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International Journal of Molecular... Aug 2023In the era of personalized medicine greatly improved by molecular diagnosis and tailor-made therapies, the survival rate of acute myeloid leukemia (AML) at 5 years... (Review)
Review
In the era of personalized medicine greatly improved by molecular diagnosis and tailor-made therapies, the survival rate of acute myeloid leukemia (AML) at 5 years remains unfortunately low. Indeed, the high heterogeneity of AML clones with distinct metabolic and molecular profiles allows them to survive the chemotherapy-induced changes, thus leading to resistance, clonal evolution, and relapse. Moreover, leukemic stem cells (LSCs), the quiescent reservoir of residual disease, can persist for a long time and activate the recurrence of disease, supported by significant metabolic differences compared to AML blasts. All these points highlight the relevance to develop combination therapies, including metabolism inhibitors to improve treatment efficacy. In this review, we summarized the metabolic differences in AML blasts and LSCs, the molecular pathways related to mitochondria and metabolism are druggable and targeted in leukemia therapies, with a distinct interest for Venetoclax, which has revolutionized the therapeutic paradigms of several leukemia subtype, unfit for intensive treatment regimens.
Topics: Humans; Mitochondria; Cell Division; Clonal Evolution; Clone Cells; Leukemia
PubMed: 37685874
DOI: 10.3390/ijms241713069 -
Journal of Thrombosis and Haemostasis :... Aug 2023Long COVID is a public health emergency affecting millions of people worldwide, characterized by heterogeneous symptoms across multiple organ systems. Here, we discuss... (Review)
Review
Long COVID is a public health emergency affecting millions of people worldwide, characterized by heterogeneous symptoms across multiple organ systems. Here, we discuss the current evidence linking thromboinflammation to postacute sequelae of COVID-19. Studies have found persistence of vascular damage with increased circulating markers of endothelial dysfunction, coagulation abnormalities with heightened thrombin generation capacity, and abnormalities in platelet counts in postacute sequelae of COVID-19. Neutrophil phenotype resembles acute COVID-19 with an increase in activation and Neutrophil Extracellular Trap formation. These insights are potentially linked by elevated platelet-neutrophil aggregate formation. This hypercoagulable state in turn can lead to microvascular thrombosis, evidenced by microclots and elevated D-dimer in the circulation as well as perfusion abnormalities in the lungs and brains of patients with long COVID. Also, COVID-19 survivors experience an increased rate of arterial and venous thrombotic events. We discuss 3 important, potentially intertwined hypotheses that might contribute to thromboinflammation in long COVID: lasting structural changes, most prominently endothelial damage, caused during initial infection; a persistent viral reservoir; and immunopathology driven by a misguided immune system. Finally, we outline the necessity for large, well-characterized clinical cohorts and mechanistic studies to clarify the contribution of thromboinflammation to long COVID.
Topics: Humans; COVID-19; Thrombosis; Inflammation; Post-Acute COVID-19 Syndrome; Thromboinflammation; Disease Progression
PubMed: 37178769
DOI: 10.1016/j.jtha.2023.04.039 -
Frontiers in Microbiology 2023Hendra virus (HeV) and Nipah virus (NiV) are biosafety level 4 zoonotic pathogens causing severe and often fatal neurological and respiratory disease. These agents have... (Review)
Review
Hendra virus (HeV) and Nipah virus (NiV) are biosafety level 4 zoonotic pathogens causing severe and often fatal neurological and respiratory disease. These agents have been recognized by the World Health Organization as top priority pathogens expected to result in severe future outbreaks. HeV has caused sporadic infections in horses and a small number of human cases in Australia since 1994. The NiV Malaysia genotype (NiV-M) was responsible for the 1998-1999 epizootic outbreak in pigs with spillover to humans in Malaysia and Singapore. Since 2001, the NiV Bangladesh genotype (NiV-B) has been the predominant strain leading to outbreaks almost every year in Bangladesh and India, with hundreds of infections in humans. The natural reservoir hosts of HeV and NiV are fruit bats, which carry the viruses without clinical manifestation. The transmission pathways of henipaviruses from bats to humans remain poorly understood. Transmissions are often bridged by an intermediate animal host, which amplifies and spreads the viruses to humans. Horses and pigs are known intermediate hosts for the HeV outbreaks in Australia and NiV-M epidemic in Malaysia and Singapore, respectively. During the NiV-B outbreaks in Bangladesh, following initial spillover thought to be through the consumption of date palm sap, the spread of infection was largely human-to-human transmission. Spillover of NiV-B in recent outbreaks in India is less understood, with the primary route of transmission from bat reservoir to the initial human infection case(s) unknown and no intermediate host established. This review aims to provide a concise update on the epidemiology of henipaviruses covering their previous and current outbreaks with emphasis on the known and potential role of livestock as intermediate hosts in disease transmission. Also included is an up-to-date summary of newly emerging henipa-like viruses and animal hosts. In these contexts we discuss knowledge gaps and new challenges in the field and propose potential future directions.
PubMed: 37529329
DOI: 10.3389/fmicb.2023.1167085 -
Nature Communications Oct 2023Currently potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-related pathopoiesis have failed to achieve expected therapeutic...
Currently potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-related pathopoiesis have failed to achieve expected therapeutic efficacy due to the complexity of the pathogenic mechanisms. Here we show Tripartite motif containing 26 (TRIM26) as a critical endogenous suppressor of CCAAT/enhancer binding protein delta (C/EBPδ), and we also confirm that TRIM26 is an C/EBPδ-interacting partner protein that catalyses the ubiquitination degradation of C/EBPδ in hepatocytes. Hepatocyte-specific loss of Trim26 disrupts liver metabolic homeostasis, followed by glucose metabolic disorder, lipid accumulation, increased hepatic inflammation, and fibrosis, and dramatically facilitates NASH-related phenotype progression. Inversely, transgenic Trim26 overexpression attenuates the NASH-associated phenotype in a rodent or rabbit model. We provide mechanistic evidence that, in response to metabolic insults, TRIM26 directly interacts with C/EBPδ and promotes its ubiquitin proteasome degradation. Taken together, our present findings identify TRIM26 as a key suppressor over the course of NASH development.
Topics: Animals; Rabbits; Non-alcoholic Fatty Liver Disease; Signal Transduction; Ubiquitination; Ubiquitin-Protein Ligases
PubMed: 37821436
DOI: 10.1038/s41467-023-42040-9 -
Frontiers in Cellular and Infection... 2023The interferon pathway is the first line of defense in viral infection in all mammals, and its induction stimulates broad expression of interferon-stimulated genes... (Review)
Review
The interferon pathway is the first line of defense in viral infection in all mammals, and its induction stimulates broad expression of interferon-stimulated genes (ISGs). In mice and also humans, the antiviral function of ISGs has been extensively studied. As an important viral reservoir in nature, bats can coexist with a variety of pathogenic viruses without overt signs of disease, yet only limited data are available for the role of ISGs in bats. There are multiple species of bats and work has begun deciphering the differences and similarities between ISG function of human/mouse and different bat species. This review summarizes the current knowledge of conserved and bat-specific-ISGs and their known antiviral effector functions.
Topics: Humans; Animals; Mice; Antiviral Agents; Interferons; Chiroptera
PubMed: 37661999
DOI: 10.3389/fcimb.2023.1224532 -
Frontiers in Genetics 2024Human endogenous retroviruses (HERVs) are derived from the infection and integration of exogenetic retroviruses. HERVs account for 8% of human genome, and the majority... (Review)
Review
Human endogenous retroviruses (HERVs) are derived from the infection and integration of exogenetic retroviruses. HERVs account for 8% of human genome, and the majority of HERVs are solitary LTRs (solo-LTRs) due to homologous recombination. Multiple findings have showed that solo-LTRs could provide an enormous reservoir of transcriptional regulatory sequences involved in diverse biological processes, especially carcinogenesis and cancer development. The link between solo-LTRs and human diseases still remains poorly understood. This review focuses on the regulatory modules of solo-LTRs, which contribute greatly to the diversification and evolution of human genes. More importantly, although inactivating mutations, insertions and deletions have been identified in solo-LTRs, the inherited regulatory elements of solo-LTRs initiate the expression of chimeric lncRNA transcripts, which have been reported to play crucial roles in human health and disease. These findings provide valuable insights into the evolutionary and functional mechanisms underlying the presence of HERVs in human genome. Taken together, in this review, we will present evidences showing the regulatory and encoding capacity of solo-LTRs as well as the significant impact on various aspects of human biology.
PubMed: 38606358
DOI: 10.3389/fgene.2024.1358078 -
JCI Insight Sep 2023Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a dramatic sex bias, affecting 9 times more women than men. Activation of Toll-like receptor 7...
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a dramatic sex bias, affecting 9 times more women than men. Activation of Toll-like receptor 7 (TLR7) by self-RNA is a central pathogenic process leading to aberrant production of type I interferon (IFN) in SLE, but the specific RNA molecules that serve as TLR7 ligands have not been defined. By leveraging gene expression data and the known sequence specificity of TLR7, we identified the female-specific X-inactive specific transcript (XIST) long noncoding RNA as a uniquely rich source of TLR7 ligands in SLE. XIST RNA stimulated IFN-α production by plasmacytoid DCs in a TLR7-dependent manner, and deletion of XIST diminished the ability of whole cellular RNA to activate TLR7. XIST levels were elevated in blood leukocytes from women with SLE compared with controls, correlated positively with disease activity and the IFN signature, and were enriched in extracellular vesicles released from dying cells in vitro. Importantly, XIST was not IFN inducible, suggesting that XIST is a driver, rather than a consequence, of IFN in SLE. Overall, our work elucidated a role for XIST RNA as a female sex-specific danger signal underlying the sex bias in SLE.
Topics: Male; Humans; Female; RNA, Long Noncoding; Toll-Like Receptor 7; Lupus Erythematosus, Systemic; Interferon Type I; Gene Expression; Ligands
PubMed: 37733447
DOI: 10.1172/jci.insight.169344 -
Travel Medicine and Infectious Disease 2023Chikungunya virus is a mosquito-borne alphavirus, transmitted by Aedes mosquitoes. Humans serve as the primary reservoir. Chikungunya infections typically appear with an... (Review)
Review
BACKGROUND
Chikungunya virus is a mosquito-borne alphavirus, transmitted by Aedes mosquitoes. Humans serve as the primary reservoir. Chikungunya infections typically appear with an abrupt onset of fever, rash, and severe joint pain. Some 40% of cases develop chronic rheumatologic complications that can persist months to years.
OBJECTIVES
To improve precision of risk characterization by analyzing cases of chikungunya by year and by country and depicting this geotemporal distribution in map form.
METHOD
Chikungunya case counts by year were compiled from national or regional health authorities from 2011 to 2022. These data were augmented by published reviews plus the Program for Monitoring Emerging Diseases (ProMED). Country-level distribution was categorized into four groups based on recency and magnitude. Data for India were mapped on a per-state basis.
RESULTS
The global map depicts distribution of chikungunya disease from 2011 through 2022. Most cases are reported in tropical and subtropical areas, but notable exceptions include the northern coast of the Mediterranean Sea. Countries of high recency and frequency include India, Brazil, Sudan, and Thailand. Countries with high frequency, but few cases reported in 2019-22 include many Latin American and Caribbean countries. Subnational foci are discussed in general and mapped for India. The range of Aedes mosquitoes is broader than the geography where chikungunya infection is typically diagnosed.
CONCLUSIONS
These maps help identify geographical regions where residents or travelers are at greatest risk of chikungunya. Once vaccines are licensed to help prevent chikungunya, maps like these can help guide future vaccine decision-making.
Topics: Animals; Humans; Chikungunya Fever; Mosquito Vectors; Chikungunya virus; Aedes; Exanthema
PubMed: 37307983
DOI: 10.1016/j.tmaid.2023.102603 -
Heliyon Dec 2023The potential biotechnological uses of bat-associated bacteria are discussed briefly, indicating avenues for biotechnological applications of bat-associated microbes.... (Review)
Review
The potential biotechnological uses of bat-associated bacteria are discussed briefly, indicating avenues for biotechnological applications of bat-associated microbes. The uniqueness of bats in terms of their lifestyle, genomes and molecular immunology may predispose bats to act as disease reservoirs. Molecular phylogenetic analysis has shown several instances of bats harbouring the ancestral lineages of bacterial (), protozoal (, ) and viral (SARS-CoV2) pathogens infecting humans. Along with the transmission of viruses from bats, we also discuss the potential roles of bat-associated bacteria, fungi, and protozoan parasites in emerging diseases. Current evidence suggests that environmental changes and interactions between wildlife, livestock, and humans contribute to the spill-over of infectious agents from bats to other hosts. Domestic animals including livestock may act as intermediate amplifying hosts for bat-origin pathogens to transmit to humans. An increasing number of studies investigating bat pathogen diversity and infection dynamics have been published. However, whether or how these infectious agents are transmitted both within bat populations and to other hosts, including humans, often remains unknown. Metagenomic approaches are uncovering the dynamics and distribution of potential pathogens in bat microbiomes, which might improve the understanding of disease emergence and transmission. Here, we summarize the current knowledge on bat zoonoses of public health concern and flag the gaps in the knowledge to enable further research and allocation of resources for tackling future outbreaks.
PubMed: 38125540
DOI: 10.1016/j.heliyon.2023.e22351 -
Viruses Sep 2023Appendix has a distinct abundance of lymphatic cells and serves as a reservoir of microbiota which helps to replenish the large intestine with healthy flora. And it is...
Appendix has a distinct abundance of lymphatic cells and serves as a reservoir of microbiota which helps to replenish the large intestine with healthy flora. And it is the primary site of IgA induction, which shapes the composition of the intestinal microbiota. Recent population-based cohort studies report that appendectomy is associated with an increased risk of acute myocardial infarction and ischemic heart disease. Here, whether appendectomy has an effect on the occurrence and development of coxsackievirus B3 (CVB3)-induced viral myocarditis is studied. 10 TCID CVB3 was inoculated i.p. into appendectomized and sham-operated mice. RNA levels of viral load and pro-inflammatory cytokines in the hearts and the intestine were detected by RT-PCR. Compared to sham-operated mice, appendectomized mice exhibited attenuated cardiac inflammation and improved cardiac function, which is associated with a systemic reduced viral load. Appendectomized mice also displayed a reduction in cardiac neutrophil and macrophage infiltration and pro-inflammatory cytokine production. Mechanistically, we found that CVB3 induced an early and potent IL-10 production in the cecal patch at 2 days post infection. Appendectomy significantly decreased intestinal IL-10 and IL-10 CD4 Treg frequency which led to a marked increase in intestinal (primary entry site for CVB3) anti-viral IFN-γ CD4 T and IFN-γ CD8 T response and viral restriction, eventually resulting in improved myocarditis. Our results suggest that appendix modulates cardiac infection and inflammation through regulating intestinal IL-10 Treg response.
Topics: Humans; Mice; Animals; Myocarditis; Interleukin-10; Appendectomy; Coxsackievirus Infections; Inflammation; Enterovirus B, Human; Mice, Inbred BALB C; Disease Models, Animal
PubMed: 37896753
DOI: 10.3390/v15101974