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BACKGROUND: Multidrug-resistant (MDR) P. aeruginosa is a rising public health concern, challenging the treatment of such a ubiquitous pathogen with monotherapeutic anti-pseudomonal agents. Worryingly, its genome plasticity contributes to the emergence of P. aeruginosa expressing different resistant phenotypes and is now responsible for notable epidemics within hospital settings. Considering this, we aimed to evaluate the synergistic combination of fortimicin with other traditional anti-pseudomonal agents and to analyze the resistome of pan-drug resistant (PDR) isolate. METHODS: Standard methods were used for analyzing the antimicrobial susceptibility tests. The checkerboard technique was used for the in vitro assessment of fortimicin antibiotic combinations against 51 MDR P. aeruginosa and whole genome sequencing was used to determine the resistome of PDR isolate. RESULTS: Out of 51 MDR P. aeruginosa, the highest synergistic effect was recorded for a combination of fortimicin with ß-lactam group as meropenem, ceftazidime, and aztreonam at 71%, 59% and 43%, respectively. Of note, 56.8%, 39.2%, and 37.2% of the tested MDR isolates that had synergistic effects were also resistant to meropenem, ceftazidime, and aztreonam, respectively. The highest additive effects were recorded for combining fortimicin with amikacin (69%) and cefepime (44%) against MDR P. aeruginosa. Resistome analysis of the PDR isolate reflected its association with the antibiotic resistance phenotype. It ensured the presence of a wide variety of antibiotic-resistant genes (ß-lactamases, aminoglycosides modifying enzymes, and efflux pump), rendering the isolate resistant to all clinically relevant anti-pseudomonal agents. CONCLUSION: Fortimicin in combination with classical anti-pseudomonal agents had shown promising synergistic activity against MDR P. aeruginosa. Resistome profiling of PDR P. aeruginosa enhanced the rapid identification of antibiotic resistance genes that are likely linked to the appearance of this resistant phenotype and may pave the way to tackle antimicrobial resistance issues shortly.
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Antibacterianos , Farmacorresistência Bacteriana Múltipla , Sinergismo Farmacológico , Genoma Bacteriano , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa , Sequenciamento Completo do Genoma , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/isolamento & purificação , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Humanos , Genoma Bacteriano/genética , Infecções por Pseudomonas/microbiologiaRESUMO
Atypical chemokine receptor 4 (ACKR4), also known as CCX-CKR, is a member of the chemokine receptor family that lacks typical G protein signaling activity. Instead, ACKR4 functions as a scavenger receptor that can bind and internalize a wide range of chemokines, influencing their availability and activity in the body. ACKR4 is involved in various physiological processes, such as immune cell trafficking and the development of thymus, spleen, and lymph nodes. Moreover, ACKR4 has been implicated in several pathological conditions, including cancer, heart and lung diseases. In cancer, ACKR4 plays a complex role, acting as a tumor suppressor or promoter depending on the type of cancer and the stage of the disease. For instance, ACKR4 may inhibit the growth and metastasis of breast cancer, but it may also promote the progression of hepatocellular carcinoma and gastric cancer. In inflammatory situations, ACKR4 has been found to modulate the recruitment and activation of immune cells, contributing to the pathogenesis of diseases such as myocardial infraction and pulmonary sarcoidosis. The study of ACKR4 is still ongoing, and further research is needed to fully understand its role in different physiological and pathological contexts. Nonetheless, ACKR4 represents a promising target for the development of novel therapeutic strategies for various diseases.
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Neoplasias da Mama , Transdução de Sinais , Feminino , HumanosRESUMO
Mesenchymal stem cell-derived exosomes (MSC-Exos) are emerging as remarkable agents in the field of immunomodulation with vast potential for diagnosing and treating various diseases, including cancer and autoimmune disorders. These tiny vesicles are laden with a diverse cargo encompassing proteins, nucleic acids, lipids, and bioactive molecules, offering a wealth of biomarkers and therapeutic options. MSC-Exos exhibit their immunomodulatory prowess by skillfully regulating pattern-recognition receptors (PRRs). They conduct a symphony of immunological responses, modulating B-cell activities, polarizing macrophages toward anti-inflammatory phenotypes, and fine-tuning T-cell activity. These interactions have profound implications for precision medicine, cancer immunotherapy, autoimmune disease management, biomarker discovery, and regulatory approvals. MSC-Exos promises to usher in a new era of tailored therapies, personalized diagnostics, and more effective treatments for various medical conditions. As research advances, their transformative potential in healthcare becomes increasingly evident.
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Exossomos , Células-Tronco Mesenquimais , Receptores de Reconhecimento de Padrão , Humanos , Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/citologia , Receptores de Reconhecimento de Padrão/metabolismo , Animais , ImunomodulaçãoRESUMO
Cancer is a significant global health concern that has a major impact on morbidity and mortality worldwide. Research has demonstrated the involvement of Interleukin-1 beta (IL1ß) in various aspects of cancer development and progression, including angiogenesis, tumor growth and metastasis. Consequently, targeting IL1ß activity represents a promising approach for cancer therapeutics. In this study, we utilized molecular docking and MD simulations to discover potent IL1ß inhibitors for the treatment of cancer. Five thousand compounds from ZINC15 database were screened against IL1ß target, and the top ten small molecules were selected based on their binding energy. The small molecule named 'ZINC08101049' was prioritized based on binding energy (-9.1 kcal/Mol) and residual interaction specifically forming seven hydrogen bonds with amino acid residues namely GLN81, GLY136, LEU134, LYS138, SER84, THR137 and TYR24 of IL1ß. Next, IL1ß alone and in complex with ZINC08101049 was subjected to MD simulations to determine their behavior at atomic level. The results of molecular docking and MD simulation revealed ZINC08101049 as a potential inhibitor of IL1ß, reflecting that ZINC08101049 can emerge as a promising small molecule paving for cancer therapeutics.Communicated by Ramaswamy H. Sarma.
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Unlike simple molecular screening, a combined hybrid computational methodology has been applied which includes quantum chemical methods, molecular docking, and molecular dynamics simulations to design some novel ketonic derivatives. The current study contains the derivatives of an experimental ligand which are designed as a trade-off between drug likeness and inhibition strength. We investigate the interaction of various newly designed ketonic compounds with the breast cancer receptor known as the Estrogen Receptor Alpha (ERα). The molecular structures of all newly designed ligands were studied quantum chemically in terms of their fully optimized structures, 3-D molecular orbital distributions, global chemical descriptors, molecular electrostatic potentials and energies of frontier molecular orbitals (FMOs). All ligands under study show good binding affinities with the ERα protein. The ligands CMR2 and CMR4 exhibit improved molecular docking interactions. The intermolecular interactions indicate that CMR4 demonstrates better hydrophobic and hydrogen bonding interactions with protein (ERα). Furthermore, molecular dynamics simulations were conducted on ligands and reference drugs interacting with the ERα protein over a time span of 120 nanoseconds. The molecular dynamics results are interpreted in terms of ligand-protein stability and flexible behaviour based on their respective values of RMSD, RMSF, H-bonds, the radius of gyration, and SASA graphs. To analyse ligand-protein interactions throughout the entire 120â¯ns trajectory, a more advanced MM/PBSA method is utilized, where six selected ligands (CMR1, CMR2, CMR3, CMR4, CMR5 and CMR9) illustrate promising results for inhibition of the ERα receptor as assessed through MM/BBSA analysis. The CMR9 has the highest MM/BBSA binding free energy (-14.46â¯kcal/mol). The ADMET analysis reveals that CMR4 has maximum intestinal absorption (6.68) and clearance rate (0.1). All the compounds are non-toxic and safe to use. These findings indicate the potential of involving different computational techniques to design the ligand structures and to study the ligand-protein interactions for better understanding and achieving more potent synthetic inhibitors for breast cancer.
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Neoplasias da Mama , Receptor alfa de Estrogênio , Humanos , Feminino , Simulação de Acoplamento Molecular , Neoplasias da Mama/tratamento farmacológico , Ligantes , Simulação de Dinâmica MolecularRESUMO
Aim: To correlate hematological, inflammatory indicators and serological responses among COVID-19 patients to point out the significant biomarkers for disease management and prognosis.Materials & methods: Standard analytical and molecular methods were used to assess various inflammatory and serological Responses among COVID-19 patients (ICU- (n = 99) and non-ICU patients (n = 64) as compared with health control (n = 40).Results: Significant differences in the Hb, WBC, Lymphocyte count, CRP and serum ferritin (p < 0.05) were observed. Patients' IgM/IgG antibodies against SARS-CoV-2 were associated with increased CRP, LDH and serum ferritin levels.Conclusion: A significant association between serum IgG/IgM and ICU admission was observed. Although serum ferritin and LDH can offer information about the extent of inflammation, they are exclusive factors for ICU admission.
This study aimed to find the best biomarkers among COVID-19 patients to be used as indicators of patient eligibility for admission to the intensive care unit and for evaluating the disease complications and proper intervention before cases deteriorated. For the COVID-19 as compared with healthy individuals, results showed significant differences in many hematological indicators such as hemoglobin level, white blood cells and Lymphocyte count. Results also showed a strong correlation between certain serum antibody levels against COVID-19 and admission to intensive care unit.
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Tuberculosis (T.B.) remains a prominent global cause of health challenges and death, exacerbated by drug-resistant strains such as multidrug-resistant tuberculosis MDR-TB and extensively drug-resistant tuberculosis XDR-TB. For an effective disease management strategy, it is crucial to understand the dynamics of T.B. infection and the impacts of treatment. In the present article, we employ AI-based machine learning techniques to investigate the immunity impact of medications. SEIPR epidemiological model is incorporated with MDR-TB for compartments susceptible to disease, exposed to risk, infected ones, preventive or resistant to initial treatment, and recovered or healed population. These masses' natural trends, effects, and interactions are formulated and described in the present study. Computations and stability analysis are conducted upon endemic and disease-free equilibria in the present model for their global scenario. Both numerical and AI-based nonlinear autoregressive exogenous NARX analyses are presented with incorporating immediate treatment and delay in treatment. This study shows that the active patients and MDR-TB, both strains, exist because of the absence of permanent immunity to T.B. Furthermore, patients who have recovered from tuberculosis may become susceptible again by losing their immunity and contributing to transmission again. This article aims to identify patterns and predictors of treatment success. The findings from this research can contribute to developing more effective tuberculosis interventions.
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The Middle East has witnessed a greater spread of infectious Dengue viruses, with serotype 2 (DENV-2) being the most prevalent form. Through this work, multi-epitope peptide vaccines against DENV-2 that target E and nonstructural (NS1) proteins were generated through an immunoinformatic approach. MHC class I and II and LBL epitopes among NS1 and envelope E proteins sequences were predicted and their antigenicity, toxicity, and allergenicity were investigated. Studies of the population coverage denoted the high prevalence of NS1 and envelope-E epitopes among different countries where DENV-2 endemic. Further, both the CTL and HTL epitopes retrieved from NS1 epitopes exhibited high conservancies' percentages with other DENV serotypes (1, 3, and 4). Three vaccine constructs were created and the expected immune responses for the constructs were estimated using C-IMMSIM and HADDOCK (against TLR 2,3,4,5, and 7). Molecular dynamics simulation for vaccine construct 2 with TLR4 denoted high binding affinity and stability of the construct with the receptor which might foretell favorable in vivo interaction and immune responses.
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Vacinas contra Dengue , Vírus da Dengue , Dengue , Sorogrupo , Vacinas de Subunidades Antigênicas , Proteínas não Estruturais Virais , Vírus da Dengue/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Vacinas contra Dengue/imunologia , Humanos , Dengue/prevenção & controle , Dengue/imunologia , Dengue/virologia , Proteínas não Estruturais Virais/imunologia , Biologia Computacional/métodos , Epitopos de Linfócito T/imunologia , Proteínas do Envelope Viral/imunologia , Simulação de Dinâmica Molecular , Epitopos/imunologia , Epitopos/química , Vacinas de Subunidades ProteicasRESUMO
The sugarcane industry often utilizes effluent for irrigation purposes; however, its intricate composition and elevated metal contaminants pose a potential risk of soil and crop contamination. Consequently, it is imperative to employ effective strategies to ensure the safe utilization of this resource for crop cultivation. One such strategy involves the dilution of sugarcane industry effluent. Dilution is a practical approach to mitigate its toxicity, minimizing its adverse impact on soil and crop health. That's why the current study explored the best dilution of sugarcane industrial effluent (SW) for cultivating canola varieties. A total of 15 canola varieties were cultivated 0%, 20%, 40%, 60%, 80%, and 100% SW. Results showed that 60% SW Faisalabad Canola and Punjab Canola improved germination, shoot length, root length, shoot fresh and dry weight, root fresh and dry weight, and chlorophyll contents compared to other treatments and control. AARI Canola and CON-III showed poor growth and chlorophyll contents under 60%SW. Dunkled and Oscar cultivars showed moderate improvement in growth and chlorophyll contents under 60SW. The 60% SW can be recommended for maximum growth benefits in canola cultivars, specifically Faisalabad Canola and Punjab Canola. At 20SW, the root dry weight of Faisalabad Canola increased by 2.7%, while Punjab Canola increased by 3.4%. Canola showed the highest increase in POD activity compared to the control, with a 55.45% increase, followed by Sandal Canola, with a 43.26% increase. However, additional field-level experiments are needed to determine the best cultivars suitable for optimal growth under 80SW and 60SW irrigation conditions.
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Brassica napus , Saccharum , Antioxidantes , Terapia Comportamental , Clorofila , SoloRESUMO
Echinococcus granulosus is a zoonotic parasite infects many livestock species, especially cattle, sheep, goat and buffalo, causing cystic echinococcosis. The aim of this study was to demonstrate the presence of the parasite and parasitic tissue damage histopathologically and to determine the role of oxidative stress in the tissue damage through the immunohistochemical detection of the oxidative damage-marker malondialdehyde (MDA) and the antioxidant response-marker superoxide dismutase (SOD). The material of the study consisted of 20 liver samples with Echinococcus cysts and 10 E.granulosus- negative healthy liver samples obtained from different cattle at various times from slaughterhouses in Kirikkale province, Turkey. Histopathologically, Echinococcus cysts of various sizes were observed along with the surrounding fibrous connective tissue. Giant cells, mononuclear cells, and eosinophilic leukocytes were found between the fibrous connective tissue and the cyst. In the parenchymal tissue distant from the cyst, inflammatory changes were observed, including vacuolation and necrosis in hepatocytes, congestion and dilation sinusoidal capillaries. Immunohistochemically, MDA immunopositivity was observed in both hepatocytes surrounding the cyst and areas distant from the cyst, while SOD immunopositivity was mainly detected in fibrous connective tissue and hepatocytes surrounding the Echinococcus cysts. A significant increase in MDA immunoreactivity was observed in E.granulosus s.l.-infected livers. Although no statistically significant change was observed in SOD immunopositivity in the liver tissues with cystic echinococcosis, regional variations were noted. Germinal layer (GL) of Echinococcus cyst showed immunopositive staining for MDA, while laminated layer (LL) exhibited immunonegative staining. To the authors' best understanding, this study represents a pioneering effort in showcasing and evaluating the immunoreactivities of MDA and SOD within the liver tissue afflicted with Echinococcus cysts. Simultaneously, the examination extends to encompass tissue damage and the infiltration of inflammatory cells. This study highlights the role of oxidative stress in the pathogenesis of Cystic Echinococcosis (CE) and the need for further investigation of antioxidant defense mechanisms and their regional variations.
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Doenças dos Bovinos , Cistos , Equinococose , Echinococcus granulosus , Animais , Bovinos , Ovinos , Antioxidantes , Doenças dos Bovinos/parasitologia , Equinococose/veterinária , Equinococose/parasitologia , Cabras , Fígado , Estresse Oxidativo , Superóxido DismutaseRESUMO
The ribosomal protein S6 kinase beta-1 (RPS6KB1), also known as p70S6 kinase, plays a crucial role in various disease-related conditions such as diabetes, obesity, and cancer. Its activity is regulated by phosphorylation events, including phosphorylation of Threonine 389 in the hydrophobic motif by the mammalian target of rapamycin complex 1 (mTORC1) and phosphorylation of Threonine 229 in the activation loop by PDK1 (phosphoinositide-dependent kinase 1). However, other phenomena connected to RPS6KB1 remain unknown. In this study, we employed virtual screening and molecular docking techniques on the molecules in the ZINC library to identify potential inhibitors. Molecular dynamics (MD) simulations and MMGBSA calculations were carried out on promising compounds to determine their binding affinity and stability. We also evaluated the drug-likeness properties of the selected compounds. A comparative study between the native RPS6KB1 structure, co-crystal ligands, and the shortlisted molecules from the ZINC dataset was carried out. The identified molecules possess significant potential for future in vitro and in vivo studies, paving the way for developing effective cancer treatments.Communicated by Ramaswamy H. Sarma.
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Multidrug-resistant (MDR) pathogens are a rising global health worry that imposes an urgent need for the discovery of novel antibiotics particularly those of natural origin. In this context, we aimed to use the metagenomic nanopore sequence analysis of soil microbiota coupled with the conventional phenotypic screening and genomic analysis for identifying the antimicrobial metabolites produced by promising soil isolate(s). In this study, whole metagenome analysis of the soil sample(s) was performed using MinION™ (Oxford Nanopore Technologies). Aligning and analysis of sequences for probable secondary metabolite gene clusters were extracted and analyzed using the antiSMASH version 2 and DeepBGC. Results of the metagenomic analysis showed the most abundant taxa were Bifidobacterium, Burkholderia, and Nocardiaceae (99.21%, followed by Sphingomonadaceae (82.03%) and B. haynesii (34%). Phenotypic screening of the respective soil samples has resulted in a promising Bacillus isolate that exhibited broad-spectrum antibacterial activities against various MDR pathogens. It was identified using microscopical, cultural, and molecular methods as Bacillus (B.) haynesii isolate MZ922052. The secondary metabolite gene analysis revealed the conservation of seven biosynthetic gene clusters of antibacterial metabolites namely, siderophore lichenicidin VK21-A1/A2 (95% identity), lichenysin (100%), fengycin (53%), terpenes (100%), bacteriocin (100%), Lasso peptide (95%) and bacillibactin (53%). In conclusion, metagenomic nanopore sequence analysis of soil samples coupled with conventional screening helped identify B. haynesii isolate MZ922052 harboring seven biosynthetic gene clusters of promising antimicrobial metabolites. This is the first report for identifying the bacteriocin, lichenysin, and fengycin biosynthetic gene clusters in B. haynesii MZ922052.
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Furan is generated in a wide array of heat-treated foods through thermal degradation, leading to severe impairments in the male reproductive system. The main objective of this study was to investigate the potential of pomegranate peel extract (PGPE) in mitigating testicular dysfunctions induced by furan. Male rats were categorized into four groups: control/untreated, PGPE, furan, and PGPE + furan group. The study results revealed that furan-treated rats exhibited significantly elevated aminotransferase and phosphatase activity, and also generated increased oxidative stress, and reduced antioxidative stress protein activity. Additionally, protein content levels (ALT, AST, ALP, and ACP) and activities of steroidogenic Leydig cell hydroxysteroid dehydrogenase (3ß-HSD and 17ß-HSD) enzymes were significantly decreased. Significant variations in testicular parameters, apoptotic genes (Bcl-2, P53, and Caspase3), inflammatory and anti-inflammatory cytokines (IL1ß, IL10), male sex hormones follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and sperm quality were also observed. Furthermore, testicular histological abnormalities were confirmed by biochemical and molecular modifications. Notably, PGPE pre-treated furan-intoxicated animals exhibited significant improvements in most of the assessed parameters compared to furan-treated groups. In conclusion, PGPE presents essential preventive measures and a novel pharmacological potential therapy against furan-induced testicular injury.
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Apoptose , Furanos , Estresse Oxidativo , Extratos Vegetais , Punica granatum , Testículo , Masculino , Animais , Estresse Oxidativo/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Ratos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Apoptose/efeitos dos fármacos , Punica granatum/química , Furanos/farmacologia , Testosterona/metabolismo , Hormônio Luteinizante , 17-Hidroxiesteroide Desidrogenases/metabolismo , Hormônio Foliculoestimulante , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Antioxidantes/metabolismoRESUMO
Objective: Owing to the rising incidence of multidrug-resistant organisms (MDRO) and the high mortality rates associated with such bacterial infections post-hematopoietic stem cell transplantation (HSCT), we investigated the MDRO colonization rate prior to transplantation using an active surveillance approach and determined its impact on subsequent infection during the pre-engraftment period. Methods: A single-center observational study was conducted, and surveillance cultures from multiple body sites, including the rectum, nasal cavity, and groin, were performed at admission to determine MDRO colonization. Serological tests were used to detect certain viruses and toxoplasmosis before HSCT. Results: In the pre-transplant setting, 59 MDRO were recovered from the 40 HSCT recipients. Of the 59 isolates recovered from one or more body sites, 29 were positive for methicillin-resistant Staphylococcus aureus (MRSA), 7 for carbapenem-resistant Enterobacterales (CRE), and 23 were positive for extended-spectrum ß-lactamase (ESBLs). Serological assessment before HSCT revealed active or reactivation of latent infection with cytomegalovirus (7.5%), Epstein-Barr virus (EBV; 5%), and Toxoplasma gondii (2.5%) among HSCT patients. In terms of factors associated with pre-engraftment infections, the type of transplant (p=0.04) was statistically significant, whereas other factors, such as age, sex, and underlying conditions, were not. In post-transplant settings, bloodstream infections (BSIs) were documented in 2 allogeneic HSCT patients (5%), and the isolated microorganisms were ESBL-producing E. coli and non-MDR Acinetobacter baumannii. Conclusion: Active screening cultures are a helpful tool for identifying patients colonized by MDRO or relevant viruses before HSCT, and for predicting those at risk of developing subsequent pre-engraftment infections. Additionally, active screening may aid in predicting those who are likely to develop subsequent pre-engraftment infections Our findings highlight the importance of pre-transplant screening for high-priority multidrug-resistant pathogens and the application of infection control interventions after HSCT.
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With the help of both theoretical as well as experimental research, in vitro binding research with CT-DNA (calf thymus) and BSA (bovine serum albumin) were carefully examined to figure out the chemotherapeutic and pharmacokinetic facets of the Erbium complex, which contains 1,10-phenanthroline (Phen). The binding characteristics and the mechanism of complex's interaction with DNA as well as the protein were determined utilizing fluorescence quenching method. Findings indicated that the complex's interaction with DNA via groove binding into DNA's minor grooves, with their binding constants falling within the 104 M-1 range. Furthermore, thermodynamic characteristics and the fluorescence emission of the tryptophan residues of the protein were obtained through fluorescence quenching studies at different temperatures. According to the results of the binding constants, the protein's interactions with the Er- complex were moderate, demonstrating that the compound may be transported effectively by the protein. Molecular docking results supported that of the experimental research. The HeLa and MCF-7 cancer cell lines, along with the normal human fibroblast cell line, were used in an MTT assay evaluation of the Er-complex cytotoxicity. The Er-complex displayed a selective inhibitory effect on the proliferation of different cancer cells.Communicated by Ramaswamy H. Sarma.
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We developed a facile electroanalytical system for the rapid and sensitive detection of pyrimethanil through the modification of carbon paste electrode surface using the as-fabricated europium doped feather-type CuO nanoflowers (FT-Eu3+-CuO NF sensor). The peak current of pyrimethanil oxidation was elevated by the sensor due to the integration of appreciable electrochemical features of the modifier, which indicates the high ability of the modified electrode to enhance the sensitivity of pyrimethanil detection. The pyrimethanil sensor under the optimized setting had a broad linear dynamic range (0.001-800.0 µM) and a narrow limit of detection (0.18 nM). The practical applicability of the as-fabricated electrode was verified by sensing pyrimethanil in real samples; it also exhibited commendable specificity, stability and reproducibility.
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Fungicidas Industriais , Pirimidinas , Água , Frutas , Reprodutibilidade dos TestesRESUMO
Hepatic tumors present a formidable challenge in cancer therapeutics, necessitating the exploration of novel treatment strategies. In recent years, targeting the immune system has attracted interest to augment existing therapeutic efficacy. The immune system in hepatic tumors includes numerous cells with diverse actions. CD8+ T lymphocytes, T helper 1 (Th1) CD4+ T lymphocytes, alternative M1 macrophages, and natural killer (NK) cells provide the antitumor immunity. However, Foxp3+ regulatory CD4+ T cells (Tregs), M2-like tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) are the key immune inhibitor cells. Tumor stroma can also affect these interactions. Targeting these cells and their secreted molecules is intriguing for eliminating malignant cells. The current review provides a synopsis of the immune system components involved in hepatic tumor expansion and highlights the molecular and cellular pathways that can be targeted for therapeutic intervention. It also overviews the diverse range of drugs, natural products, immunotherapy drugs, and nanoparticles that have been investigated to manipulate immune responses and bolster antitumor immunity. The review also addresses the potential advantages and challenges associated with these approaches.
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Produtos Biológicos , Neoplasias Hepáticas , Nanopartículas , Neoplasias , Humanos , Produtos Biológicos/uso terapêutico , Produtos Biológicos/metabolismo , Neoplasias/patologia , Imunoterapia , Macrófagos/patologia , Neoplasias Hepáticas/patologia , Nanopartículas/uso terapêutico , Microambiente TumoralRESUMO
The expression of the nuclear paraspeckle assembly transcript 1 (NEAT1), as a well-known long non-coding RNA (lncRNA), is often upregulated in varied types of cancers and associated with poor survival outcomes in patients suffering from tumors. NEAT1 promotes the tumors growth by influencing the various genes' expression profile that regulate various aspects of tumor cell behavior, in particular tumor growth, metastasis and drug resistance. This suggests that NEAT1 are capable of serving as a new diagnostic biomarker and target for therapeutic intervention. Through interrelation with enhancer of zeste homolog 2 (EZH2), NEAT1 acts as a scaffold RNA molecule, and thus regulating the expression EZH2-associated genes. Additionally, by perform as miRNA sponge, it constrains suppressing the interactions between miRNAs-mediated degradation of target mRNAs. In light of this, NEAT1 inhibition by small interfering RNA (siRNA) hampers tumorgenesis. We summarize recent findings about the expression, biological functions, and regulatory process of NEAT1 in human tumors. It specifically emphasizes the clinical significance of NEAT1 as a novel diagnostic biomarker and a promising therapeutic mark for many types of cancers.
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Chimeric Antigen Receptor (CAR) based therapies are becoming increasingly important in treating patients. CAR-T cells have been shown to be highly effective in the treatment of hematological malignancies. However, harmful therapeutic barriers have been identified, such as the potential for graft-versus-host disease (GVHD), neurotoxicity, and cytokine release syndrome (CRS). As a result, CAR NK-cell therapy is expected to be a new therapeutic option. NK cells act as cytotoxic lymphocytes, supporting the innate immune response against autoimmune diseases and cancer cells by precisely detecting and eliminating malignant cells. Genetic modification of these cells provides a dual approach to the treatment of AD and cancer. It can be used through both CAR-independent and CAR-dependent mechanisms. The use of CAR-based cell therapies has been successful in treating cancer patients, leading to further investigation of this innovative treatment for alternative diseases, including AD. The complementary roles of CAR T and CAR NK cells have stimulated exploration in this area. Our study examines the latest research on the therapeutic effectiveness of these cells in treating both cancer and ADs.
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Doenças Autoimunes , Imunoterapia Adotiva , Células Matadoras Naturais , Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/transplante , Receptores de Antígenos Quiméricos/imunologia , Neoplasias/terapia , Neoplasias/imunologia , Doenças Autoimunes/terapia , Doenças Autoimunes/imunologia , Imunoterapia Adotiva/métodos , AnimaisRESUMO
Pulmonary toxicity is a serious side effect of some specific anticancer drugs. Bleomycin is a well-known anticancer drug that triggers severe reactions in the lungs. It is an approved drug that may be prescribed for the treatment of testicular cancers, Hodgkin's and non-Hodgkin's lymphomas, ovarian cancer, head and neck cancers, and cervical cancer. A large number of experimental studies and clinical findings show that bleomycin can concentrate in lung tissue, leading to massive oxidative stress, alveolar epithelial cell death, the proliferation of fibroblasts, and finally the infiltration of immune cells. Chronic release of pro-inflammatory and pro-fibrotic molecules by immune cells and fibroblasts leads to pneumonitis and fibrosis. Both fibrosis and pneumonitis are serious concerns for patients who receive bleomycin and may lead to death. Therefore, the management of lung toxicity following cancer therapy with bleomycin is a critical issue. This review explains the cellular and molecular mechanisms of pulmonary injury following treatment with bleomycin. Furthermore, we review therapeutic targets and possible promising strategies for ameliorating bleomycin-induced lung injury.