blockade (ICB) agents targeting programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) as a treatment regimen for head and neck squamous cell carcinomas (HNSCC). Studies have reported the role of immune checkpoint inhibitors as targeted therapeutic regimens that unleash the immune response against HNSCC tumors. However, the overall response rates to immunotherapy vary between 14–32% in recurrent or metastatic HNSCC, with clinical response and treatment success being unpredictable. Keeping this perspective in mind, it is imperative to understand the role of T cells, natural killer cells, and antigen-presenting cells in modulating the immune response to immunotherapy. In lieu of this, these immune molecules could serve as prognostic and predictive biomarkers to facilitate longitudinal monitoring and understanding of treatment dynamics. These immune biomarkers could pave the path for personalized monitoring and management of HNSCC. In this review, we aim to provide updated immunological insight on the mechanism of action, expression, and the clinical application of immune cells' stimulatory and inhibitory molecules as prognostic and predictive biomarkers in HNC. The review is focused mainly on CD27 and CD137 (members of the TNF-receptor superfamily), natural killer group 2 member D (NKG2D), tumor necrosis factor receptor superfamily member 4 (TNFRSF4 or OX40), S100 proteins, PD-1, PD-L1, PD-L2, T cell immunoglobulin and mucin domain 3 (TIM-3), cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), indoleamine-pyrrole 2,3-dioxygenase (IDO), B and T lymphocyte attenuator (BTLA). It also highlights the importance of T, natural killer, and antigen-presenting cells as robust biomarker tools for understanding immune checkpoint inhibitor-based treatment dynamics. Though a comprehensive review, all aspects of the immune molecules could not be covered as they were beyond the scope of the review; Further review articles can cover other aspects to bridge the knowledge gap. [Display omitted] • Diversity of immune checkpoints molecules exert modulatory role in the response to Immune checkpoint inhibitors. • T, natural killer, and antigen-presenting cells can serve as predictive and prognostic biomarker tools. • Clinical trials on immune molecules to improve response rate and enhancing the anti-tumor response are underway in HNSCC. [ABSTRACT FROM AUTHOR]

The correlation between chronic inflammation and cancer was initially identified in the 19th century. Biomolecules like interleukins, chemokines, tumor necrosis factors, growth factors, and adhesion molecules, which regulate inflammation, are recognized contributors to neoplastic transformation through various mechanisms, including oncogenic mutations, resistance to apoptosis, and adaptive responses like angiogenesis. This review aims to establish connections between the intricate and complex mechanisms of chronic inflammation and cancer. We illuminate implicit signaling mechanisms that drive the association between chronic inflammation and the initiation/progression of cancer, exploring potential impacts on other diseases. Additionally, we discuss the modalities of currently available therapeutic options for chronic inflammation and cancer, emphasizing the dual nature of such therapies. A thorough understanding of the molecular basis of chronic inflammation is crucial for developing novel approaches in the prevention and treatment of cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Breast cancer remains a major global health challenge. Its rising incidence is attributed to factors such as delayed diagnosis, the complexity of its subtypes, and increasing drug resistance, all contributing to less-than-ideal patient outcomes. Central to the progression of breast cancer are epigenetic aberrations, which significantly contribute to drug resistance and the emergence of cancer stem cell traits. These include alterations in DNA methylation, histone modifications, and the expression of non-coding RNAs. Understanding these epigenetic changes is crucial for developing advanced breast cancer management strategies despite their complexity. Investigating these epigenetic modifications offers the potential for novel diagnostic markers, more accurate prognostic indicators, and the identification of reliable predictors of treatment response. This could lead to the development of new targeted therapies. However, this requires sustained, focused research efforts to navigate the challenges of understanding breast cancer carcinogenesis and its epigenetic underpinnings. A deeper understanding of epigenetic mechanisms in breast cancer can revolutionize personalized medicine. This could lead to significant improvements in patient care, including early detection, precise disease stratification, and more effective treatment options. [ABSTRACT FROM AUTHOR]

Previous studies have established the role of Na+/H+ exchanger isoform-1 (NHE1) and cathepsin B (Cat B) in the development of cardiomyocyte hypertrophy (CH). Both NHE1 and Cat B are activated under acidic conditions suggesting that their activities might be interrelated. The inhibition of NHE1 has been demonstrated to reduce cardiac hypertrophy but the mechanism that contributes to the anti-hypertrophic effect of NHE1 inhibition still remains unclear. H9c2 cardiomyoblasts were stimulated with Angiotensin (Ang) II in the presence and absence of N-[2-methyl-4,5-bis(methylsulphonyl)-benzoyl]-guanidine, hydrochloride (EMD, EMD 87580), an NHE1 inhibitor or CA-074Me, a Cat B inhibitor, and various cardiac hypertrophic parameters, namely cell surface area, protein content and atrial natriuretic peptide (ANP) mRNA were analyzed. EMD significantly suppressed markers of cardiomyocyte hypertrophy and inhibited Ang II stimulated Cat B protein and gene expression. Cat B is located within the acidic environment of lysosomes. Cat B proteases are released into the cytoplasm upon disintegration of the lysosomes. EMD or CA-074Me prevented the dispersal of the lysosomes induced by Ang II and reduced the ratio of LC3-II to LC3-I, a marker of autophagy. Moreover, Cat B protein expression and MMP-9 activity in the extracellular space were significantly attenuated in the presence of EMD or CA-074Me. Our study demonstrates a novel mechanism for attenuation of the hypertrophic phenotype by NHE1 inhibition that is mediated by a regression in Cat B. The inhibition of Cat B via EMD or CA-074Me attenuates the autosomal-lysosomal pathway and MMP-9 activation. [ABSTRACT FROM AUTHOR]

Microbially induced calcium carbonate precipitation (MICP) is a process that has emerged as an alternative and sustainable ground improvement approach in geotechnical and civil engineering for improving the mechanical properties of soil. Urease-producing bacteria accelerate the process of MICP by converting urea into ammonium and carbonates ions. Precipitated CaCO 3 acts as a binder to adjacent soil particles, forming larger aggregates that eventually lead to increased soil strength and stiffness. In this review, we explore the importance of MICP to improve the mechanical properties of soil so that it will be more suitable for construction and environmental purposes. Furthermore, different treatment processes and environmental factors are also discussed that affect the production of urease and carbonate precipitation. This method has many features as compared to the conventional methods. For example, it is eco-friendly, improves vegetation, bears the lower operational cost, and is sustainable. MICP is mostly studied for lab-scale and limited to field-scale application. In order to achieve its large-scale application in natural and engineered conditions, we need to encourage collaboration among the microbiologists, geologists, and geotechnical engineers throughout the world. Unlabelled Image • This review demonstrates the ubiquitous problem of soil and the application of MICP with ureolysis for soil stabilization. • Mostly microorganisms are able to precipitate CaCO 3 , however, S. pasteurii is often preferred organism for MICP process. • Different environmental factors would significantly affect the process of MICP. • The use of low-grade reagents may lead the process of MICP very cheaply for field-scale implementation. • The process of MICP has shown a promise and countless prospective for both lab-scale and field-scale applications. [ABSTRACT FROM AUTHOR]

Resistance in cancer cells to therapeutic measures is challenging and requires a rigorous delineation of the underlying mechanisms. Emerging findings reflect the characteristics of tumor cells to do the reprogramming of signaling machinery in order to overturn the therapeutic responses. Recent evidence shows that the tumor acquires drug resistance due to the presence of cancer stem cells (CSCs). Hence the understanding that how tumor cells reprogram their signaling mechanisms converging towards the stemness of CSCs is imperative for novel and effective therapy. This review outlines the current updates on how CSC-associated signaling pathways and its enhanced stemness trigger the development of drug resistance. Furthermore, we also discussed the strategies with a combinational approach that can simultaneously target both CSC-induced stemness and the resistance-related signaling pathways, which may provide an optimal outcome to overcome the problem of drug resistance in cancer therapy. [ABSTRACT FROM AUTHOR]

The High-Mobility Group Box-1 (HMGB1), a non-histone chromatin-associated protein, plays a crucial role in cancer growth and response to therapy as it retains a pivotal role in promoting both cell death and survival. HMGB1 has been reported to regulate several signaling pathways engaged in inflammation, genome stability, immune function, cell proliferation, cell autophagy, metabolism, and apoptosis. However, the association between HMGB1 and cancer is complex and its mechanism in tumorigenesis needs to be further elucidated. This review aims to understand the role of HMGB1 in human malignancies and discuss the signaling pathways linked to this process to provide a comprehensive understanding on the association of HMGB1 with carcinogenesis. Further, we will review the role of HMGB1 as a target/biomarker for cancer therapy, the therapeutic strategies used to target this protein, and its potential role in preventing or treating cancers. In light of the recent growing evidence linking HMGB1 to cancer progression, we think that it may be suggested as a novel and emergent therapeutic target for cancer therapy. Hence, HMGB1 warrants paramount investigation to comprehensively map its role in tumorigenesis. [Display omitted] • HMGB1 plays a crucial role in tumor growth and response to therapy and promotes both cell death and survival. • HMGB1 involves different pathways associated with cancer development and progression. • HMGB1 inhibition can enhance response to immune checkpoint blockade in cancer. • HMGB1 is a novel and emergent therapeutic target for cancer prevention and treatment. [ABSTRACT FROM AUTHOR]

Paraneoplastic syndromes are complex clinical manifestations that occur because of the underlying malignancy in which the malignant cells produce hormones, cytokines, peptides or antibodies that causes symptoms and may affect multiple organ systems. These paraneoplastic conditions may be associated with different solid and hematological malignancies. Multiple Myeloma (MM) accounts for 10–15 % of hematological malignancies and 1–2 % of all malignancies. It is associated with some atypical clinical and laboratory paraneoplastic manifestations. Although there is a low incidence of these paraneoplastic, significant knowledge of these manifestations may assist in making a differential diagnosis in cases of doubt. The clinical presentation may vary and be evident even before or after the diagnosis of malignancy. These include vascular, neurological, dermatological, physiological, and other atypical conditions. Furthermore, these rare paraneoplastic manifestations need more valid, relevant scientific information, as most information about these conditions is derived from case reports. After the literature search, we have reported the paraneoplastic manifestations associated with multiple myeloma, published in the English literature, and the cognate management in this review article. To our knowledge, this is the first review article discussing various paraneoplastic manifestations of multiple myeloma. [ABSTRACT FROM AUTHOR]

Suppressing glutaminolysis does not always induce cancer cell death in glutamine dependent tumors because cells may switch to alternative energy sources. To reveal compensatory metabolic pathways, we investigated the metabolome-wide cellular response to inhibited glutaminolysis in cancer cells. Glutaminolysis inhibition with C.968 suppressed cell proliferation but was insufficient to induce cancer cell death. We found that lipid catabolism was activated as a compensation for glutaminolysis inhibition. Accelerated lipid catabolism, together with oxidative stress induced by glutaminolysis inhibition, triggered autophagy. Simultaneously inhibiting glutaminolysis and either beta oxidation with trimetazidine or autophagy with chloroquine both induced cancer cell death. Here we identified metabolic escape mechanisms contributing to cancer cell survival under treatment and we suggest potentially translational strategy for combined cancer therapy, given that chloroquine is an FDA approved drug. Our findings are first to show efficiency of combined inhibition of glutaminolysis and beta oxidation as potential anti-cancer strategy as well as add to the evidence that combined inhibition of glutaminolysis and autophagy may be effective in glutamine-addicted cancers. [ABSTRACT FROM AUTHOR]

More information about a person's genetic makeup, drug response, multi-omics response, and genomic response is now available leading to a gradual shift towards personalized treatment. Additionally, the promotion of non-animal testing has fueled the computational toxicogenomics as a pivotal part of the next-gen risk assessment paradigm. Artificial Intelligence (AI) has the potential to provid new ways analyzing the patient data and making predictions about treatment outcomes or toxicity. As personalized medicine and toxicogenomics involve huge data processing, AI can expedite this process by providing powerful data processing, analysis, and interpretation algorithms. AI can process and integrate a multitude of data including genome data, patient records, clinical data and identify patterns to derive predictive models anticipating clinical outcomes and assessing the risk of any personalized medicine approaches. In this article, we have studied the current trends and future perspectives in personalized medicine & toxicology, the role of toxicogenomics in connecting the two fields, and the impact of AI on personalized medicine & toxicology. In this work, we also study the key challenges and limitations in personalized medicine, toxicogenomics, and AI in order to fully realize their potential. [Display omitted] • Established the relationship between personalized medicine and toxicology. • Outlined the importance of artificial intelligence in the current clinical decision-making process. • Overview of the various bottlenecks in artificial intelligence applications. • Provided a roadmap to future researchers on integrating precision medicine, toxicology and artificial intelligence. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most common solid malignancies. Tissue biopsy is the standard method for accurately diagnosing lung and many other malignancies over decades. However, molecular profiling of tumors leads to establishing a new horizon in the field of precision medicine, which has now entered the mainstream in clinical practice. In this context, a minimally invasive complementary method has been proposed as a liquid biopsy (LB) which is a blood-based test that is gaining popularity as it provides the opportunity to test genotypes in a unique, less invasive manner. Circulating tumor cells (CTC) captivating the Circulating-tumor DNA (Ct-DNA) are often present in the blood of lung cancer patients and are the fundamental concept behind LB. There are multiple clinical uses of Ct-DNA, including its role in prognostic and therapeutic purposes. The treatment of lung cancer has drastically evolved over time. Therefore, this review article mainly focuses on the current literature on circulating tumor DNA and its clinical implications and future goals in non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) present pivotal roles in cancer tumorigenesis and progression. Recently, nuclear paraspeckle assembly transcript 1 (NEAT1) as a lncRNA has been shown to mediate cell proliferation, migration, and EMT in tumor cells. NEAT1 by targeting several miRNAs/mRNA axes could regulate cancer cell behavior. Therefore, NEAT1 may function as a potent biomarker for the prediction and treatment of some human cancers. In this review, we summarized various NEAT1-related signaling pathways that are critical in cancer initiation and progression. [ABSTRACT FROM AUTHOR]

Vitamin C is an important nutrient implicated in different physiological functions in humans. Despite its important biological functions, therapeutic applications of vitamin C are rare and its use is further impacted by low chemical stability. Several nano-encapsulation techniques have been described in the literature and yet, there are only a handful of clinical investigations dedicated to unlocking the therapeutic applications of nano-encapsulated vitamin C. Clearly, further investigations are warranted in order to affirm the promising clinical potential of nano-encapsulated vitamin C. In this review, we describe the mechanisms of vitamin C activity as a modulator of crucial therapeutic uses in biological systems. We look at key factors affecting the chemical stability of vitamin C alone and in nano-encapsulated and explore pre-clinical and clinical evidence on current vitamin C nano-formulations along with their therapeutic applications. Finally, we critically appraise the gaps and opportunities prevailing in nano-vitamin C research and its potential translation towards relevant clinical outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]

Glioma is the most common malignant brain tumor that develops in the glial tissue. Several studies have identified that glioma cancer stem cells (GCSCs) play important roles in tumor-initiating features in malignant gliomas. GCSCs are a small population in the brain that presents an essential role in the metastasis of glioma cells to other organs. These cells can self-renew and differentiate, which are thought to be involved in the pathogenesis of glioma. Therefore, targeting GCSCs might be a novel strategy for the treatment of glioma. Accumulating evidence revealed that several signaling pathways, including Notch, TGF-β, Wnt, STAT3, AKT, and EGFR mediated GCSC growth, proliferation, migration, and invasion. Besides, non-coding RNAs (ncRNAs), including miRNAs, circular RNAs, and long ncRNAs have been found to play pivotal roles in the regulation of GCSC pathogenesis and drug resistance. Therefore, targeting these pathways could open a new avenue for glioma management. In this review, we summarized critical signaling pathways involved in the stimulation or prevention of GCSCs tumorigenesis and invasiveness. • Glioma cancer stem cells (GCSCs) are tumor-initiating cells. • GCSCs can promote tumor growth, invasion and metastasis. • Several signaling pathways are involved in GCSCs proliferation and tumorigenesis. • Some miRNAs can suppress the pathogenesis of GCSCs. • · Long non-coding RNAs play pivotal roles in GCSCs tumorigenesis. [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma is a frequent skin cancer still demanding to understand the underlying mechanisms for better clinical outcomes. Pristimerin, a natural quinonemethide triterpenoid , has shown promising therapeutic outcome due to its anti-cancer activity and multi-targeting potential. We explored the underlying mechanisms of pristimerin-induced programmed cell death of primary (A431) and metastatic (A388) cutaneous squamous cell carcinoma (cSCC) cells. Our results show that pristimerin inhibits growth and proliferation of cSCC through JNK activation. Moreover, pristimerin causes cell cycle arrest and induces cell death via apoptosis and autophagy. Interestingly, use of apoptosis (z-VAD-FMK) and autophagy (3-methyladenine) inhibitors confirmed vital role of programmed cell death in pristimerin-mediated anti-cancer actions. JNK inhibitor, SP600125, also mitigated pristimerin-induced apoptotic and autophagic actions. Moreover, pristimerin-mediated anti-cancer activity acts by generating reactive oxygen species (ROS) thereby inducing JNK signaling. Use of N-acetyl cystine (NAC), a universal ROS scavenger, significantly reversed pristimerin-induced programmed cell death through downregulation of JNK. Pristimerin sensitized skin cancer cells to conventional anticancer drugs cisplatin, azacytidine and doxorubicin through JNK activation, as confirmed by SP600125. Our results indicate that pristimerin mediates programmed cell death and sensitized skin cancer cells to conventional anti-cancer drugs via ROS-mediated JNK activation. [Display omitted] • Skin cancer is one of the most common human cancer with increasing challenges. • Pristimerin has shown promising therapeutic outcome due its multi-targeting potential. • Pristimerin induces programmed cell death via ROS-mediated JNK activation. • Pristimerin sensitized skin cancer cells to conventional anti-cancer drugs. • Pristimerin attenuated stemness markers in skin cancer cells. [ABSTRACT FROM AUTHOR]

Curcumin (CUR) manifests anti-colon cancer activity but suffers from low solubility, bioavailability, and instability, rendering it not as effective as its chemotherapeutic cousins. Here, we conjugate CUR to succinic anhydride (SA), (CUR.SA conjugate), subsequently formulated in mannose-conjugated chitosan nanoparticles (CUR-NPs and CUR.SA-NPs). Instrumental analyses confirmed formation of CUR.SA and mannosylated chitosan (CM) conjugates, with CUR.SA being less crystalline thus, more soluble. Average particle size of CUR-NPs and CUR.SA-NPs were 268 ± 6 nm and 342 ± 4.6 nm, with drug entrapment of 93.34 ± 0.40 % and 98.46 ± 0.06 % respectively. In vitro releases of CUR and CUR.SA from nanoparticles in pH 1.2 and 6.8 media were slow and sustained over 2 h and 72 h, respectively. The physical characteristics of the nanoparticles were unchanged over 3 weeks of storage. Thus, a successful CUR.SA conjugate has been developed, couriered in CM nanoparticles, with favorable attributes that warrant further anti-colon cancer studies, which is ongoing. [Display omitted] [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) or hepatoma is malignant cancer that starts from the main liver cells. Although various classical methods have been used for patients with HCC, various molecular mechanisms involved in HCC progression should be invested. Previous studies demonstrated that abnormal expression of long non-coding RNAs (lncRNAs) presented important roles in the pathogenesis of HCC cells. LncRNA TUG1 was found to mediate HCC cell growth, EMT, and metastasis. Therefore, targeting TUG1 and its downstream genes may be a suitable approach for patients with HCC. In this review, we summarized the potential roles of TUG1 in HCC. [Display omitted] [ABSTRACT FROM AUTHOR]

Cancer is a devastating disease and is the second leading cause of death worldwide. Surgery, chemotherapy (CT), and/or radiation therapy (RT) are the treatment of choice for most advanced tumors. Unfortunately, treatment failure due to intrinsic and acquired resistance to the current CT and RT is a significant challenge associated with poor patient prognosis. There is an urgent need to develop and identify agents that can sensitize tumor cells to chemo-radiation therapy (CRT) with minimal cytotoxicity to the healthy tissues. While many recent studies have identified the underlying molecular mechanisms and therapeutic targets for CRT failure, using small molecule inhibitors to chemo/radio sensitize tumors is associated with high toxicity and increased morbidity. Natural products have long been used as chemopreventive agents in many cancers. Combining many of these compounds with the standard chemotherapeutic agents or with RT has shown synergistic effects on cancer cell death and overall improvement in patient survival. Based on the available data, there is strong evidence that natural products have a robust therapeutic potential along with CRT and their well-known chemopreventive effects in many solid tumors. This review article reports updated literature on different natural products used as CT or RT sensitizers in many solid tumors. This is the first review discussing CT and RT sensitizers together in cancer. [Display omitted] • Even though chemo and radiotherapy represent an essential component of cancer treatment, most cancer patients experience harmful side effects. • Several agents are utilized in clinical settings to boost the effectiveness of chemo and radiotherapy while reducing normal tissue toxicity. • Agents that enhance chemo or radiation-induced tumor cell killing or protect normal tissues from side effects are termed modifiers or sensitizers. • Natural‐based alternatives with less toxicity and their ability to sensitize tumor cells are in dire need. [ABSTRACT FROM AUTHOR]

Skin, the largest vital organ of the human body, provides the first line of defense against biological, non-biological and xenobiotics exposure. Over the years, due to increased anthropogenic activities including industrialization and pollution, a steep increase in cutaneous pathological conditions such as malignancies, dermatitis, and psoriasis has been detected. Indeed, due to the complex nature of cutaneous inflammatory diseases, further investigations are required to produce a better outcome in patient care. However, research obtained over the last few decades has revolutionized the understanding of cutaneous disease pathogenesis and therapeutic developments. In this line, increasing data from pre-clinical and clinical studies implicates the crucial role of oxidative stress in pathogenesis and complications of cutaneous inflammatory diseases, including atopic dermatitis and psoriasis. Taking into consideration the current challenge, this review aims to highlight the novel updates exploring reactive oxygen species (ROS) induced mechanistic signaling mechanisms in conjunction with pathways converging towards atopic dermatitis and psoriasis. Additionally, an exploration of the clinical importance of natural products for management of cutaneous diseases has been included. Overall, this review highlights the therapeutic importance of targeting oxidative stress in the pathogenesis, symptoms, and complications of inflammatory diseases of the skin. [Display omitted] • Cutaneous inflammatory diseases are the major concern for the dermatologist. • Oxidative and inflammatory mediators are critical in inflammatory diseases. • Aberrant signaling pathways of immune regulation drives skin disease pathogenesis. • Natural and synthetic products have shown promising outcomes. • Targeting deregulated signaling may provide positive clinical outcomes. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of death and significantly burdens the healthcare system. Due to its prevalence, there is undoubtedly an unmet need to discover novel anticancer drugs. The use of natural products as anticancer agents is an acceptable therapeutic approach due to accessibility, applicability, and reduced cytotoxicity. Natural products have been an incomparable source of anticancer drugs in the modern era of drug discovery. Along with their derivatives and analogs, natural products play a major role in cancer treatment by modulating the cancer microenvironment and different signaling pathways. These compounds are effective against several signaling pathways, mainly cell death pathways (apoptosis and autophagy) and embryonic developmental pathways (Notch pathway, Wnt pathway, and Hedgehog pathway). The historical record of natural products is strong, but there is a need to investigate the current role of natural products in the discovery and development of cancer drugs and determine the possibility of natural products being an important source of future therapeutic agents. Many target-specific anticancer drugs failed to provide successful results, which accounts for a need to investigate natural products with multi-target characteristics to achieve better outcomes. The potential of natural products to be promising novel compounds for cancer treatment makes them an important area of research. This review explores the significance of natural products in inhibiting the various signaling pathways that serve as drivers of carcinogenesis and thus pave the way for developing and discovering anticancer drugs. [Display omitted] [ABSTRACT FROM AUTHOR]

Vitamin C also known as L -ascorbic acid is a nutrient naturally occurring in many fruits and vegetables and widely known for its potent antioxidant activity. Several studies have highlighted the importance of using high dose vitamin C as an adjuvant anti-cancer therapy. Interestingly, it has been shown that vitamin C is able to modulate the anti-cancer immune response and to help to overcome the resistance to immune checkpoints blockade (ICB) drugs such as cytotoxic T-lymphocyte antigen 4 (CLTA-4) and programmed cell death ligand 1 (PD-L1/PD-1) inhibitors. Indeed, it was reported that vitamin C regulates several mechanisms developed by cancer cells to escape T cells immune response and resist ICB. Understanding the role of vitamin C in the anti-tumor immune response will pave the way to the development of novel combination therapies that would enhance the response of cancer patients to ICB immunotherapy. In this review, we discuss the effect of vitamin C on the immune system and its potential role in empowering cancer immunotherapy through its pro-oxidant potential, its ability to modulate epigenetic factors and its capacity to regulate the expression of different cytokines involved in the immune response. [Display omitted] • Vitamin C is a powerful molecule with pleiotropic functions. • It exerts an anti-cancer effect by inducing oxidative stress, and regulating epigenetic factors and cytokines secretion. • It has been involved in different pathways known to modulate the anti-tumor immune response. • It might enhance the response to immune checkpoint inhibitors in cancer patients. • Vitamin C would represent a good candidate as an adjuvant to cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract: We provide evidence that thymoquinone (TQ), a natural compound isolated from Nigella sativa, induces growth inhibition and apoptosis in several primary effusion lymphoma (PEL) cell lines. Our data demonstrate that TQ treatment results in down-regulation of constitutive activation of AKT via generation of reactive oxygen species (ROS) and it causes conformational changes in Bax protein, leading to loss of mitochondrial membrane potential and release of cytochrome c to the cytosol. This leads to activation of caspase-9, caspase-3, and polyadenosine 5′-diphosphate ribose polymerase cleavage, leading to caspase-dependent apoptosis. Pretreatment of PEL cells with N-acetylcysteine, a scavenger of ROS, prevented TQ-mediated effects. In addition, subtoxic doses of TQ sensitized PEL cells to TRAIL via up-regulation of DR5. Altogether, these findings demonstrate that TQ is a potent inducer of apoptosis in PEL cells via release of ROS. They also raise the possibility that incorporation of TQ in treatment regimens for primary effusion lymphomas may provide a novel approach to sensitizing malignant cells and provide a molecular basis for such future translational efforts. [Copyright &y& Elsevier]

Effective treatment of lung cancer remains a significant clinical challenge due to its multidrug resistance and side effects of the current treatment options. The high mortality associated with this malignancy indicates the need for new therapeutic interventions with fewer side effects. Natural compounds offer various benefits such as easy access, minimal side effects, and multi-molecular targets and thus, can prove useful in treating lung cancer. Sanguinarine (SNG), a natural compound, possesses favorable therapeutic potential against a variety of cancers. Here, we examined the underlying molecular mechanisms of SNG in Non-Small Cell Lung Cancer (NSCLC) cells. SNG suppressed cell growth and induced apoptosis via downregulation of the constitutively active JAK/STAT pathway in all the NSCLC cell lines. siRNA silencing of STAT3 in NSCLC cells further confirmed the involvement of the JAK/STAT signaling cascade. SNG treatment increased Bax/Bcl-2 ratio, which contributed to a leaky mitochondrial membrane leading to cytochrome c release accompanied by caspase activation. In addition, we established the antitumor effects of SNG through reactive oxygen species (ROS) production, as inhibiting ROS production prevented the apoptosis-inducing potential of SNG. In vivo xenograft tumor model further validated our in vitro findings. Overall, our study investigated the molecular mechanisms by which SNG induces apoptosis in NSCLC, providing avenues for developing novel natural compound-based cancer therapies. [Display omitted] • Anticancer effect of SNG on human NSCLC cells has not been fully defined. • JAK/STAT signaling cascade is constitutively activated in NSCLC. • SNG inhibited cell growth and induced apoptosis via JAK/STAT inhibition • SNG induced ROS production in NSCLC cells, causing apoptosis • SNG inhibited the tumor growth in xenograft mice [ABSTRACT FROM AUTHOR]

Reactive oxygen species play crucial role in biological homeostasis and pathogenesis of human diseases including cancer. In this line, now it has become evident that ROS level/concentration is a major factor in the growth, progression and stemness of cancer cells. Moreover, cancer cells maintain a delicate balance between ROS and antioxidants to promote pathogenesis and clinical challenges via targeting a battery of signaling pathways converging to cancer hallmarks. Recent findings also entail the therapeutic importance of ROS for the better clinical outcomes in cancer patients as they induce apoptosis and autophagy. Moreover, poor clinical outcomes associated with cancer therapies are the major challenge and use of natural products have been vital in attenuation of these challenges due to their multitargeting potential with less adverse effects. In fact, most available drugs are derived from natural resources, either directly or indirectly and available evidence show the clinical importance of natural products in the management of various diseases, including cancer. ROS play a critical role in the anticancer actions of natural products, particularly phytochemicals. Benzophenanthridine alkaloids of the benzyl isoquinoline family of alkaloids, such as sanguinarine, possess several pharmacological properties and are thus being studied for the treatment of different human diseases, including cancer. In this article, we review recent findings, on how benzophenanthridine alkaloid-induced ROS play a critical role in the attenuation of pathological changes and stemness features associated with human cancers. In addition, we highlight the role of ROS in benzophenanthridine alkaloid-mediated activation of the signaling pathway associated with cancer cell apoptosis and autophagy. [Display omitted] • Benzophenanthridine alkaloids possess important translational and pharmacological properties. • Benzophenanthridine alkaloids via ROS generation attenuates pathological changes associated with human cancers. • ROS generated by benzophenanthridine alkaloids activates underlying mechanisms converging to apoptosis and autophagy. • Benzophenanthridine alkaloids cab be used in inactivation of cancer stem cells or stemness in cancer progression. [ABSTRACT FROM AUTHOR]

Objective: The mechanisms by which interferon α (IFN-α) induces antileukemic responses in chronic myelogenous leukemia (CML) cells are not known. We examined whether a member of the protein kinase C (PKC) family of proteins, PKC-δ, is activated during treatment of BCR-ABL cells with IFN-α and participates in the induction of interferon responses. Methods: Immunoblots and immune complex kinase assays were performed to study the phosphorylation and activation of PKC-δ in response to IFN-α in CML-derived cell lines. The effects of pharmacological inhibition of PKC-δ on the suppressive effects of IFN-α on leukemic CFU-GM progenitors from CML patients were assessed by clonogenic assays in methylcellulose. Results: IFN-α treatment of the sensitive CML-derived KT-1 cell line resulted in phosphorylation of PKC-δ and activation of its kinase domain. Such phosphorylation/activation of PKC-δ was required for phosphorylation of Stat1 on serine 727, as inhibition of PKC-δ activity blocked the IFN-α–dependent serine phosphorylation of Stat1 and IFN-α–inducible gene transcription. IFN-α treatment strongly inhibited leukemic CFU-GM progenitor colony fromation from bone marrow or peripheral blood of patients with CML, and such inhibition was reversed by concomitant treatment of the cells with the PKC-δ pharmacologic inhibitor rottlerin. Conclusion: Taken altogether, our data demonstrate that PKC-δ plays a critical role in Type I IFN signaling in BCR-ABL expressing cells, acting as a serine kinase for Stat1, to regulate transcriptional activation of interferon-regulated genes and induction of antileukemic responses. [Copyright &y& Elsevier]

All-trans-retinoic acid (RA) is a potent inhibitor of leukemia cell proliferation and induces differentiation of acute promyelocytic leukemia cells in vitro and in vivo. For RA to induce its biological effects in target cells, binding to specific retinoic acid nuclear receptors is required. The resulting complexes bind to RA-responsive elements (RAREs) in the promoters of RA-inducible genes to initiate gene transcription and to generate protein products that mediate the biological effects of RA. In this report, we provide evidence that a member of the protein kinase C (PKC) family of proteins, PKCδ, is activated during RA treatment of the NB-4 and HL-60 acute myeloid leukemia cell lines as well as the MCF-7 breast cancer cell line. Such RA-dependent phosphorylation was also observed in primary acute promyelocytic leukemia cells and resulted in activation of the kinase domain of PKCδ. In studies aimed at understanding the functional relevance of PKCδ in the induction of RA responses, we found that pharmacological inhibition of PKCδ (but not of other PKC isoforms) diminished RA-dependent gene transcription via RAREs. On the other hand, overexpression of a constitutively active form of the kinase strongly enhanced RA-dependent gene transcription via RAREs. Gel shift assays and chromatin immunoprecipitation studies demonstrated that PKCδ associated with retinoic acid receptor-α and was present in an RA-inducible protein complex that bound to RAREs. Pharmacological inhibition of PKCδ activity abrogated the induction of cell differentiation and growth inhibition of NB-4 blast cells, demonstrating that its function is required for such effects. Altogether, our data provide strong evidence that PKCδ is activated in an RA-dependent manner and plays a critical role in the generation of the biological effects of RA in malignant cells. [ABSTRACT FROM AUTHOR]

Tranilast (TRN) or (N-3,4 -dimethoxy cinnamoyl]-anthranilic acid) is an analog of a tryptophan metabolite and is identified mainly as an anti-allergic agent with limited side effects. The anti-cancer effects of tranilast either alone or in combination with chemotherapeutic drugs have been evidenced in several pre-clinical studies. The main mechanism of action of tranilast includes targeting and modulation of various signaling and immune regulatory pathways including Transforming growth factor-beta (TGF-β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphatidylinositol 3-kinase (PI3K), MAP-Kinase (MAPK), Protein kinase B (‎Akt/PKB), c-Jun N-terminal kinase, modulation of cancer stem cells, etc. Most of these pathways are involved in tumor proliferation, invasion, and metastasis and it is postulated that tranilast, with its low toxicity profile and high anti-carcinogenic abilities, can serve as a potential anti-tumorigenic agent. The main aim of this review is to provide updated information on the anti-cancer effects of tranilast and its significance as a therapeutic agent. [Display omitted] • Tranilast is a non-oncology anti-inflammatory drug that exhibits anticancer potential with low toxicity profile. • It modulates TGF-β, inhibits apoptosis, angiogenesis and stemness potential of cancer cells. • Combination treatment with Tranilast improves efficacy of chemotherapeutic and immunotherapeutic drugs. • Tranilast has also shown potential utility in cancer nanomedicine. [ABSTRACT FROM AUTHOR]