CAGE-B and SAGE-B models better predict the hepatitis B virus-related hepatocellular carcinoma after 5-year entecavir treatment than PAGE-B.

OBJECTIVES: The PAGE-B model consists of variables at the initiation of antiviral therapy (AVT), whereas the SAGE-B and CAGE-B models consist of variables after 5 years of AVT. We aimed to compare the predictive accuracy of three risk prediction models for hepatocellular carcinoma (HCC) development after 5 years of AVT in patients with chronic hepatitis B (CHB). METHODS: A total of 1335 patients who initiated entecavir (ETV) treatment between 2006 and 2011 and were followed up for more than 5 years were enrolled in the study. RESULTS: At ETV initiation, the median age was 49 years and the median score of the PAGE-B model was 14. After 5 years of ETV treatment, the median SAGE-B and CAGE-B scores were 6 and 6. During the study period, 93 (7.0%) patients developed HCC after 5-year treatment. In multivariate analysis, PAGE-B (hazard ratio [HR] 1.151, 95% confidence interval [CI] 1.087-1.219), SAGE-B (HR 1.340, 95% CI 1.228-1.463), and CAGE-B (HR 1.327, 95% CI 1.223-1.440) models independently predicted HCC development after 5 years of treatment (all P < 0.001). The high-risk groups of the three risk prediction models showed a significantly higher risk of HCC development compared to the medium- and low-risk groups (both P < 0.05). The AUROC of the SAGE-B (0.772-0.844) and CAGE-B (0.785-0.838) models was significantly higher than those of the PAGE-B model (0.696-0.745) in predicting HCC development after 5 years of treatment (both P < 0.05). CONCLUSION: The SAGE-B and CAGE-B models might be better than the PAGE-B model in predicting HCC development after 5 years of ETV treatment.

Diabetes mellitus and diabetic foot ulcer: Etiology, biochemical and molecular based treatment strategies via gene and nanotherapy.

Diabetes mellitus (DM) is a collection of metabolic and pathophysiological disorders manifested with high glucose levels in the blood due to the inability of ß-pancreatic cells to secrete an adequate amount of insulin or insensitivity of insulin towards receptor to oxidize blood glucose. Nevertheless, the preceding definition is only applicable to people who do not have inherited or metabolic disorders. Suppose a person who has been diagnosed with Type 1 or Type 2DM sustains an injury and the treatment of the damage is complicated and prolonged. In that case, the injury is referred to as a diabetic foot ulcer (DFU). In the presence of many proliferating macrophages in the injury site for an extended period causes the damage to worsen and become a diabetic wound. In this review, the scientific information and therapeutic management of DM/DFU with nanomedicine, and other related data were collected (Web of Science and PubMed) from January 2000 to January 2022. Most of the articles revealed that standard drugs are usually prescribed along with hypoglycaemic medications. Conversely, such drugs stabilize the glucose transporters and homeostasis for a limited period, resulting in side effects such as kidney damage/failure, absorption/gastrointestinal problems, and hypoglycemic issues. In this paper, we review the current basic and clinical evidence about the potential of medicinal plants, gene therapy, chemical/green synthesized nanoparticles to improving the metabolic profile, and facilitating the DM and DFU associated complications. Preclinical studies also reported lower plasma glucose with molecular targets in DM and DFU. Research is underway to explore chemical/green synthesized nanoparticle-based medications to avoid such side effects. Hence, the present review is intended to address the current challenges, recently recognized factors responsible for DM and DFU, their pathophysiology, insulin receptors associated with DM, medications in trend, and related complications.

Ferulic Acid Induces Keratin 6α via Inhibition of Nuclear ß-Catenin Accumulation and Activation of Nrf2 in Wound-Induced Inflammation.

Injured tissue triggers complex interactions through biological process associated with keratins. Rapid recovery is most important for protection against secondary infection and inflammatory pain. For rapid wound healing with minimal pain and side effects, shilajit has been used as an ayurvedic medicine. However, the mechanisms of rapid wound closure are unknown. Here, we found that shilajit induced wound closure in an acute wound model and induced migration in skin explant cultures through evaluation of transcriptomics via microarray testing. In addition, ferulic acid (FA), as a bioactive compound, induced migration via modulation of keratin 6α (K6α) and inhibition of ß-catenin in primary keratinocytes of skin explant culture and injured full-thickness skin, because accumulation of ß-catenin into the nucleus acts as a negative regulator and disturbs migration in human epidermal keratinocytes. Furthermore, FA alleviated wound-induced inflammation via activation of nuclear factor erythroid-2-related factor 2 (Nrf2) at the wound edge. These findings show that FA is a novel therapeutic agent for wound healing that acts via inhibition of ß-catenin in keratinocytes and by activation of Nrf2 in wound-induced inflammation.

Glutaminase 1 inhibition reduces thymidine synthesis in NSCLC.

We found that non-small cell lung cancer (NSCLC) is remarkably sensitive to the regulation of glutamine supply by testing the metabolic dependency of 11 cancer cell lines against regulation of glycolysis, autophagy, fatty acid synthesis, and glutamine supply. Glutamine is known as a key supplement of cancer cell growth that is converted to α-ketoglutarate for anabolic biogenesis via glutamate by glutaminase 1 (GLS1). GLS1 inhibition using 10 µM of bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) showed about 50% cell growth arrest by SRB assay. By testing the synergistic effects of conventional therapeutics, BPTES combined with 5-fluorouracil (5-FU), an irreversible inhibitor of thymidylate synthase, significant effects were observed on cell growth arrest in NSCLC. We found that GLS1 inhibition using BPTES reduced metabolic intermediates including thymidine and carbamoyl phosphate. Reduction of thymidine and carbamoyl-phosphate synthesis by BPTES treatment exacerbated pyrimidine supply by combination with 5-FU, which induced cell death synergistically in NSCLC.

Transcriptomic Analysis Reveals Wound Healing of Morus alba Root Extract by Up-Regulating Keratin Filament and CXCL12/CXCR4 Signaling.

Facilitation of the wound healing process is important because a prolonged wound site increases pain and the risk of infection. In oriental medicine, an extract of Morus alba root (MA) has usually been prescribed as traditional treatment for accelerating wound healing, and it has been proven to be safe for centuries. To study the molecular mechanism of MA-mediated skin wound healing, we performed a primary cell culture and a skin explant culture and observed significant difference between the groups with and without MA extract. In the cellular system, a real-time cell analysis and real-time quantitative PCR were performed. It was found that MA extract enhanced proliferation in a dose-dependent manner on Kera-308 cell line, and up-regulated keratin expression including wound-induced Krt6a. In skin explant culture, the mRNA level derived from cell outgrowth displayed a tendency toward more up-regulated mRNA associated keratin filaments and toward a more up-regulated mRNA level of C-X-C motif chemokine 12 (CXCL12) and a chemokine receptor 4 (CXCR4) axis signaling pathway downstream. In this process, we concluded that MA extract had a scientific possibility of wound repair by increasing intracellular and extracellular supports and by inducing a CXCL12/CXCR4 signaling pathway.

Spray pyrolysis prepared yellow to red color tunable Sr1-xCaxSe:Eu²+ phosphors for white LED.

The spherical and submicron size of Sr1-xCaxSe:Eu²âº phosphors were successfully prepared by ultrasonic spray pyrolysis. The phosphors adopted a cubic structure, and the replacement of Sr²âº with Ca²âº decreased the lattice parameter. The Sr1-xCaxSe:Eu²âº showed broad and strong excitation under 420-460 nm blue light, and the emission band could be tuned from 565 to 607 nm by increasing the Ca²âº ratio in the host lattice. In addition, the doping of Zn²âº into Sr²âº or Ca²âº enhanced the emission intensity with a small red shift due to the change in crystal field strength and nephelauxetic effects. The warm and high CRI of white LED was achieved using blue LED pumped with blending phosphors of 612 nm emitting Ca0.98Zn0.02Se:Eu²âº and 565 nm emitting YAG. The correlated color temperatures and CRI were 4719.2K, and 86.3, respectively, and an acceptable color variation was also observed at operating currents ranging from 20 to 70 mA.

Direct lipiodol injection used for a radio-opaque lung marker: stability and histopathologic effects.

The objective of this study was to evaluate the effects on the histopathologic findings of directly injected lipiodol into lung and to identify the existence of remaining lipiodol in the lung according to the follow-up time. Forty rats were randomly assigned to 1 of 4 groups: group I (n = 10) served as the control group and received 0.2 mL of normal saline; groups II (n = 10), III (n = 10), and IV (n = 10) served as experimental groups and received 0.1-0.2 mL of lipiodol under fluoroscopy. At 3 hours (groups I and II), 24 hours (group III), and 1 week (group IV) after injection, the radiographic presence of lipiodol and histopathologic findings of each group were evaluated. Minimal acute lung injuries developed and the radio-opaque lipiodol nodule remained in group II. In group III, acute lung injuries were the most serious. However, acute injuries disappeared and foamy macrophages accumulated within the alveolar space in group IV. In this group, remaining lipiodol was also identified on radiograph. Directly injected lipiodol caused acute lung injury, which disappeared at 1 week along with the resolving process. On radiographs, directly injected lipiodol remained after 1 week. Lipiodol could be used as a safe and stable biomaterial for marking pulmonary nodules.

Hydroxy-alpha-sanshool activates TRPV1 and TRPA1 in sensory neurons.

Sanshools are major active ingredients of Zanthoxylum piperitum and are used as food additives in East Asia. Sanshools cause irritant, tingling and sometimes paresthetic sensations on the tongue. However, the molecular mechanism underlying the pungent or tingling sensation induced by sanshools is not known. Because many transient receptor potential (TRP) channels are responsible for the sensations induced by various spices and food additives, we expressed 17 TRP channels in human embryonic kidney (HEK) cells and investigated their activation by hydroxy-alpha-sanshool (HalphaSS) or hydroxy-beta-sanshool (HbetaSS) isolated from Zanthoxylum piperitum. It was found that HalphaSS, but not HbetaSS, depolarized sensory neurons with concomitant firing of action potentials and evoked inward currents. Among 17 TRP channels expressed in HEK cells, HalphaSS caused Ca(2+) influx in cells transfected with TRPV1 or TRPA1, and evoked robust inward currents in cells transfected with TRPV1 or TRPA1. In primary cultured sensory neurons, HalphaSS induced inward currents and Ca(2+) influx in a capsazepine-dependent manner. Moreover, HalphaSS-induced currents and Ca(2+) influx were greatly diminished in TRPV1(-/-) mice. HalphaSS evoked licking behavior when injected into a single hind paw of wild-type mice, but this was much reduced in TRPV1-deficient mice. These results indicate that TRPV1 and TRPA1 are molecular targets of HalphaSS in sensory neurons. We conclude that the activations of TRPV1 and TRPA1 by HalphaSS explain its unique pungent, tingling sensation.

Enhanced anticancer efficacy of alpha-tocopheryl succinate by conjugation with polyethylene glycol.

Alpha-tocopheryl polyethylene glycol succinate (TPGS) has been used to enhance the bioavailability of poorly absorbed drugs and as a vehicle for drug delivery systems. In response to recent reports that alpha-tocopheryl succinate (TOS) acts as an anticancer agent, we investigated whether its polyethylene glycol (PEG) conjugate, TPGS, also possesses anticancer activity. TPGS inhibited the growth of human lung carcinoma cells implanted in nude mice, and in an in vitro cell culture, even more potently than TOS. The time-dependent uptake of TPGS into cells did not differ from that of TOS, indicating that the enhanced antitumor efficacy of TPGS was not due to its increased uptake into cells. Compared with TOS, TPGS was more effective at inducing apoptosis and the generation of reactive oxygen species, suggesting that the superior anticancer efficacy of TPGS is associated with its increased ability to induce apoptosis. Our data suggest that further studies assessing the potential usefulness of TPGS in cancer therapeutics are warranted, since its use as a vehicle in the formulation of anticancer drugs may provide an effective way to improve their therapeutic efficacy.