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Theriogenology Jun 2024Although anti-Müllerian hormone (AMH) is involved in the regulation of granulosa cell function in female animals, its role in tissues other than ovarian follicles...
Although anti-Müllerian hormone (AMH) is involved in the regulation of granulosa cell function in female animals, its role in tissues other than ovarian follicles remains poorly understood. It has also been suggested that cows with high circulating AMH concentrations have increased fertility; however, the mechanism has not been elucidated. This study was conducted to identify the presence of the AMH-signaling system and its target cells in the bovine corpus luteum formed from an ovulated follicle. Immunoblotting revealed that the proteolytically cleaved C-terminal region in AMH (AMH), a biologically active peptide, was present in trace amounts in the early corpus luteum and significantly increased during the mid to regressed stages. AMH and cleaved N-terminal region (AMH) in AMH generate a noncovalent isoform that improves the activity of AMH signaling. An immunohistochemical analysis revealed that AMH, AMH, and type II AMH receptor (AMHR2) were localized to luteal cells during the entire estrous cycle. AMH in the corpus luteum seemed to be newly synthesized since AMH expression was detected. These findings suggest that AMH signaling is involved in the regulation of luteal cell function through an autocrine and post-translational processing mechanism. The level of AMHR2 and mRNA expression of AMHR2 and type I AMH receptors (activin-like kinase 2, 3, and 6) were highest in the mid stage. Thus, AMH signaling in the corpus luteum may also be regulated by changes in the receptor levels. Since the transforming growth factor-beta superfamily, to which AMH belongs, is a multifunctional polypeptide growth factor, further studies are needed to evaluate whether AMH signaling has a role in facilitating or inhibiting luteal cell functions.
PubMed: 38924892
DOI: 10.1016/j.theriogenology.2024.06.017 -
Cells Jun 2024Preimplantation embryo culture, pivotal in assisted reproductive technology (ART), has lagged in innovation compared to embryo selection advancements. This review... (Review)
Review
Preimplantation embryo culture, pivotal in assisted reproductive technology (ART), has lagged in innovation compared to embryo selection advancements. This review examines the persisting gap between in vivo and in vitro embryo development, emphasizing the need for improved culture conditions. While in humans this gap is hardly estimated, animal models, particularly bovines, reveal clear disparities in developmental competence, cryotolerance, pregnancy and live birth rates between in vitro-produced (IVP) and in vivo-derived (IVD) embryos. Molecular analyses unveil distinct differences in morphology, metabolism, and genomic stability, underscoring the need for refining culture conditions for better ART outcomes. To this end, a deeper comprehension of oviduct physiology and embryo transport is crucial for grasping embryo-maternal interactions' mechanisms. Research on autocrine and paracrine factors, and extracellular vesicles in embryo-maternal tract interactions, elucidates vital communication networks for successful implantation and pregnancy. In vitro, confinement, and embryo density are key factors to boost embryo development. Advanced dynamic culture systems mimicking fluid mechanical stimulation in the oviduct, through vibration, tilting, and microfluidic methods, and the use of innovative softer substrates, hold promise for optimizing in vitro embryo development.
Topics: Animals; Humans; Embryo Culture Techniques; Embryo, Mammalian; Embryonic Development; Pregnancy; Female; Blastocyst
PubMed: 38920627
DOI: 10.3390/cells13120996 -
Oncoimmunology 2024Improving cancer immunotherapy efficacy hinges on identifying key T-cell populations critical for tumor control and response to Immune Checkpoint Blockade (ICB). We have...
Improving cancer immunotherapy efficacy hinges on identifying key T-cell populations critical for tumor control and response to Immune Checkpoint Blockade (ICB). We have recently reported that while the co-expression of PD-1 and CD28 is associated with impaired functionality in peripheral blood, it significantly enhances T-cell fitness in the tumor site of non-small cell lung cancer (NSCLC) patients. To uncover the underlying mechanisms, we explored the role of CD26, a key player in T-cell activation through its interaction with adenosine deaminase (ADA), a crucial intra/extracellular enzyme able to neutralize local adenosine (ADO). We found that an autocrine ADA/CD26 axis enhances CD8PD-1CD28 T-cell function, particularly within an immunosuppressive environment marked by CD39 expression. Then, we interrogated the TCGA and OAK datasets to gain insight into the prognostic/predictive potential of our findings. We identified a signature predicting overall survival (OS) in LUAD patients and response to atezolizumab in advanced LUAD cases. These findings suggest promising avenues for therapeutic intervention targeting the ADA/CD26 axis.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; CD8-Positive T-Lymphocytes; CD28 Antigens; Prognosis; Programmed Cell Death 1 Receptor; Dipeptidyl Peptidase 4; Adenosine Deaminase; Immune Checkpoint Inhibitors; Antibodies, Monoclonal, Humanized; Female; Male; Apyrase
PubMed: 38915783
DOI: 10.1080/2162402X.2024.2371051 -
Molecular Biology Reports Jun 2024Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia... (Review)
Review
Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components.
Topics: Humans; Renin-Angiotensin System; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Angiotensin II; Leukemia, Myeloid, Acute; Signal Transduction; Angiotensin I; Neovascularization, Pathologic; Animals; Peptide Fragments
PubMed: 38904729
DOI: 10.1007/s11033-024-09659-3 -
Oncogene Jun 2024Advanced hepatocellular carcinoma (HCC) is a lethal disease, with limited therapeutic options. Mixed Lineage Kinase 3 (MLK3) is a key regulator of liver diseases,...
Advanced hepatocellular carcinoma (HCC) is a lethal disease, with limited therapeutic options. Mixed Lineage Kinase 3 (MLK3) is a key regulator of liver diseases, although its role in HCC remains unclear. Analysis of TCGA databases suggested elevated MAP3K11 (MLK3 gene) expression, and TMA studies showed higher MLK3 activation in human HCCs. To understand MLK3's role in HCC, we utlized carcinogen-induced HCC model and compared between wild-type and MLK3 knockout (MLK3) mice. Our studies showed that MLK3 kinase activity is upregulated in HCC, and MLK3 deficiency alleviates HCC progression. MLK3 deficiency reduced proliferation in vivo and MLK3 inhibition reduced proliferation and colony formation in vitro. To obtain further insight into the mechanism and identify newer targets mediating MLK3-induced HCCs, RNA-sequencing analysis was performed. These showed that MLK3 deficiency modulates various gene signatures, including EMT, and reduces TGFB1&2 expressions. HCC cells overexpressing MLK3 promoted EMT via autocrine TGFβ signaling. Moreover, MLK3 deficiency attenuated activated hepatic stellate cell (HSC) signature, which is increased in wild-type. Interestingly, MLK3 promotes HSC activation via paracrine TGFβ signaling. These findings reveal TGFβ playing a key role at different steps of HCC, downstream of MLK3, implying MLK3-TGFβ axis to be an ideal drug target for advanced HCC management.
PubMed: 38858590
DOI: 10.1038/s41388-024-03055-8 -
Discovery Medicine May 2024Inflammation is a key pathological process in bacterial meningitis, and the transforming growth factor-beta-activated kinase 1 (TAK1)/nuclear factor-kappa B (NF-κB)...
BACKGROUND
Inflammation is a key pathological process in bacterial meningitis, and the transforming growth factor-beta-activated kinase 1 (TAK1)/nuclear factor-kappa B (NF-κB) pathway is implicated in the activation of microglia and the production of inflammatory factors. Interleukin (IL)-10 is an anti-inflammatory cytokine acting in an autocrine fashion in macrophages to limit inflammatory responses by decreasing the production of pro-inflammatory cytokines. This paper investigates how IL-10 can inhibit microglia activation and reduce the inflammatory response of nervous system diseases.
METHODS
This study used a pneumococcal-induced in Pneumococcal meningitis (PM) C57BL/6 mice and BV-2 cells model of microglial activation, assessing the effects of IL-10 on the TAK1/NF-κB pathway. The impact of IL-10 on microglial autophagy was investigated through western blot and immunofluorescence. The effects of IL-10 were evaluated by examining cellular activation markers and the activity of molecular signaling pathways (such as phosphorylation levels of TAK1 and NF-κB).
RESULTS
Pneumococcus induced the activation of microglia and reduced IL-10. IL-10 inhibited the TAK1/NF-κB pathway, reducing the pneumococcal-induced inflammatory response in microglia. IL-10 ameliorated pneumococcal infection-induced microglial injury by inhibiting autophagy. Animal experiment results also showed that IL-10 inhibited inflammation and autophagy during Pneumococcal meningitis in mice.
CONCLUSION
Our study demonstrates that IL-10 reduces the inflammatory response of microglia by inhibiting the TAK1/NF-κB pathway. Additionally, IL-10 ameliorates pneumococcal infection-induced microglial injury by inhibiting the process of autophagy. These results provide a new theoretical basis and offer new insights for developing strategies to treat bacterial meningitis.
Topics: Animals; Interleukin-10; Microglia; Mice; Mice, Inbred C57BL; Meningitis, Pneumococcal; NF-kappa B; MAP Kinase Kinase Kinases; Signal Transduction; Inflammation; Autophagy; Disease Models, Animal; Cell Line; Streptococcus pneumoniae
PubMed: 38798253
DOI: 10.24976/Discov.Med.202436184.87 -
Viruses May 2024The pathogenesis of viral infection is attributed to two folds: intrinsic cell death pathway activation due to the viral cytopathic effect, and immune-mediated extrinsic... (Review)
Review
The pathogenesis of viral infection is attributed to two folds: intrinsic cell death pathway activation due to the viral cytopathic effect, and immune-mediated extrinsic cellular injuries. The immune system, encompassing both innate and adaptive immunity, therefore acts as a double-edged sword in viral infection. Insufficient potency permits pathogens to establish lifelong persistent infection and its consequences, while excessive activation leads to organ damage beyond its mission to control viral pathogens. The innate immune response serves as the front line of defense against viral infection, which is triggered through the recognition of viral products, referred to as pathogen-associated molecular patterns (PAMPs), by host cell pattern recognition receptors (PRRs). The PRRs-PAMPs interaction results in the induction of interferon-stimulated genes (ISGs) in infected cells, as well as the secretion of interferons (IFNs), to establish a tissue-wide antiviral state in an autocrine and paracrine manner. Cumulative evidence suggests significant variability in the expression patterns of PRRs, the induction potency of ISGs and IFNs, and the IFN response across different cell types and species. Hence, in our understanding of viral hepatitis pathogenesis, insights gained through hepatoma cell lines or murine-based experimental systems are uncertain in precisely recapitulating the innate antiviral response of genuine human hepatocytes. Accordingly, this review article aims to extract and summarize evidence made possible with bona fide human hepatocytes-based study tools, along with their clinical relevance and implications, as well as to identify the remaining gaps in knowledge for future investigations.
Topics: Humans; Hepatitis D; Hepatitis Delta Virus; Hepatocytes; Host-Pathogen Interactions; Immunity, Innate; Interferons; Pathogen-Associated Molecular Pattern Molecules; Receptors, Pattern Recognition
PubMed: 38793622
DOI: 10.3390/v16050740 -
NPJ Precision Oncology May 2024Of all gynecologic cancers, epithelial-ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard...
Of all gynecologic cancers, epithelial-ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The precise mechanism by which leukemia inhibitory factor (LIF) and its receptor (LIFR) contribute to the progression of OCa remains unknown. Analysis of cancer databases revealed that elevated expression of LIF or LIFR was associated with poor progression-free survival of OCa patients and a predictor of poor response to chemotherapy. Using multiple primary and established OCa cell lines or tissues that represent five subtypes of epithelial-OCa, we demonstrated that LIF/LIFR autocrine signaling is active in OCa. Moreover, treatment with LIFR inhibitor, EC359 significantly reduced OCa cell viability and cell survival with an IC ranging from 5-50 nM. Furthermore, EC359 diminished the stemness of OCa cells. Mechanistic studies using RNA-seq and rescue experiments unveiled that EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system. Using multiple in vitro, ex vivo and in vivo models including cell-based xenografts, patient-derived explants, organoids, and xenograft tumors, we demonstrated that EC359 dramatically reduced the growth and progression of OCa. Additionally, EC359 therapy considerably improved tumor immunogenicity by robust CD45 leukocyte tumor infiltration and polarizing tumor-associated macrophages (TAMs) toward M1 phenotype while showing no impact on normal T-, B-, and other immune cells. Collectively, our findings indicate that the LIF/LIFR autocrine loop plays an essential role in OCa progression and that EC359 could be a promising therapeutic agent for OCa.
PubMed: 38789520
DOI: 10.1038/s41698-024-00612-y -
Biochimica Et Biophysica Acta. Reviews... Jul 2024Tumor recurrence is a mechanism triggered in sparse populations of cancer cells that usually remain in a quiescent state after strict stress and/or therapeutic factors,... (Review)
Review
Tumor recurrence is a mechanism triggered in sparse populations of cancer cells that usually remain in a quiescent state after strict stress and/or therapeutic factors, which is affected by a variety of autocrine and microenvironmental cues. Despite thorough investigations, the biology of dormant and/or cancer stem cells is still not fully elucidated, as for the mechanisms of their reawakening, while only the major molecular patterns driving the relapse process have been identified to date. These molecular patterns profoundly interfere with the elements of cellular proteostasis systems that support the efficiency of the recurrence process. As a major proteostasis machinery, we review the role of the ubiquitin-proteasome system (UPS) in tumor cell dormancy and reawakening, devoting particular attention to the functions of its components, E3 ligases, deubiquitinating enzymes and proteasomes in cancer recurrence. We demonstrate how UPS components functionally or mechanistically interact with the pivotal proteins implicated in the recurrence program and reveal that modulators of the UPS hold promise to become an efficient adjuvant therapy for eradicating refractory tumor cells to impede tumor relapse.
Topics: Humans; Proteasome Endopeptidase Complex; Neoplasms; Ubiquitin; Neoplasm Recurrence, Local; Animals; Ubiquitin-Protein Ligases; Neoplastic Stem Cells; Tumor Microenvironment
PubMed: 38761982
DOI: 10.1016/j.bbcan.2024.189119 -
Molecular Therapy : the Journal of the... May 2024Interleukin (IL)18 is a potent pro-inflammatory cytokine that is activated upon caspase 1 cleavage of the latent precursor, pro-IL18. Therapeutic T cell armoring with...
Interleukin (IL)18 is a potent pro-inflammatory cytokine that is activated upon caspase 1 cleavage of the latent precursor, pro-IL18. Therapeutic T cell armoring with IL18 promotes autocrine stimulation and positive modulation of the tumor microenvironment (TME). However, existing strategies are imperfect since they involve constitutive/poorly regulated activity or fail to modify the TME. Here, we have substituted the caspase 1 cleavage site within pro-IL18 with that preferred by granzyme B, yielding GzB-IL18. We demonstrate that GzB-IL18 is constitutively released but remains functionally latent unless chimeric antigen receptor (CAR) T cells are activated, owing to concomitant granzyme B release. Armoring with GzB-IL18 enhances cytolytic activity, proliferation, interferon (IFN)-γ release, and anti-tumor efficacy by a similar magnitude to constitutively active IL18. We also demonstrate that GzB-IL18 provides a highly effective armoring strategy for γδ CAR T cells, leading to enhanced metabolic fitness and significant potentiation of therapeutic activity. Finally, we show that constitutively active IL18 can unmask CAR T cell-mediated cytokine release syndrome in immunocompetent mice. By contrast, GzB-IL18 promotes anti-tumor activity and myeloid cell re-programming without inducing such toxicity. Using this stringent system, we have tightly coupled the biological activity of IL18 to the activation state of the host CAR T cell, favoring safer clinical implementation of this technology.
PubMed: 38745414
DOI: 10.1016/j.ymthe.2024.05.013