Associations of PNPLA3 and LEP genetic polymorphisms with metabolic-associated fatty liver disease in Thai people living with human immunodeficiency virus.

BACKGROUND: The prevalence of metabolic-associated fatty liver disease (MAFLD) is a growing public health issue in people living with human immunodeficiency virus (PLWH). However, the pathophysiology of MAFLD is still unknown, and the role of genetic variables is only now becoming evident. AIM: To evaluate the associations of gene-polymorphism-related MAFLD in PLWH. METHODS: The study employed transient elastography with a controlled attenuation parameter ≥ 248 dB/m to identify MAFLD in patients from a Super Tertiary Hospital in central Thailand. Candidate single-nucleotide polymorphisms (SNPs) were genotyped using TaqMan® MGB probe 5' nuclease assays for seven MAFLD-related genes. Statistical analyses included SNP frequency analysis, Fisher's Exact and Chi-square tests, odds ratio calculations, and multivariable logistic regression. RESULTS: The G-allele carriers of PNPLA3 (rs738409) exhibited a two-fold rise in MAFLD, increasing by 2.5 times in MAFLD with human immunodeficiency virus infection. The clinical features and genetic patterns imply that LEP rs7799039 A-allele carriers had a nine times (P = 0.001) more significant chance of developing aberrant triglyceride among PLWH. CONCLUSION: The current study shows an association between PNPLA3 rs738409 and LEP rs7799039 with MAFLD in PLWH.

GRP78/BiP determines senescence evasion cell fate after cisplatin-based chemotherapy.

Cisplatin (CDDP) induces senescence characterized by senescence-associated secretory phenotypes (SASP) and the unfolded protein response (UPR). In this study, we investigated the proteins related to the UPR during the senescence cell fate. Strikingly, we found that one of the critical ER-resident proteins, GRP78/BiP, was significantly altered. Here we show that GRP78 levels differentially expressed depending on non-small lung cancer subtypes. GRP78 indeed regulates the evasion of senescence in adenocarcinoma A549 cells, in which the increased GRP78 levels enable them to re-proliferate after CDDP removal. Conversely, GRP78 is downregulated in the senescence H460 cells, making them lacking senescence evasion capability. We observed that the translational regulation critically contributed to the GRP78 protein levels in CDDP-induces senescence. Furthermore, the increased GRP78 level during senescence confers resistance to senolytic drug, Bortezomib, as observed by a twofold increase in IC50 in A549 senescence cells compared to the wild-type. This observation is also consistent in the cells that have undergone genetic manipulation by transfection with pcDNA3.1(+)-GRP78/BiP plasmids and pSpCas9(BB)-2A-Puro containing guide RNA sequence targeting GRP78 exon 3 to induce the overexpression and downregulation of GRP78 in H460 cells, respectively. Our findings reveal a unique role of GRP78 on the senescence evasion cell fate and senolytic drug resistance after cisplatin-based chemotherapy.

Evaluation of the topical spray containing Centella asiatica extract and its efficacy on excision wounds in rats.

Centella asiatica was extracted by methanol. The assay content of triterpenes in the extract was 0.12 % asiatic acid, 0.54 % madecassic acid, 0.25 % asiaticoside and 1.02 % madecassoside. The extract was complexed with hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and formulated with Eudragit E100, glycerol, PEG 400, copovidone, ethanol and purified water. A clear yellowish solution (F1-F8) was obtained. The formulations had a pH of 5.5-6.0 with viscosity in the range of 20-60 mPa s, surface tension 20.3-24.6 mN m-1 and contact angle less than 20°. The amount of PEG 400 and copovidone affected the film and spreadability. The content of triterpenes in the spray formulation was close to 100 % compared to triterpenes in the extract. The skin irritation study indicated that the formulation was non-irritating in a rat model. An in vivo excision wound healing model showed that wound excision was completely healed after 14 days.

Imperatorin sensitizes anoikis and inhibits anchorage-independent growth of lung cancer cells.

The anoikis-sensitization activity of imperatorin, an active furanocoumarin component of Angelica dahurica root, is reported herein for the first time. The present study demonstrated that the imperatorin treatment at sub-toxic concentrations enhanced human lung cancer H23 cell apoptosis after detachment. A Western blot analysis showed that imperatorin significantly enhanced the p53 protein level, which subsequently down-regulated Mcl-1 protein and up-regulated Bax, while it had a minimal effect on Bcl-2 expression. In addition, an anchorage-independent growth assay was performed to support the anti-metastasis potential of imperatorin. Consistent with anoikis assay, imperatorin exhibited a strong inhibitory effect on the anchorage-independent growth of the cells. Further, this study demonstrated that imperatorin sensitizes anoikis in other lung cancer cells, namely, H292 and A549. Because anoikis was shown to be a critical hindrance in preventing cancer cell metastasis, the knowledge regarding such an activity and an underlying mechanism may lead to the development of this compound for a cancer therapy.