Biology subjects

Nik-Akhtar, A.

Publications and source records attributed to Nik-Akhtar, A..

3 recordsLinked to original sources

bioRxiv2026

PARP1/2-linked ADP-ribosylation impairs trophoblast mitochondrial respiration in a TNF-α model of inflammation-mediated preeclampsia.

Inflammation-mediated preeclampsia (I-PE) is associated with increased placental NAD+-dependent ADP-ribosylation and NAD+ depletion. We investigated whether PARP1/2- or tankyrase-sensitive ADP-ribosylation contributes to inflammation-associated trophoblast dysfunction and whether pharmacological inhibition improves trophoblast function under inflammatory stress. We profiled mRNA expression of genes encoding enzymes that catalyze poly-ADP-ribosylation (PARP1, PARP2, TNKS1, TNKS2) and selected enzymes that catalyze mono-ADP-ribosylation (PARP7, PARP10, PARP12, and PARP14), in human I-PE placentas (control n=23; I-PE n=10) and an LPS-induced rat model of I-PE (control n=8, LPS n=8). HTR-8/SVneo cells were treated with TNF- alone or with olaparib, (PARP1/2 inhibitor) or XAV939 (TNKS1/2 inhibitor). Global mono- and poly-ADP-ribosylation (MAR/PAR), including a PARP1-associated ~120-kDa ADP-ribosylation signal and pathway enrichment of proteins identified from this region, were assessed alongside mitochondrial respiration, OXPHOS protein abundance, 4-hydroxynonenal, migration, and viability. In human I-PE placentas, mRNA abundance of poly-ADP-ribosylating enzymes did not differ significantly from controls, whereas mono-ADP-ribosylating enzymes were increased in LPS-exposed rat placentas. In HTR-8/SVneo cells, TNF- induced a prominent PARP1 associated ~120-kDa MAR/PAR signal that was suppressed by olaparib, but not XAV939. Proteins identified from this ~120-kDa region were enriched for known PARP1 targets and immune/stress-response pathways. Olaparib, but not XAV939, improved basal and maximal respiration, ATP production, and spare respiratory capacity. TNF- did not significantly alter oxidative phosphorylation (OXPHOS) subunits, 4-HNE abundance, viability, or migration at 24 h. These data support PARP1/2-sensitive ADP-ribosylation, most consistent with PARP1-linked activity, as a contributor to inflammation-mediated trophoblast bioenergetic dysfunction. The PARP1/2-NAD+ axis may therefore represent a mechanism-directed target for future studies of I-PE.

cell biology↗

bioRxiv2026

Prenatal fentanyl and Δ9-tetrahydrocannabinol exposure disrupt placental function and fetal growth in a mouse model of multidrug use

Opioid and cannabis co-use during pregnancy is increasingly common, yet the placental mechanisms linking combined exposure to adverse fetal outcomes remain poorly defined. Using a controlled mouse model of gestational drug exposure, we tested how fentanyl, {Delta}9-tetrahydrocannabinol (THC), or their combination altered placental structure, immune signaling, and gene expression and how these changes related to fetal growth. Drug exposure produced fetal growth restriction and reduced placental efficiency, with the greatest impairment in the combined fentanyl+THC group. Placental alterations were detectable by mid-gestation, when fentanyl exposure increased nucleated red blood cells within the labyrinth, consistent with hypoxic stress. By term, placentas showed compartment-specific remodeling, with THC selectively expanding the labyrinth and combined fentanyl+THC exposure increasing decidual area. Labyrinth composition and proliferative activity were altered, ultrastructural analysis revealed disruption of the maternal-fetal exchange interface, and placental interleukin-10 and interferon-{beta} levels were reduced across exposure groups. Transcriptomic analyses identified suppression of innate immune and antiviral defense pathways together with treatment-specific stress responses, and integration of placental gene expression with fetal weight showed coordinated repression of vascular and developmental regulators and activation of hypoxia- and metabolic stress-associated genes. These findings identify the placenta as a key mediator of adverse fetal outcomes associated with prenatal polysubstance exposure.

molecular biology↗

bioRxiv2022

Inhibition of GCN5 decreases skeletal muscle fat metabolism during high fat diet feeding

IntroductionGCN5 (Kat2a) is a lysine acetyl transferase capable of acetylating and inhibiting PGC-1 activity. As such, it is described as a negative regulator of PGC-1 and subsequently restricts mitochondrial content. However, elimination of GCN5 in skeletal muscle does not increase mitochondrial content or alter lipid metabolism under normal metabolic conditions. GCN5 levels increase with high-fat diet (HFD) feeding in rodents. Additionally, the GCN5 homolog, PCAF, has previously been shown to also acetylate and inhibit PGC-1 and therefore may possibly compensate for loss of GCN5. ObjectiveThe objective of this study was to examine if with HFD feeding that elimination of GCN5 (Kat2a gene) from skeletal muscle would elicit improvements in mitochondrial and metabolic markers. MethodsSkeletal muscle specific GCN5 knockouts (Gcn5 skm-/-) were fed an HFD. Body composition, cardio-metabolic and physical fitness outcomes were monitored. Additionally, cultured myotubes were treated with a pan-GCN5/PCAF inhibitor and examined for changes in mitochondrial markers. ResultsElimination of skeletal muscle GCN5 did not alter body composition, tissue masses, energy intake, or energy expenditure measurements of mice fed an HFD. Furthermore, whole body glucose homeostasis and cardiac measurements were not altered. There were few differences in lipid metabolism genes, relatively more glucose oxidation versus Gcn5 skm+/+ (wildtype) mice, and a reduction in Pdk4 expression. Exercise capacity and mitochondrial content levels were not altered in Gcn5 skm-/- mice. Further, elimination of GCN5 in skeletal muscle increased Kat2b (PCAF) mRNA expression; however, inhibition of GCN5/PCAF bromodomains in cultured myotubes did not increase oxidative metabolism genes and decreased expression of some mitochondrial genes and Pdk4 mRNA. ConclusionsNeither elimination of GCN5, nor simultaneous inhibition of GCN5 and its homolog PCAF improved skeletal muscle mitochondrial content under normal or HFD-fed conditions. Despite this, GCN5 may play a role in regulating macronutrient preference by regulating Pdk4 content. Thus, HFD/macronutrient excess revealed novel roles of GCN5 in skeletal muscle. Highlights- Skeletal muscle specific elimination of Gcn5/Kat2a decreases fat oxidation without 1) preventing high-fat diet induced weight gain, 2) improving whole body glucose handling, or 3) improving skeletal muscle mitochondrial content. - Inhibition of the GCN5 and PCAF bromodomains and Gcn5 ablation decreases expression of Pdk4. - Expression of Kat2b increases with Gcn5 elimination in skeletal muscle. - Inhibition of the GCN5 and PCAF bromodomains do not result in increased skeletal muscle mitochondrial content.

physiology↗