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GPR81 is a G-protein-coupled receptor for lactate, which is upregulated in breast cancer and plays an autocrine role to promote tumor growth by tumor cell-derived lactate. Here we asked whether lactate has any paracrine role via activation of GPR81 in cells present in tumor microenvironment to help tumor growth. First, we showed that deletion of Gpr81 suppresses breast cancer growth in a constitutive breast cancer mouse model (MMTV-PyMT-Tg). We then used a syngeneic transplant model by monitoring tumor growth from a mouse breast cancer cell line (AT-3, Gpr81-negative) implanted in mammary fat pad of wild-type mice and Gpr81-null mice. Tumor growth was suppressed in Gpr81-null mice compared with wild-type mice. There were more tumor-infiltrating T cells and MHCIIhi-immune cells in tumors from Gpr81-null mice compared with tumors from wild-type mice. RNA-seq analysis of tumors indicated involvement of immune cells and antigen presentation in Gpr81-dependent tumor growth. Antigen-presenting dendritic cells expressed Gpr81 and activation of this receptor by lactate suppressed cell-surface presentation of MHCII. Activation of Gpr81 in dendritic cells was associated with decreased cAMP, IL-6 and IL-12. These findings suggest that tumor cell-derived lactate activates GPR81 in dendritic cells and prevents presentation of tumor-specific antigens to other immune cells. This paracrine mechanism is complementary to the recently discovered autocrine mechanism in which lactate induces PD-L1 in tumor cells via activation of GPR81 in tumor cells, thus providing an effective means for tumor cells to evade immune system. As such, blockade of GPR81 signaling could boost cancer immunotherapy.

In mammalian cells, autophagy is the major pathway for the degradation and recycling of obsolete and potentially noxious cytoplasmic materials, including proteins, lipids, and whole organelles, through the lysosomes. Autophagy maintains cellular and tissue homeostasis and provides a mechanism to adapt to extracellular cues and metabolic stressors. Emerging evidence unravels a critical function of autophagy in endothelial cells (ECs), the major components of the blood vasculature, which delivers nutrients and oxygen to the parenchymal tissue. EC-intrinsic autophagy modulates the response of ECs to various metabolic stressors and has a fundamental role in redox homeostasis and EC plasticity. In recent years moreover, genetic evidence suggests that autophagy regulates pathological angiogenesis, a hallmark of solid tumors. In the hypoxic, nutrient-deprived, and pro-angiogenic tumor microenvironment, heightened autophagy in the blood vessels is emerging as a critical mechanism enabling ECs to dynamically accommodate their higher bioenergetics demands to the extracellular environment and connect with other components of the tumor stroma through paracrine signaling. In this review, we provide an overview of the major cellular mechanisms regulated by autophagy in ECs and discuss their potential role in tumor angiogenesis, tumor growth, and response to anticancer therapy.Vascular homeostasis relies on the proper behavior of endothelial cells (ECs). Emerging evidence indicate a critical role of autophagy, a vesicular process for lysosomal degradation of cytoplasmic content, in EC biology. While EC-intrinsic autophagy promotes EC function and quiescent state through redox homeostasis and possibly metabolic control, a role for EC-associated autophagy in cancer seems more complex.

Following uncontrolled proliferation, a subset of primary tumour cells acquires additional traits/mutations to trigger phenotypic changes that enhance migration and are hypothesized to be the initiators of metastasis. This study reveals an adaptive mechanism that harnesses synergistic paracrine signalling via IL-6/8, which is amplified by cell proliferation and cell density, to directly promote cell migration. This effect occurs in metastatic human sarcoma and carcinoma cells– but not in normal or non-metastatic cancer cells-, and likely involves the downstream signalling of WASF3 and Arp2/3. The transcriptional phenotype of high-density cells that emerges due to proliferation resembles that of low-density cells treated with a combination of IL-6/8. Simultaneous inhibition of IL-6/8 receptors decreases the expression of WASF3 and Arp2/3 in a mouse xenograft model and reduces metastasis. This study reveals a potential mechanism that promotes tumour cell migration and infers a strategy to decrease metastatic capacity of tumour cells. Tumor cell proliferation and migration, key drivers of metastasis, can be mechanistically coupled in matrix embedded human sarcoma and carcinoma cells through cell density via a synergistic, paracrine signaling mechanism between Interleukins 6/8. Inhibition of this mechanism significantly decreases metastasis in mouse xenograft models.

Acute kidney injury (AKI) is a common, severe emergency case in clinics, with high incidence, significant mortality and increased costs. Despite development in the understanding of its pathophysiology, the therapeutic choices are still confined to dialysis and renal transplantation. Considering their antiapoptotic, immunomodulatory, antioxidative and pro‐angiogenic effects, mesenchymal stem cells (MSCs) may be a promising candidate for AKI management. Based on these findings, some clinical trials have been performed, but the results are contradictory (NCT00733876, NCT01602328). The low engraftment, poor survival rate, impaired paracrine ability and delayed administration of MSCs are the four main reasons for the limited clinical efficacy. Investigators have developed a series of preconditioning strategies to improve MSC survival rates and paracrine ability. In this review, by summarizing these encouraging studies, we intend to provide a comprehensive understanding of various preconditioning strategies on AKI therapy and improve the prognosis of AKI patients by regenerative medicine.

The major differentiated function of melanocytes is the synthesis of melanin, a pigmented heteropolymer that is synthesized in specialized cellular organelles termed melanosomes. Mature melanosomes are transferred to neighboring keratinocytes and are arranged in a supranuclear cap, protecting the DNA against incident ultraviolet light (UV) irradiation. The synthesis and distribution of melanin in the epidermis involves several steps: transcription of melanogenic proteins, melanosome biogenesis, sorting of melanogenic proteins into the melanosomes, transport of melanosomes to the tips of melanocyte dendrites and finally transfer into keratinocytes. These events are tightly regulated by a variety of paracrine and autocrine factors in response to endogenous and exogenous stimuli, principally UV irradiation.

Abstract IL-17A, IL-17F, and IL-25 belong to the IL-17 family of cytokines, and are well known to play important roles in the host defense against infection and inflammatory diseases. IL-17C, also a member of the IL-17 family, is highly expressed in the epithelium; however, the function and regulatory mechanism of IL-17C in airway epithelium remain poorly understood. In this study, we demonstrate that polyinosinic–polycytidylic acid (polyI:C), the ligand to Toll-like receptor 3, is a potent inducer of IL-17C mRNA and protein expression in primary normal human bronchial epithelial (NHBE) cells. IL-17C induction by polyI:C was both time dependent and dose dependent, and was attenuated by inhibitors of the Toll-IL-1 receptor domain–containing adaptor–inducing INF-β (TRIF)–NF-κB pathway, Pepinh-TRIF, BAY11, NF-κB inhibitor III, and NF-κB p65 small interfering RNA, suggesting that IL-17C expression is induced by polyI:C via the Toll-like receptor 3–TRIF–NF-κB pathway. Both IL-17C and polyI:C increased the expression of antimicrobial peptides and proinflammatory cytokines, such as human β-defensin (hBD) 2, colony-stimulating factor 3 (CSF3), and S100A12 in NHBE cells. Knockdown of IL-17 receptor (IL-17R) E, the specific receptor for IL-17C, using IL-17RE small interfering RNA, attenuated polyI:C-induced hBD2, CSF3, and S100A12 expression, without any reduction of polyI:C-induced IL-17C expression, which suggest that IL-17C enhances hBD2, CSF, and S100A12 expression in an autocrine/paracrine manner in NHBE cells. Knockdown of IL-17C also decreased polyI:C-induced hBD2, CSF3, and S100A12 expression. Thus, our data demonstrate that IL-17C is an essential epithelial cell–derived cytokine that enhances mucosal host defense responses in a unique autocrine/paracrine manner in the airway epithelium.

Direct evidence for a role of endogenous retinoic acid (RA), the active metabolite of vitamin A in the initial differentiation and meiotic entry of spermatogonia, and thus in the initiation of spermatogenesis is still lacking. RA is synthesized by dedicated enzymes, the retinaldehyde dehydrogenases (RALDH), and binds to and activates nuclear RA receptors (RARA, RARB, and RARG) either within the RA-synthesizing cells or in the neighboring cells. In the present study, we have used a combination of somatic genetic ablations and pharmacological approaches in vivo to show that during the first, prepubertal, spermatogenic cycle (i) RALDH-dependent synthesis of RA by Sertoli cells (SC), the supporting cells of the germ cell (GC) lineage, is indispensable to initiate differentiation of A aligned into A1 spermatogonia; (ii) RARA in SC mediates the effects of RA, possibly through activating Mafb expression, a gene whose Drosophila homolog is mandatory to GC differentiation; (iii) RA synthesized by premeiotic spermatocytes cell autonomously induces meiotic initiation through controlling the RAR-dependent expression of Stra8 . Furthermore, we show that RA of SC origin is no longer necessary for the subsequent spermatogenic cycles but essential to spermiation. Altogether, our data establish that the effects of RA in vivo on spermatogonia differentiation are indirect, via SC, but direct on meiotic initiation in spermatocytes, supporting thereby the notion that, contrary to the situation in the female, RA is necessary to induce meiosis in the male.

Scirrhous gastric cancer, which has the worst prognosis among the various types of gastric cancer, is highly invasive and associated with abundant stromal fibroblasts. Although cancer-associated fibroblasts (CAFs) have been proposed to generate a tumor-supportive extracellular matrix that promotes the expansion of this type of cancer, the molecular mechanisms by which CAFs assist cancer cells are not yet fully understood. Here, we show for the first time that Asporin, a small leucine-rich proteoglycan (SLRP), is predominantly expressed in CAFs, and has essential roles in promoting co-invasion of CAFs and cancer cells. CAFs of scirrhous gastric cancer possess high potential for invasion, and invasion by CAFs frequently proceeded invasion by cancer cells, both in vitro and in vivo . Expression of Asporin was induced in fibroblasts by exposure to gastric cancer cells. Asporin secreted from CAFs activates Rac1 via an interaction with CD44 and promotes invasion by CAFs themselves. Moreover, Asporin promoted invasion by neighboring cancer cells, via paracrine effects mediated by activation of the CD44–Rac1 pathway. These results suggest that Asporin is a unique SLRP that promotes progression of scirrhous gastric cancer and is required for coordinated invasion by CAFs and cancer cells. Therefore, Asporin may represent a new therapeutic target molecule for the development of drugs aimed at manipulating the cancer microenvironment.

β-Glucan derived from cell walls of is a potent immune modulator. It has been shown to induce trained immunity in monocytes via epigenetic and metabolic reprogramming and to protect from lethal sepsis if applied prior to infection. Since β-glucan-trained monocytes have not been classified within the system of mononuclear phagocytes we analyzed these cells metabolically, phenotypically and functionally with a focus on monocyte-to-macrophage differentiation and compared them with naïve monocytes and other types of monocyte-derived cells such as classically (M1) or alternatively (M2) activated macrophages and monocyte-derived dendritic cells (moDCs). We show that β-glucan inhibits spontaneous apoptosis of monocytes independent from autocrine or paracrine M-CSF release and stimulates monocyte differentiation into macrophages. β-Glucan-differentiated macrophages exhibit increased cell size and granularity and enhanced metabolic activity when compared to naïve monocytes. Although β-glucan-primed cells expressed markers of alternative activation and secreted higher levels of IL-10 after lipopolysaccharide (LPS), their capability to release pro-inflammatory cytokines and to kill bacteria was unaffected. Our data demonstrate that β-glucan priming induces a population of immune competent long-lived monocyte-derived macrophages that may be involved in immunoregulatory processes.

Background Low-intensity pulsed ultrasound (LIPUS) is an effective therapy for craniofacial bone regeneration. Paracrine signaling from mesenchymal stem cells (MSCs) plays a critical role in bone repair, but the impact of LIPUS on MSC-derived secretome remains unclear. This study investigates whether LIPUS enhances the osteogenic and angiogenic potential of MSCs through modulation of growth factor secretion. Methods Bone marrow-derived MSCs (BMSCs) were treated with or without LIPUS to generate conditioned media (LIPUS-CM and Ctrl-CM). Concentrations of IGF-1, VEGF, and TGF-β were quantified. These media were applied to other BMSCs and rat aortic endothelial cells (RAOECs). In vitro assays evaluated cell proliferation, migration, osteogenic differentiation, and angiogenesis. Data were analyzed using GraphPad and Image J, with significance set at α = 0.05. Results LIPUS significantly upregulated IGF-1 and VEGF secretion in BMSCs, while TGF-β levels remained unchanged. RAOECs cultured in LIPUS-CM demonstrated enhanced proliferation, migration, and angiogenic capacity. Likewise, BMSCs cultured in LIPUS-CM showed improved proliferation, migration, and osteogenic differentiation compared to the Ctrl-CM group. Conclusion LIPUS promotes osteogenic differentiation of BMSCs and angiogenesis in RAOECs through the paracrine signaling of BMSCs, at least by increasing IGF-1 and VEGF secretion. This suggests that LIPUS can regulate the secretome of BMSCs and may serve as a key mechanism in promoting bone tissue regeneration.