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International Journal of Molecular... Jul 2023Hepatocytes exert pivotal roles in metabolism, protein synthesis and detoxification. Non-parenchymal liver cells (NPCs), largely comprising macrophages, dendritic cells,... (Review)
Review
Hepatocytes exert pivotal roles in metabolism, protein synthesis and detoxification. Non-parenchymal liver cells (NPCs), largely comprising macrophages, dendritic cells, hepatic stellate cells and liver sinusoidal cells (LSECs), serve to induce immunological tolerance. Therefore, the liver is an important target for therapeutic approaches, in case of both (inflammatory) metabolic diseases and immunological disorders. This review aims to summarize current preclinical nanodrug-based approaches for the treatment of liver disorders. So far, nano-vaccines that aim to induce hepatitis virus-specific immune responses and nanoformulated adjuvants to overcome the default tolerogenic state of liver NPCs for the treatment of chronic hepatitis have been tested. Moreover, liver cancer may be treated using nanodrugs which specifically target and kill tumor cells. Alternatively, nanodrugs may target and reprogram or deplete immunosuppressive cells of the tumor microenvironment, such as tumor-associated macrophages. Here, combination therapies have been demonstrated to yield synergistic effects. In the case of autoimmune hepatitis and other inflammatory liver diseases, anti-inflammatory agents can be encapsulated into nanoparticles to dampen inflammatory processes specifically in the liver. Finally, the tolerance-promoting activity especially of LSECs has been exploited to induce antigen-specific tolerance for the treatment of allergic and autoimmune diseases.
Topics: Humans; Liver; Hepatocytes; Hepatitis; Hepatic Stellate Cells; Liver Neoplasms; Tumor Microenvironment
PubMed: 37511628
DOI: 10.3390/ijms241411869 -
Cancer Research and Treatment Jul 2023Cancer is a leading cause of disease-related mortality worldwide. Drug resistance is one of the primary reasons for the failure of anticancer therapy. There are a number... (Review)
Review
Cancer is a leading cause of disease-related mortality worldwide. Drug resistance is one of the primary reasons for the failure of anticancer therapy. There are a number of underlying mechanisms for anticancer drug resistance including genetic/epigenetic modifications, microenvironmental factors, and tumor heterogeneity. In the present scenario, researchers have focused on these novel mechanisms and strategies to tackle them. Recently, researchers have recognized the ability of cancer to become dormant because of anticancer drug resistance, tumor relapse, and progression. Currently, cancer dormancy is classified into "tumor mass dormancy" and "cellular dormancy." Tumor mass dormancy represents the equilibrium between cell proliferation and cell death under the control of blood supply and immune responses. Cellular dormancy denotes the state in which cells undergo quiescence and is characterized by autophagy, stress-tolerance signaling, microenvironmental cues, and epigenetic modifications. Cancer dormancy has been regarded as the stem of primary or distal recurrent tumor formation and poor clinical outcomes in cancer patients. Despite the insufficiency of reliable models of cellular dormancy, the mechanisms underlying the regulation of cellular dormancy have been clarified in numerous studies. A better understanding of the biology of cancer dormancy is critical for the development of effective anticancer therapeutic strategies. In this review, we summarize the characteristics and regulatory mechanisms of cellular dormancy, introduce several potential strategies for targeting cellular dormancy, and discuss future perspectives.
Topics: Humans; Neoplasm Recurrence, Local; Neoplasms; Cell Death; Signal Transduction; Autophagy; Antineoplastic Agents
PubMed: 36960624
DOI: 10.4143/crt.2023.468 -
Heliyon Mar 2024Extrachromosomal DNAs (ecDNAs) are a pervasive feature found in cancer and contain oncogenes and their corresponding regulatory elements. Their unique structural... (Review)
Review
Extrachromosomal DNAs (ecDNAs) are a pervasive feature found in cancer and contain oncogenes and their corresponding regulatory elements. Their unique structural properties allow a rapid amplification of oncogenes and alter chromatin accessibility, leading to tumorigenesis and malignant development. The uneven segregation of ecDNA during cell division enhances intercellular genetic heterogeneity, which contributes to tumor evolution that might trigger drug resistance and chemotherapy tolerance. In addition, ecDNA has the ability to integrate into or detach from chromosomal DNA, such progress results into structural alterations and genomic rearrangements within cancer cells. Recent advances in multi-omics analysis revealing the genomic and epigenetic characteristics of ecDNA are anticipated to make valuable contributions to the development of precision cancer therapy. Herein, we conclud the mechanisms of ecDNA generation and the homeostasis of its dynamic structure. In addition to the latest techniques in ecDNA research including multi-omics analysis and biochemical validation methods, we also discuss the role of ecDNA in tumor development and treatment, especially in drug resistance, and future challenges of ecDNA in cancer therapy.
PubMed: 38545177
DOI: 10.1016/j.heliyon.2024.e27733 -
MBio Jun 2023Mounting evidence demonstrates that nutritional environment can alter pathogen drug sensitivity. While the rich media used for culture contains supraphysiological...
Mounting evidence demonstrates that nutritional environment can alter pathogen drug sensitivity. While the rich media used for culture contains supraphysiological nutrient concentrations, pathogens encounter a relatively restrictive environment . We assessed the effect of nutrient limitation on the protozoan parasite that causes malaria and demonstrated that short-term growth under physiologically relevant mild nutrient stress (or "metabolic priming") triggers increased tolerance of a potent antimalarial drug. We observed beneficial effects using both short-term survival assays and longer-term proliferation studies, where metabolic priming increases parasite survival to a level previously defined as resistant (>1% survival). We performed these assessments by either decreasing single nutrients that have distinct roles in metabolism or using a media formulation that simulates the human plasma environment. We determined that priming-induced tolerance was restricted to parasites that had newly invaded the host red blood cell, but the effect was not dependent on genetic background. The molecular mechanisms of this intrinsic effect mimic aspects of genetic tolerance, including translational repression and protein export. This finding suggests that regardless of the impact on survival rates, environmental stress could stimulate changes that ultimately directly contribute to drug tolerance. Because metabolic stress is likely to occur more frequently compared to the stable environment, priming-induced drug tolerance has ramifications for how results translate to studies. Improving our understanding of how pathogens adjust their metabolism to impact survival of current and future drugs is an important avenue of research to slow the evolution of resistance. There is a dire need for effective treatments against microbial pathogens. Yet, the continuing emergence of drug resistance necessitates a deeper knowledge of how pathogens respond to treatments. We have long appreciated the contribution of genetic evolution to drug resistance, but transient metabolic changes that arise in response to environmental factors are less recognized. Here, we demonstrate that short-term growth of malaria parasites in a nutrient-limiting environment triggers cellular changes that lead to better survival of drug treatment. We found that these strategies are similar to those employed by drug-tolerant parasites, which suggests that starvation "primes" parasites to survive and potentially evolve resistance. Since the environment of the human host is relatively nutrient restrictive compared to growth conditions in standard laboratory culture, this discovery highlights the important connections among nutrient levels, protective cellular pathways, and resistance evolution.
Topics: Humans; Plasmodium falciparum; Artemisinins; Malaria; Antimalarials; Drug Tolerance; Drug Resistance; Nutrients
PubMed: 37097173
DOI: 10.1128/mbio.00705-23 -
Neuroscience Sep 2023Morphine has a strong analgesic effect and is suitable for various types of pain, so it is widely used. But long-term usage of morphine can lead to drug tolerance, which... (Review)
Review
Morphine has a strong analgesic effect and is suitable for various types of pain, so it is widely used. But long-term usage of morphine can lead to drug tolerance, which limits its clinical application. The complex mechanisms underlying the development of morphine analgesia into tolerance involve multiple nuclei in the brain. Recent studies reveal the signaling at the cellular and molecular levels as well as neural circuits contributing to morphine analgesia and tolerance in the ventral tegmental area (VTA), which is traditionally considered a critical center of opioid reward and addiction. Existing studies show that dopamine receptors and μ-opioid receptors participate in morphine tolerance through the altered activities of dopaminergic and/or non-dopaminergic neurons in the VTA. Several neural circuits related to the VTA are also involved in the regulation of morphine analgesia and the development of drug tolerance. Reviewing specific cellular and molecular targets and related neural circuits may provide novel precautionary strategies for morphine tolerance.
Topics: Humans; Morphine; Ventral Tegmental Area; Analgesics, Opioid; Pain; Analgesia
PubMed: 37286162
DOI: 10.1016/j.neuroscience.2023.05.026 -
Molecular Medicine Reports Nov 2023Melatonin (MLT) is a biologically active indoleamine involved in regulating various biological rhythms, which is deficient in individuals with Type 2 diabetes. The...
Melatonin (MLT) is a biologically active indoleamine involved in regulating various biological rhythms, which is deficient in individuals with Type 2 diabetes. The present study examined the effects of MLT on diabetic neuropathy (DN). Diabetic rats received MLT treatment for 12 weeks, after which changes in kidney histology, oxidative damage, mitochondrial morphology and autophagy were measured. The glucose tolerance‑ and isoflurane tolerance‑area under the curve (AUC) values and the relative renal weight index (RI) in the diabetes mellitus (DM) group of rats were significantly higher compared with those in the control group. A significant increase in malondialdehyde (MDA) content, and decreases in the activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH‑Px) and GSH were demonstrated in the kidneys of DM rats compared with those in the control rats. Histological staining of DM rat kidney tissue with hematoxylin and eosin, Masson's trichome and Periodic acid‑Schiff demonstrated glomerular and tubule lesions, and an increase in collagen compared with control rats. Protein expression levels of LC3II, P62, collagen IV (COL‑IV) and α‑SMA were increased in DM rats and HG‑induced NRK‑52E cells compared with those in the control groups. Phosphorylation of AMPK was reduced, whereas phosphorylation of PI3K, Akt and mTOR were increased and . Notably, MLT treatment significantly reduced glucose tolerance‑AUC and RI, decreased MDA content, and increased SOD, CAT, GSH‑Px and GSH activity. Glomerular and tubule lesions improved, collagen was decreased and mitochondrial damage was alleviated by MLT treatment. MLT treatment also decreased the protein expression levels of LC3II, P62 and COL‑IV, whereas the phosphorylation of AMPK was significantly increased, which inhibited the phosphorylation of PI3K, AKT and mTOR and . These results demonstrated that MLT protects against DN and NRK‑52E cell injury through inhibiting oxidative damage and regulating autophagy via the PI3K/AKT/mTOR signaling pathway.
Topics: Rats; Animals; Melatonin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; AMP-Activated Protein Kinases; Kidney; Kidney Diseases; Oxidative Stress; TOR Serine-Threonine Kinases; Glutathione Peroxidase; Autophagy; Glucose; Superoxide Dismutase
PubMed: 37772370
DOI: 10.3892/mmr.2023.13101 -
Biomedicine & Pharmacotherapy =... Dec 2023Regulatory T cells are a subgroup of T cells with immunomodulatory functions. Different from most cytotoxic T cells and helper T cells, they play a supporting role in... (Review)
Review
Regulatory T cells are a subgroup of T cells with immunomodulatory functions. Different from most cytotoxic T cells and helper T cells, they play a supporting role in the immune system. What's more, regulatory T cells often play an immunosuppressive role, which mainly plays a role in maintaining the stability of the immune system and regulating the immune response in the body. However, recent studies have shown that not only playing a role in autoimmune diseases, organ transplantation, and other aspects, regulatory T cells can also play a role in the immune escape of tumors in the body, through various mechanisms to help tumor cells escape from the demic immune system, weakening the anti-cancer effect in the body. For a better understanding of the role that regulatory T cells can play in cancer, and to be able to use regulatory T cells for tumor immunotherapy more quickly. This review focuses on the research progress of various mechanisms of regulatory T cells in the tumor environment, the related research of tumor cells acting on regulatory T cells, and the existing various therapeutic methods acting on regulatory T cells.
Topics: Humans; T-Lymphocytes, Regulatory; Immunotherapy; Neoplasms; T-Lymphocytes, Cytotoxic; Immunomodulation; Tumor Microenvironment
PubMed: 37806087
DOI: 10.1016/j.biopha.2023.115142 -
Journal of Anesthesia, Analgesia and... Jul 2023Breakthrough cancer pain (BTcP) is a complex and variegate phenomenon that may change its presentation during the course of patients' disease in the same individual. An... (Review)
Review
Breakthrough cancer pain (BTcP) is a complex and variegate phenomenon that may change its presentation during the course of patients' disease in the same individual. An appropriate assessment is fundamental for depicting the pattern of BTcP. This information is determinant for a personalized management of BTcP. The use of opioids as needed is recommended for the management of BTcP. There are several options which should be chosen according to the individual pattern of BTcP. In general, a drug with a short onset and offset should be preferred. Although oral opioids may still have specific indications, fentanyl products have been found to be more rapid and effective. The most controversial point regards the opioid dose to be used. The presence of opioid tolerance suggests to use a dose proportional to the dose used for background analgesia. In contrast, regulatory studies have suggested to use the minimal available dose to be titrated until the effective dose. Further large studies should definitely settle this never ended question.
PubMed: 37480136
DOI: 10.1186/s44158-023-00101-x -
Drug Delivery and Translational Research Jun 2024Antimicrobial resistance and tolerance (AMR&T) are urgent global health concerns, with alarmingly increasing numbers of antimicrobial drugs failing and a corresponding... (Review)
Review
Antimicrobial resistance and tolerance (AMR&T) are urgent global health concerns, with alarmingly increasing numbers of antimicrobial drugs failing and a corresponding rise in related deaths. Several reasons for this situation can be cited, such as the misuse of traditional antibiotics, the massive use of sanitizing measures, and the overuse of antibiotics in agriculture, fisheries, and cattle. AMR&T management requires a multifaceted approach involving various strategies at different levels, such as increasing the patient's awareness of the situation and measures to reduce new resistances, reduction of current misuse or abuse, and improvement of selectivity of treatments. Also, the identification of new antibiotics, including small molecules and more complex approaches, is a key factor. Among these, novel DNA- or RNA-based approaches, the use of phages, or CRISPR technologies are some potent strategies under development. In this perspective article, emerging and experienced leaders in drug delivery discuss the most important biological barriers for drugs to reach infectious bacteria (bacterial bioavailability). They explore how overcoming these barriers is crucial for producing the desired effects and discuss the ways in which drug delivery systems can facilitate this process.
Topics: Humans; Anti-Bacterial Agents; Drug Delivery Systems; Animals; Drug Resistance, Microbial; Drug Resistance, Bacterial; Bacteria; Drug Tolerance
PubMed: 38341386
DOI: 10.1007/s13346-023-01513-6 -
Journal of Biomedical Science Oct 2023mRNA-based drugs have tremendous potential as clinical treatments, however, a major challenge in realizing this drug class will promise to develop methods for safely... (Review)
Review
mRNA-based drugs have tremendous potential as clinical treatments, however, a major challenge in realizing this drug class will promise to develop methods for safely delivering the bioactive agents with high efficiency and without activating the immune system. With regard to mRNA vaccines, researchers have modified the mRNA structure to enhance its stability and promote systemic tolerance of antigenic presentation in non-inflammatory contexts. Still, delivery of naked modified mRNAs is inefficient and results in low levels of antigen protein production. As such, lipid nanoparticles have been utilized to improve delivery and protect the mRNA cargo from extracellular degradation. This advance was a major milestone in the development of mRNA vaccines and dispelled skepticism about the potential of this technology to yield clinically approved medicines. Following the resounding success of mRNA vaccines for COVID-19, many other mRNA-based drugs have been proposed for the treatment of a variety of diseases. This review begins with a discussion of mRNA modifications and delivery vehicles, as well as the factors that influence administration routes. Then, we summarize the potential applications of mRNA-based drugs and discuss further key points pertaining to preclinical and clinical development of mRNA drugs targeting a wide range of diseases. Finally, we discuss the latest market trends and future applications of mRNA-based drugs.
Topics: Humans; COVID-19; COVID-19 Vaccines; Drug Tolerance; RNA, Messenger; mRNA Vaccines; Nanoparticles
PubMed: 37805495
DOI: 10.1186/s12929-023-00977-5