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Experimental & Molecular Medicine Jul 2024Serine is a key contributor to the generation of one-carbon units for DNA synthesis during cellular proliferation. In addition, it plays a crucial role in the production... (Review)
Review
Serine is a key contributor to the generation of one-carbon units for DNA synthesis during cellular proliferation. In addition, it plays a crucial role in the production of antioxidants that prevent abnormal proliferation and stress in cancer cells. In recent studies, the relationship between cancer metabolism and the serine biosynthesis pathway has been highlighted. In this context, 3-phosphoglycerate dehydrogenase (PHGDH) is notable as a key enzyme that functions as the primary rate-limiting enzyme in the serine biosynthesis pathway, facilitating the conversion of 3-phosphoglycerate to 3-phosphohydroxypyruvate. Elevated PHGDH activity in diverse cancer cells is mediated through genetic amplification, posttranslational modification, increased transcription, and allosteric regulation. Ultimately, these characteristics allow PHGDH to not only influence the growth and progression of cancer but also play an important role in metastasis and drug resistance. Consequently, PHGDH has emerged as a crucial focal point in cancer research. In this review, the structural aspects of PHGDH and its involvement in one-carbon metabolism are investigated, and PHGDH is proposed as a potential therapeutic target in diverse cancers. By elucidating how PHGDH expression promotes cancer growth, the goal of this review is to provide insight into innovative treatment strategies. This paper aims to reveal how PHGDH inhibitors can overcome resistance mechanisms, contributing to the development of effective cancer treatments.
PubMed: 38945960
DOI: 10.1038/s12276-024-01268-1 -
Experimental & Molecular Medicine Jul 2024Angiotensin II (AngII) induces the contraction and proliferation of vascular smooth muscle cells (VSMCs). AngII activates phospholipase C-β (PLC-β), thereby inducing...
Angiotensin II (AngII) induces the contraction and proliferation of vascular smooth muscle cells (VSMCs). AngII activates phospholipase C-β (PLC-β), thereby inducing Ca mobilization as well as the production of reactive oxygen species (ROS). Since contraction is a unique property of contractile VSMCs, signaling cascades related to the proliferation of VSMCs may differ. However, the specific molecular mechanism that controls the contraction or proliferation of VSMCs remains unclear. AngII-induced ROS production, migration, and proliferation were suppressed by inhibiting PLC-β3, inositol trisphosphate (IP) receptor, and NOX or by silencing PLC-β3 or NOX1 but not by NOX4. However, pharmacological inhibition or silencing of PLC-β3 or NOX did not affect AngII-induced VSMC contraction. Furthermore, the AngII-dependent constriction of mesenteric arteries isolated from PLC-β3, NOX1, NOX4 and normal control mice was similar. AngII-induced VSMC contraction and mesenteric artery constriction were blocked by inhibiting the L-type calcium channel Rho-associated kinase 2 (ROCK2) or myosin light chain kinase (MLCK). The activation of ROCK2 and MLCK was significantly induced in PLC-β3 mice, whereas the depletion of Ca in the extracellular medium suppressed the AngII-induced activation of ROCK2, MLCK, and vasoconstriction. AngII-induced hypertension was significantly induced in NOX1 and PLC-β3 mice, whereas LCCA ligation-induced neointima formation was significantly suppressed in NOX1 and PLC-β3 mice. These results suggest that PLC-β3 is essential for vascular hyperplasia through NOX1-mediated ROS production but is nonessential for vascular constriction or blood pressure regulation.
PubMed: 38945956
DOI: 10.1038/s12276-024-01271-6 -
Experimental & Molecular Medicine Jul 2024The development of chemoresistance is a major challenge in the treatment of several types of cancers in clinical settings. Stemness and chemoresistance are the chief... (Review)
Review
The development of chemoresistance is a major challenge in the treatment of several types of cancers in clinical settings. Stemness and chemoresistance are the chief causes of poor clinical outcomes. In this context, we hypothesized that understanding the signaling pathways responsible for chemoresistance in cancers is crucial for the development of novel targeted therapies to overcome drug resistance. Among the aberrantly activated pathways, the PI3K-Akt/Wnt/β-catenin signaling pathway is clinically implicated in malignancies such as colorectal cancer (CRC) and glioblastoma multiforme (GBM). Aberrant dysregulation of phospholipase D (PLD) has been implicated in several malignancies, and oncogenic activation of this pathway facilitates tumor proliferation, stemness, and chemoresistance. Crosstalk involving the PLD and Wnt/β-catenin pathways promotes the progression of CRC and GBM and reduces the sensitivity of cancer cells to standard therapies. Notably, both pathways are tightly regulated and connected at multiple levels by upstream and downstream effectors. Thus, gaining deeper insights into the interactions between these pathways would help researchers discover unique therapeutic targets for the management of drug-resistant cancers. Here, we review the molecular mechanisms by which PLD signaling stimulates stemness and chemoresistance in CRC and GBM. Thus, the current review aims to address the importance of PLD as a central player coordinating cross-talk between the PI3K/Akt and Wnt/β-catenin pathways and proposes the possibility of targeting these pathways to improve cancer therapy and overcome drug resistance.
PubMed: 38945955
DOI: 10.1038/s12276-024-01260-9 -
Experimental & Molecular Medicine Jul 2024The hypoxia-inducible factor-1α (HIF-1α) pathway coordinates skeletal bone homeostasis and endocrine functions. Activation of the HIF-1α pathway increases glucose...
The hypoxia-inducible factor-1α (HIF-1α) pathway coordinates skeletal bone homeostasis and endocrine functions. Activation of the HIF-1α pathway increases glucose uptake by osteoblasts, which reduces blood glucose levels. However, it is unclear whether activating the HIF-1α pathway in osteoblasts can help normalize glucose metabolism under diabetic conditions through its endocrine function. In addition to increasing bone mass and reducing blood glucose levels, activating the HIF-1α pathway by specifically knocking out Von Hippel‒Lindau (Vhl) in osteoblasts partially alleviated the symptoms of streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM), including increased glucose clearance in the diabetic state, protection of pancreatic β cell from STZ-induced apoptosis, promotion of pancreatic β cell proliferation, and stimulation of insulin secretion. Further screening of bone-derived factors revealed that islet regeneration-derived protein III gamma (RegIIIγ) is an osteoblast-derived hypoxia-sensing factor critical for protection against STZ-induced T1DM. In addition, we found that iminodiacetic acid deferoxamine (SF-DFO), a compound that mimics hypoxia and targets bone tissue, can alleviate symptoms of STZ-induced T1DM by activating the HIF-1α-RegIIIγ pathway in the skeleton. These data suggest that the osteoblastic HIF-1α-RegIIIγ pathway is a potential target for treating T1DM.
PubMed: 38945950
DOI: 10.1038/s12276-024-01257-4 -
Experimental Animals Jun 2024The complement active product, C3a, and the receptor C3aR comprise an axis that exerts various biological functions, such as protection against infection. C3a is highly...
The complement active product, C3a, and the receptor C3aR comprise an axis that exerts various biological functions, such as protection against infection. C3a is highly expressed in the inflamed skin and blood from patients with psoriasiform dermatitis. However, the role of the C3a/C3aR axis in psoriasiform dermatitis remains unclear because conflicting results using C3 mice have been published. In this study, to elucidate the contribution of commensal microbiota in C3 and wild-type (WT) mice were subjected to imiquimod-induced psoriasiform dermatitis under different housing conditions. C3 mice showed increased epidermal thickness and keratinocyte proliferation markers in the inflamed ear compared to WT mice upon treatment with IMQ. These inflamed phenotypes were observed in both cohoused and separately housed conditions, and antibiotic treatment did not abolish the aggravation of IMQ-induced psoriasiform dermatitis in C3 mice. These results suggested that the difference of commensal microbiota is not important for the C3-involved psoriasiform dermatitis. Keratinocyte hyperproliferation is a major feature of the inflamed skin in patients with psoriasiform dermatitis. In vitro experiments showed that C3a and C3aR agonists inhibited keratinocyte proliferation, which was abolished by introduction of a C3aR antagonist. Collectively, these results suggest that the C3a/C3aR axis plays a critical role in psoriasiform dermatitis development by inhibiting keratinocyte proliferation, regardless of the regulation of the commensal microbiota.
PubMed: 38945882
DOI: 10.1538/expanim.24-0043 -
International Journal of Biological... Jun 2024Bioactive hydrogels are currently receiving significant attention. In this study, silk fibroin tyramine-modified gelatin hydrogels (SF-TG) with varying degrees of...
Bioactive hydrogels are currently receiving significant attention. In this study, silk fibroin tyramine-modified gelatin hydrogels (SF-TG) with varying degrees of tyramine root substitution were explored. The physicochemical property and biocompatibility of low degree of substitution tyramine-modified gelatin hydrogel (SF-LTG) and high degree of substitution tyramine-modified gelatin hydrogel (SF-HTG) were compared. The results showed that SF-LTG possessed better mechanical property and higher biocompatibility. Thus, SF-LTG was selected as a bioactive matrix and loaded with basic fibroblast growth factor (bFGF); subsequently, curcumin-coupled chitosan rods (CCCRs-EGF) enriched with epidermal growth factor (EGF) were added to obtain SF-LTG-bFGF@CCCRs-EGF hydrogels. The results showed that SF-LTG-bFGF@CCCRs-EGF retained the basic structural and mechanical properties of the SF-LTG matrix gel material and underwent multiple loading and orderly release with different activities while displaying antioxidant, anti-inflammatory, antimicrobial, and pro-cellular proliferation activities and orderly regulation of activity during wound healing. Therefore, the SF-LTG-bFGF@CCCRs-EGF hydrogel is of great value in healing complex wounds.
PubMed: 38945708
DOI: 10.1016/j.ijbiomac.2024.133251 -
Immunobiology Jun 2024The pro-tumorigenic or anti-tumorigenic role of tumor infiltrating mast cells (TIMs) in tumors depends not only on the type of cancer and the degree of tumor...
The pro-tumorigenic or anti-tumorigenic role of tumor infiltrating mast cells (TIMs) in tumors depends not only on the type of cancer and the degree of tumor progression, but also on their location in the tumor bulk. In our investigation, we employed immunohistochemistry to reveal that the mast cells (MCs) in the tumor stroma are positively correlated with metastasis of ovarian cancer (OC), but not in the tumor parenchyma. To delve deeper into the influence of different culture matrix stiffness on MCs' biological functions within the tumor parenchymal and stromal regions, we conducted a transcriptome analysis of the mouse MC line (P815) cultured in two-dimensional (2D) or three-dimensional (3D) culture system. Further research has found that the softer 3D extracellular matrix stiffness could improve the mitochondrial activity of MCs to promote proliferation by increasing the expression levels of mitochondrial activity-related genes, namely Pet100, atp5md, and Cox7a2. Furthermore, employing LASSO regression analysis, we identified that Pet100 and Cox7a2 were closely associated with the prognosis of OC patients. These two genes were subsequently employed to construct a risk score model, which revealed that the high-risk group model as one of the prognostic factors for OC patients. Additionally, the XCell algorithm analysis showed that the high-risk group displayed a broader spectrum of immune cell infiltrations. Our research revealed that TIMs in the tumor stroma could promote the metastasis of OC, and mitochondrial activity-related proteins Pet100/Cox7a2 can serve as biomarkers for prognostic evaluation of OC.
PubMed: 38944891
DOI: 10.1016/j.imbio.2024.152831 -
Mymensingh Medical Journal : MMJ Jul 2024Multiple myeloma (MM), mature B-cell lineage neoplasm, is characterized by abnormal clonal proliferation of plasma cells and presence of monoclonal protein (M protein)....
Multiple myeloma (MM), mature B-cell lineage neoplasm, is characterized by abnormal clonal proliferation of plasma cells and presence of monoclonal protein (M protein). The study was conducted to reveal presenting features, laboratory findings, Eastern Cooperative Oncology Group (ECOG) performance status and skeletal survey on patients with multiple myeloma. This descriptive, cross-sectional study was carried out in the Department of Haematology, Dhaka Medical College Hospital, Dhaka, Bangladesh from January 2019 to July 2020 with a sample size of 81. Data were collected in a case record form after obtaining informed verbal consent from patients and /or their legal guardians. Relevant ethical issues and data quality assurance were taken into consideration. Data were analyzed with SPSS, Version 25.0 with presentation in figures and tables with frequency, percentage, mean and standard deviation based on data nature. Statistical tests were carried out as appropriate with 5.0% level of significance for assessing statistical association. Mean age of the patients was 58.9±12.0 years. Male female ratio was 2:1. 35(43.2%) patients were smokers with only 2(2.5%) had family history of haematological malignancies. Bone pain (72.8%) was the most common presenting feature, while hypertension (59.1%), diabetes mellitus (29.5%), respiratory illness (11.3%) and cardiac disease (11.4%) were the common co-morbidities. Most common ECOG performance status was ECOG-1(48.1%). Mean haemoglobin (Hb) was 9.4±2.3gm/dl and mean erythrocyte sedimentation rate (ESR) was 89.5±42.1 mm in 1st hour. Mean serum creatinine level was 2.0±1.85 mg/dl and ≥2.0mg/dl in 42(34.2%). Among 50 documentation serum lactate dehydrogenase (LDH) was raised in 18(36.0%). Mean serum calcium level was 9.6±1.8mg/dl >11.0mg/dL in 10(14.5%) cases. Serum albumin <3.5gm/dl in 37(49.3%), β2-microglobulin >5.5mg/dl in 37(57.8%) cases, International staging system (ISS) stage III was in 59.4% and Bence Jones Protein (BJP) was present in 46.7% cases. Lytic lesions were present in 75.0%, In 38(74.5%) patients vertebrae were involved, while in 18(35.2%) ribs were involved, in 14(27.5%) patients skull was involved and in 3(5.9%) patients involved bones were femur, humerus, sternum and scapula. Mean plasma cells percentage was 62.1±24.9%. Immuno-Fixation Electrophoresis (IFE) revealed IgG (72.7%), IgA (18.2%), Free light chain (FLC) (9.1%). FLC ratio was ≥100 in 29.0% cases. Significant statistical association was observed between serum creatinine with Hb concentration (p<0.05), serum creatinine level with ISS staging (p<0.05) and serum calcium level (p<0/05), while insignificant association was revealed between BJP present status and serum creatinine level (p>0.05). Bone pain, fatigue, fever and neurological impairment were the common presenting features. Anaemia, renal impairment and skeletal lytic events were the prominent physical findings. ISS staging was statistically associated with serum creatinine level, while serum calcium level was associated with serum creatinine and lytic lesions.
Topics: Humans; Multiple Myeloma; Male; Female; Middle Aged; Cross-Sectional Studies; Tertiary Care Centers; Aged; Bangladesh; Adult
PubMed: 38944730
DOI: No ID Found -
Anatomia, Histologia, Embryologia Jul 2024The spleen is the largest secondary lymphoid organ with significant roles in pathogen clearance. It is involved in several avian diseases. The cattle egret is a wild...
The spleen is the largest secondary lymphoid organ with significant roles in pathogen clearance. It is involved in several avian diseases. The cattle egret is a wild insectivorous bird of agricultural and socioeconomic importance. Data related to microstructural features of cattle egret spleen are lacking. The present study investigated the gross anatomical, histological and immunohistochemical characteristics of the cattle egret spleen. Proliferation (PCNA and PHH3), apoptosis (cleaved caspase 3, C.CASP3) and T-cell (CD3 and CD8) markers were assessed. Grossly, the spleen appeared brownish red, oval-shaped and located at the oesophago-proventricular junction. Histologically, the spleen was surrounded by a thin capsule sending a number of trabeculae which contained branches of the splenic vessels. The white pulp consisted of the periarteriolar lymphoid sheath and periellipsoidal lymphatic sheath (PELS). The red pulp was formed of sinusoids and cords. The penicillar capillaries, which represent the terminal segments of the splenic arterial tree were highly branched, wrapped by prominent ellipsoids and directly connected to the splenic sinusoids, suggesting a closed type of circulation. Immunohistochemically, proliferating cell nuclear antigen (PCNA)-expressing cells were distributed with high counts throughout the splenic parenchyma, being highest within the splenic cords and PELS. Both PHH3- and C.CASP3-expressing cells revealed a similar pattern to that of PCNA, although with fewer counts. Large numbers of T cells were observed throughout the splenic parenchyma, mainly within the cords, as revealed by CD3 and CD8 immunoreaction. The present study provides a clear insight into the precise structure of the spleen in cattle egrets and thus improves our understanding about birds' immunity.
Topics: Animals; Spleen; Apoptosis; Cell Proliferation; Proliferating Cell Nuclear Antigen; T-Lymphocytes; Birds; Immunohistochemistry; CD3 Complex; Biomarkers; Caspase 3
PubMed: 38944689
DOI: 10.1111/ahe.13082 -
Journal of Extracellular Vesicles Jul 2024Extracellular vesicles (EVs) play a crucial role in triggering tumour-aggressive behaviours. However, the energetic process by which tumour cells produce EVs remains...
Extracellular vesicles (EVs) play a crucial role in triggering tumour-aggressive behaviours. However, the energetic process by which tumour cells produce EVs remains poorly understood. Here, we demonstrate the involvement of β-hexosaminidase B (HEXB) in mediating EV release in response to oxidative stress, thereby promoting the development of hepatocellular carcinoma (HCC). Mechanistically, reactive oxygen species (ROS) stimulate the nuclear translocation of transcription factor EB (TFEB), leading to the upregulation of both HEXB and its antisense lncRNA HEXB-AS. HEXB-AS can bind HEXB to form a protein/RNA complex, which elevates the protein stability of HEXB. The stabilized HEXB interacts with lysosome-associated membrane glycoprotein 1 (LAMP1), disrupting lysosome-multivesicular body (MVB) fusion, which protects EVs from degradation. Knockdown of HEXB efficiently inhibits EV release and curbs HCC growth both in vitro and in vivo. Moreover, targeting HEXB by M-31850 significantly inhibits HCC growth, especially when combined with GW4869, an inhibitor of exosome release. Our results underscore the critical role of HEXB as a modulator that promotes EV release during HCC development.
Topics: Extracellular Vesicles; Carcinoma, Hepatocellular; Animals; Oxidative Stress; Humans; Liver Neoplasms; Mice; Up-Regulation; Cell Line, Tumor; Cell Proliferation; RNA, Long Noncoding; Reactive Oxygen Species; Gene Expression Regulation, Neoplastic; Male; Mice, Nude
PubMed: 38944674
DOI: 10.1002/jev2.12468