Gedunin isolated from the mangrove plant Xylocarpus granatum exerts its anti-proliferative activity in ovarian cancer cells through G2/M-phase arrest and oxidative stress-mediated intrinsic apoptosis.

Gedunin is a natural tetranorterpenoid secondary metabolite found in plants of the Meliaceae family, which has been reported for its antiparasitic, antifungal and anticancer activities. Here, we describe the molecular mechanisms underlying the in vitro anti proliferative activity of gedunin (isolated from the mangrove plant Xylocarpus granatum) in human ovarian cancer cells. We observed that gedunin triggered severe ROS generation leading to DNA damage and cell cycle arrest in G2/M phase thus inhibiting cell proliferation. ROS upregulation also led to mitochondrial stress and membrane depolarization, which eventually resulted in mitochondria-mediated apoptosis following cytochrome C release, caspase 9, 3 activation, and PARP cleavage. Transmission electron microscopy of gedunin treated cells revealed sub-cellular features typical of apoptosis. Moreover, an upregulation in stress kinases like phospho-ERK 1/2, phospho-p38 and phospho-JNK was also observed in gedunin treated cells. Free radical scavenger N-Acetyl-L-Cysteine (NAC) reversed all these effects resulting in increased cell survival, abrogation of cell cycle arrest, rescue of mitochondrial membrane potential and suppression of apoptotic markers. Interestingly, gedunin is also an inhibitor of the evolutionarily conserved molecular chaperone Heat Shock Protein 90 (hsp90) responsible for maintaining cellular homeostasis. Targeting this chaperone could be an attractive strategy for developing cancer therapeutics since many oncogenic proteins are also client proteins of hsp90. Collectively, our findings provide insights into the molecular mechanism of action of gedunin, which may aid drug development efforts against ovarian cancer.

Neurometabolic alterations in children and adolescents with functional neurological disorder.

OBJECTIVES: In vivo magnetic resonance spectroscopy (MRS) was used to investigate neurometabolic homeostasis in children with functional neurological disorder (FND) in three regions of interest: supplementary motor area (SMA), anterior default mode network (aDMN), and posterior default mode network (dDMN). Metabolites assessed included N-acetyl aspartate (NAA), a marker of neuron function; myo-inositol (mI), a glial-cell marker; choline (Cho), a membrane marker; glutamate plus glutamine (Glx), a marker of excitatory neurotransmission; γ-aminobutyric acid (GABA), a marker of inhibitor neurotransmission; and creatine (Cr), an energy marker. The relationship between excitatory (glutamate and glutamine) and inhibitory (GABA) neurotransmitter (E/I) balance was also examined. METHODS: MRS data were acquired for 32 children with mixed FND (25 girls, 7 boys, aged 10.00 to 16.08 years) and 41 healthy controls of similar age using both short echo point-resolved spectroscopy (PRESS) and Mescher-Garwood point-resolved spectroscopy (MEGAPRESS) sequences in the three regions of interest. RESULTS: In the SMA, children with FND had lower NAA/Cr, mI/Cr (trend level), and GABA/Cr ratios. In the aDMN, no group differences in metabolite ratios were found. In the pDMN, children with FND had lower NAA/Cr and mI/Cr (trend level) ratios. While no group differences in E/I balance were found (FND vs. controls), E/I balance in the aDMN was lower in children with functional seizures-a subgroup within the FND group. Pearson correlations found that increased arousal (indexed by higher heart rate) was associated with lower mI/Cr in the SMA and pDMN. CONCLUSIONS: Our findings of multiple differences in neurometabolites in children with FND suggest dysfunction on multiple levels of the biological system: the neuron (lower NAA), the glial cell (lower mI), and inhibitory neurotransmission (lower GABA), as well as dysfunction in energy regulation in the subgroup with functional seizures.

Polyvinyl alcohol-chitosan based oleanolic acid nanofibers against bacterial infection: In vitro studies and in vivo evaluation by optical and laser Doppler imaging modalities.

The present work focuses on the fabrication of polyvinyl alcohol-chitosan-loaded oleanolic acid-nanofibers (PVA-CS-OLA-NFs) for bacterial infection. The prepared PVA-CS-OLA-NFs were characterized for contact angle, SEM, AFM, XRD, FTIR, and TGA. The solid-state characterization and in vitro performance evaluation of nanofibers reveal consistent interconnection and diameters ranging from 102 ± 9.5 to 386 ± 11.6 nm. The nanofibers have a flat surface topography and exhibit efficient drug entrapment. Moreover, the in vitro release profile of PVA-CS-OLA-NFs was found to be 51.82 ± 1.49 % at 24 h. Furthermore, the hemocompatibility study showed that the developed PVA-CS-OLA-NFs are non-hemolytic to human blood. The PVA-CS-OLA-NFs demonstrate remarkable antibacterial capabilities, as evidenced by their MBC and MIC values, which range from 128 and 32 µg/mL, against the strains of S. aureus. The in-vivo fluorescence optical imaging showed the sustained PVA-CS-OLA-NFs release at the wound site infected with S. aureus for a longer duration of time. Moreover, the PVA-CS-OLA-NFs showed superior wound healing performance against S. aureus infected wounds compared to the marketed formulation. Further, the laser Doppler imaging system improved oxygen saturation, blood supply, and wound healing by providing real-time blood flow and oxygen saturation information.

EGFR targeted albumin nanoparticles of oleanolic acid: In silico screening of nanocarrier, cytotoxicity and pharmacokinetics for lung cancer therapy.

This study aimed to develop cetuximab (CTX) functionalized albumin nanoparticles (ALB-NPs) of oleanolic acid for EGFR targeted lung cancer therapy. The molecular docking methodology has been applied for a selection of suitable nanocarrier. Various physicochemical parameters like particle size, polydispersity, zeta potential, morphology, entrapment efficiency, and in-vitro drug release of all the ALB-NPs were analyzed. Furthermore, the in-vitro qualitative and quantitative cellular uptake study revealed that higher uptake of CTX conjugated ALB-NPs than nontargeted ALB-NPs in A549 cells. The in-vitro MTT assay revealed that the IC50 value of CTX-OLA-ALB-NPs (4.34 ± 1.90 µg/mL) was significantly reduced (p < 0.001) than OLA-ALB-NPs (13.87 ± 1.28 µg/mL) in A-549 cells. CTX-OLA-ALB-NPs caused apoptosis in A-549 cells at concentrations equivalent to its IC50 value and blocked the cell cycle in the G0/G1 phases. The hemocompatibility, histopathology and lung safety study confirmed the biocompatibility of the developed NPs. In vivo ultrasound and photoacoustic imaging confirmed the targeted delivery of the NPs to lung cancer. The findings demonstrated that CTX-OLA-ALB-NPs have potential for site-specific delivery of OLA for effective and targeted therapy of lung carcinoma.