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International Journal of Molecular... Jun 2024While much has been learned about sphingolipids, originally named for their sphinx-like enigmatic properties, there are still many unanswered questions about the... (Review)
Review
While much has been learned about sphingolipids, originally named for their sphinx-like enigmatic properties, there are still many unanswered questions about the possible effect(s) of the composition of ceramide on the synthesis and/or behavior of a glycosphingolipid (GSL). Over time, studies of their ceramide component, the sphingoid base containing the lipid moiety of GSLs, were frequently distinct from those performed to ascertain the roles of the carbohydrate moieties. Due to the number of classes of GSLs that can be derived from ceramide, this review focuses on the possible role(s) of ceramide in the synthesis/function of just one GSL class, derived from glucosylceramide (Glc-Cer), namely sialylated ganglio derivatives, initially characterized and named gangliosides (GGs) due to their presence in ganglion cells. While much is known about their synthesis and function, much is still being learned. For example, it is only within the last 15-20 years or so that the mechanism by which the fatty acyl component of ceramide affected its transport to different sites in the Golgi, where it is used for the synthesis of Glu- or galactosyl-Cer (Gal-Cer) and more complex GSLs, was defined. Still to be fully addressed are questions such as (1) whether ceramide composition affects the transport of partially glycosylated GSLs to sites where their carbohydrate chain can be elongated or affects the activity of glycosyl transferases catalyzing that elongation; (2) what controls the differences seen in the ceramide composition of GGs that have identical carbohydrate compositions but vary in that of their ceramide and vice versa; (3) how alterations in ceramide composition affect the function of membrane GGs; and (4) how this knowledge might be applied to the development of therapies for treating diseases that correlate with abnormal expression of GGs. The availability of an updatable data bank of complete structures for individual classes of GSLs found in normal tissues as well as those associated with disease would facilitate research in this area.
Topics: Ceramides; Humans; Animals; Gangliosides; Glycosphingolipids; Sphingolipids; Glucosylceramides
PubMed: 38928016
DOI: 10.3390/ijms25126312 -
Cancers Jun 2024The skeletal system is a common site for metastasis from breast cancer. In our prior work, we developed induced tumor-suppressing cells (iTSCs) capable of secreting a...
BACKGROUND
The skeletal system is a common site for metastasis from breast cancer. In our prior work, we developed induced tumor-suppressing cells (iTSCs) capable of secreting a set of tumor-suppressing proteins. In this study, we examined the possibility of identifying anticancer peptides (ACPs) from trypsin-digested protein fragments derived from iTSC proteomes.
METHODS
The efficacy of ACPs was examined using an MTT-based cell viability assay, a Scratch-based motility assay, an EdU-based proliferation assay, and a transwell invasion assay. To evaluate the mechanism of inhibitory action, a fluorescence resonance energy transfer (FRET)-based GTPase activity assay and a molecular docking analysis were conducted. The efficacy of ACPs was also tested using an ex vivo cancer tissue assay and a bone microenvironment assay.
RESULTS
Among the 12 ACP candidates, P18 (TDYMVGSYGPR) demonstrated the most effective anticancer activity. P18 was derived from Arhgdia, a Rho GDP dissociation inhibitor alpha, and exhibited inhibitory effects on the viability, migration, and invasion of breast cancer cells. It also hindered the GTPase activity of RhoA and Cdc42 and downregulated the expression of oncoproteins such as Snail and Src. The inhibitory impact of P18 was additive when it was combined with chemotherapeutic drugs such as Cisplatin and Taxol in both breast cancer cells and patient-derived tissues. P18 had no inhibitory effect on mesenchymal stem cells but suppressed the maturation of RANKL-stimulated osteoclasts and mitigated the bone loss associated with breast cancer. Furthermore, the P18 analog modified by N-terminal acetylation and C-terminal amidation (Ac-P18-NH2) exhibited stronger tumor-suppressor effects.
CONCLUSIONS
This study introduced a unique methodology for selecting an effective ACP from the iTSC secretome. P18 holds promise for the treatment of breast cancer and the prevention of bone destruction by regulating GTPase signaling.
PubMed: 38927935
DOI: 10.3390/cancers16122230 -
Biomolecules Jun 2024Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of...
Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of treatment with the gasdermin D inhibitor necrosulfonamide on experimental AAAs. AAAs were induced in male apolipoprotein E-deficient mice by subcutaneous angiotensin II infusion (1000 ng/kg body weight/min), with daily administration of necrosulfonamide (5 mg/kg body weight) or vehicle starting 3 days prior to angiotensin II infusion for 30 days. Necrosulfonamide treatment remarkably suppressed AAA enlargement, as indicated by reduced suprarenal maximal external diameter and surface area, and lowered the incidence and reduced the severity of experimental AAAs. Histologically, necrosulfonamide treatment attenuated medial elastin breaks, smooth muscle cell depletion, and aortic wall collagen deposition. Macrophages, CD4 T cells, CD8 T cells, and neovessels were reduced in the aneurysmal aortas of necrosulfonamide- as compared to vehicle-treated angiotensin II-infused mice. Atherosclerosis and intimal macrophages were also substantially reduced in suprarenal aortas from angiotensin II-infused mice following necrosulfonamide treatment. Additionally, the levels of serum interleukin-1β and interleukin-18 were significantly lower in necrosulfonamide- than in vehicle-treated mice without affecting body weight gain, lipid levels, or blood pressure. Our findings indicate that necrosulfonamide reduced experimental AAAs by preserving aortic structural integrity as well as reducing mural leukocyte accumulation, neovessel formation, and systemic levels of interleukin-1β and interleukin-18. Thus, pharmacologically inhibiting gasdermin D activity may lead to the establishment of nonsurgical therapies for clinical AAA disease.
Topics: Animals; Angiotensin II; Aortic Aneurysm, Abdominal; Mice; Male; Sulfonamides; Apolipoproteins E; Phosphate-Binding Proteins; Disease Models, Animal; Mice, Inbred C57BL; Macrophages; Indoles; Mice, Knockout, ApoE; Gasdermins
PubMed: 38927129
DOI: 10.3390/biom14060726 -
Biomolecules May 2024Transient Receptor Potential Ankyrin 1 (TRPA1) is a non-selective cation channel involved in sensitivity to a plethora of irritating agents and endogenous mediators of...
Transient Receptor Potential Ankyrin 1 (TRPA1) is a non-selective cation channel involved in sensitivity to a plethora of irritating agents and endogenous mediators of oxidative stress. TRPA1 influences neuroinflammation and macrophage and lymphocyte functions, but its role is controversial in immune cells. We reported earlier a detectable, but orders-of-magnitude-lower level of mRNA in monocytes and lymphocytes than in sensory neurons by qRT-PCR analyses of cells from lymphoid organs of mice. Our present goals were to (a) further elucidate the expression of mRNA in immune cells by RNAscope in situ hybridization (ISH) and (b) test the role of TRPA1 in lymphocyte activation. RNAscope ISH confirmed that transcripts were detectable in CD14 and CD4 cells from the peritoneal cavity of mice. A selective TRPA1 agonist JT010 elevated Ca levels in these cells only at high concentrations. However, a concentration-dependent inhibitory effect of JT010 was observed on T-cell receptor (TcR)-induced Ca signals in CD4 T lymphocytes, while JT010 neither modified B cell activation nor ionomycin-stimulated Ca level. Based on our present and past findings, TRPA1 activation negatively modulates T lymphocyte activation, but it does not appear to be a key regulator of TcR-stimulated calcium signaling.
Topics: TRPA1 Cation Channel; Animals; Mice; Lymphocyte Activation; T-Lymphocytes; Ligands; CD4-Positive T-Lymphocytes; Acetanilides; Mice, Inbred C57BL; Calcium; Receptors, Antigen, T-Cell; RNA, Messenger; Male; Calcium Signaling
PubMed: 38927036
DOI: 10.3390/biom14060632 -
Biomolecules May 2024Hydrogels are three-dimensional crosslinked functional materials with water-absorbing and swelling properties. Many hydrogels can store a variety of small functional... (Review)
Review
Hydrogels are three-dimensional crosslinked functional materials with water-absorbing and swelling properties. Many hydrogels can store a variety of small functional molecules to structurally and functionally mimic the natural extracellular matrix; hence, they have been extensively studied for biomedical applications. Polyamidoamine (PAMAM) dendrimers have an ethylenediamine core and a large number of peripheral amino groups, which can be used to engineer various polymer hydrogels. In this review, an update on the progress of using PAMAM dendrimers for multifunctional hydrogel design was given. The synthesis of these hydrogels, which includes click chemistry reactions, aza-Michael addition, Schiff base reactions, amidation reactions, enzymatic reactions, and radical polymerization, together with research progress in terms of their application in the fields of drug delivery, tissue engineering, drug-free tumor therapy, and other related fields, was discussed in detail. Furthermore, the biomedical applications of PAMAM-engineered nano-hydrogels, which combine the advantages of dendrimers, hydrogels, and nanoparticles, were also summarized. This review will help researchers to design and develop more functional hydrogel materials based on PAMAM dendrimers.
Topics: Hydrogels; Dendrimers; Humans; Tissue Engineering; Polyamines; Drug Delivery Systems; Animals; Click Chemistry; Biocompatible Materials
PubMed: 38927024
DOI: 10.3390/biom14060620 -
BMC Pediatrics Jun 2024Despite the highest (88%) Prevention of Mother-To-Child Transmission (PMTCT) of HIV coverage in Eastern Africa, 50% of new HIV infections in children aged 0-14 years...
Feeding modalities, HIV transmission and its predictors among HIV-exposed infants visited Gamo and Gofa zones public health facilities, Southern Ethiopia: a retrospective follow up study.
BACKGROUND
Despite the highest (88%) Prevention of Mother-To-Child Transmission (PMTCT) of HIV coverage in Eastern Africa, 50% of new HIV infections in children aged 0-14 years occur in the region.
OBJECTIVE
The aim of this study was to assess the feeding modalities, the rate of HIV transmission and its predictors among HIV exposed infants (HIV-EIs) visited Gamo and Gofa Zones public health facilities, Southern Ethiopia from January 2013 to February 2019.
METHOD AND MATERIALS
Institution-based retrospective follow up study was employed among 450 HIV-EIs having DNA/PCR test results. All infant-mother pair records in selected health facilities were reviewed using a standard data extraction tool from March to July 2019. HIV transmission probabilities were assessed by Kaplan-Meier time-to-event analysis method and log-rank tests were used to compare the risk among different groups. The Cox-proportional hazards model, adjusted on infant feeding modalities and other co-variants was used to identify predictors of HIV transmission, and statistical significance was declared at a p-value of < 0.05.
RESULTS
In total, 383 complete records were analyzed. In the study, 85.6% (95%CI: 81.6%, 89.1%) of HIV-EIs were exclusively breastfed in the first six months. The 18 months probability of infant HIV transmission was 64 (16.7%) (95%CI: 13.1%-20.8%). The risk of HIV-transmission was higher among infants who were delivered at the hospital than health centers/health posts (AHR = 3.07; 95%CI: 1.19, 7.95); discontinued Cotrimoxazole prophylaxis in at least one visit (AHR = 6.32; 95%CI: 3.35, 11.94); did not exclusively breastfeed (AHR = 3.07; 95%CI: 1.72, 5.47) and came from urban areas (AHR = 5.90; 95%CI: 1.40, 24.85).
CONCLUSIONS
The study showed that HIV-EIs had a greater rate of 18 months HIV transmission than the national pooled prevalence. The risk of transmission is higher among infants who do not breastfeed exclusively for the first 6 months, and the risk increases with the number of months spent by breastfeeding. Therefore, strengthening counselling on safer feeding options and Cotrimoxazole prophylaxis use; provision of quality PMTCT service with special focus in hospitals and urban residents were recommended.
Topics: Humans; Ethiopia; HIV Infections; Infectious Disease Transmission, Vertical; Retrospective Studies; Infant; Female; Breast Feeding; Male; Infant, Newborn; Follow-Up Studies; Bottle Feeding; Trimethoprim, Sulfamethoxazole Drug Combination; Adult; Risk Factors; Infant Formula
PubMed: 38926639
DOI: 10.1186/s12887-024-04894-w -
Journal of Clinical and Experimental... 2024
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides; Rituximab; Bridged Bicyclo Compounds, Heterocyclic; Retrospective Studies; Male; Aged; Female; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Japan; Treatment Outcome; Aged, 80 and over; East Asian People
PubMed: 38925975
DOI: 10.3960/jslrt.24014 -
PloS One 2024Spilanthes filicaulis (Schumach. & Thonn.) C. D Adam is a shrubby plant of the Asteraceae family that has medicinal benefits for the pharmaceutical and cosmetic...
Spilanthes filicaulis (Schumach. & Thonn.) C. D Adam leaf extract prevents assault of streptozotocin on liver cells via inhibition of oxidative stress and activation of the NrF2/Keap1, PPARγ, and PTP1B signaling pathways.
BACKGROUND
Spilanthes filicaulis (Schumach. & Thonn.) C. D Adam is a shrubby plant of the Asteraceae family that has medicinal benefits for the pharmaceutical and cosmetic industries.
PURPOSE
The purpose of this study was to assess the effectiveness of Spilanthes filicaulis leaf extract in a streptozotocin (STZ)-induced rat model and the associated signaling pathways.
METHODS
A sample of 25 male Wistar rats was randomly assigned to groups I, II, III, IV, and V. Each group included five animals, i.e., control rats, diabetic control rats, diabetic rats treated with metformin, and diabetic rats treated with 150 mg/kg/bw and 300 mg/kg/bw of the methanolic extract of S. filicaulis leaves (MESFL). Treatment was administered for 15 successive days via oral gavage. After 15 days, the rats were evaluated for fasting blood glucose (FBG), glycated hemoglobin (HbA1c), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), reduced glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), lipid peroxidation (MDA), hexokinase, and glucose-6-phosphatase activities. Gene expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor gamma (PPAR-γ), kelch-like ECH-associated protein 1 (Keap1), protein tyrosine phosphatase 1B (PTP1B) and the antiapoptotic protein caspase-3 were examined.
RESULTS
MESFL was administered to diabetic rats, and changes in body weight, fasting blood glucose (FBG) and HbA1c were restored. Furthermore, in diabetic rats, S. filicaulis significantly reduced the levels of triglycerides (TGs), total cholesterol (TC), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) and significantly increased HDL. S. filicaulis improved ALT, AST, and ALP enzyme activity in diabetic rats. MDA levels decreased considerably with increasing activity of antioxidant enzymes, such as GST, SOD, CAT and GSH, in diabetic liver rats treated with S. filicaulis. Diabetic rats treated with MESFL and metformin exhibited upregulated mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor gamma (PPAR-γ). Kelch-like ECH-associated protein 1 (Keap1) and protein tyrosine phosphatase 1B (PTP1B) mRNA expression in the liver was downregulated in diabetic rats treated with MESFL and metformin. In addition, MESFL downregulated the mRNA expression of caspase-3 in diabetic rats.
CONCLUSION
It can be concluded from the data presented in this study that MESFL exerts a protective effect on diabetic rats due to its antidiabetic, antioxidant, antihyperlipidemic and antiapoptotic effects and may be considered a treatment for T2DM.
Topics: Animals; NF-E2-Related Factor 2; Male; Plant Extracts; Kelch-Like ECH-Associated Protein 1; Oxidative Stress; Plant Leaves; Signal Transduction; Rats; Rats, Wistar; Diabetes Mellitus, Experimental; PPAR gamma; Liver; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Asteraceae; Streptozocin; Hypoglycemic Agents
PubMed: 38924022
DOI: 10.1371/journal.pone.0306039 -
PloS One 2024Antibiotic persistence is a phenomenon, where a small fraction of a bacterial population expresses a phenotypic variation that allows them to survive antibiotic...
Antibiotic persistence is a phenomenon, where a small fraction of a bacterial population expresses a phenotypic variation that allows them to survive antibiotic treatment, which is lethal to the rest of the population. These cells are called persisters cells, and their occurrence has been associated with recurrent disease. Streptococcus agalactiae is a human pathobiont, able to cause invasive infections, and recurrent infections have been reported to occur in both newborns and adults. In this study, we demonstrated that S. agalactiae NEM316 can form persister cells when exposed to antibiotics from different classes. The frequency of persister cell formation was dependent on bacterial growth phase and the class of antibiotics. The ability to form persister cells in response to penicillin was shown to be a general trait among different clinical S. agalactiae isolates, independent of sero- and sequence-type. Taken together, this study shows the existence of antibiotic tolerant S. agalactiae persister cells, which may explain why this bacterial species frequently persists after treatment of invasive infection and can be associated with recurrent disease.
Topics: Streptococcus agalactiae; Anti-Bacterial Agents; Humans; Microbial Sensitivity Tests; Streptococcal Infections; Drug Resistance, Bacterial; Penicillins
PubMed: 38924011
DOI: 10.1371/journal.pone.0303271 -
Cancer Medicine Jun 2024A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene....
INTRODUCTION
A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK-TKIs.
METHOD
To investigate the mechanism of resistance to NTRK-TKIs, we established cells resistant to three types of NTRK-TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3-NTRK1 rearrangement.
RESULT
Overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12-LR, KM12-ER, and KM12-SR) by microarray analysis. Lower expression of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12-ER and KM12-SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12-LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK-TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK-TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK-TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK-TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone.
CONCLUSION
These results suggest that HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance.
Topics: Humans; Animals; Drug Resistance, Neoplasm; Mice; Cell Line, Tumor; Protein Kinase Inhibitors; Mevalonic Acid; Xenograft Model Antitumor Assays; Colonic Neoplasms; Receptor, trkA; Hydroxymethylglutaryl-CoA Synthase; Benzamides; Pyrimidines; Pyrazoles; Indazoles
PubMed: 38923428
DOI: 10.1002/cam4.7393