Upper Blepharoplasty through Infrabrow Skin Excision to Treat Dermatochalasis with Lateral Hooding and Medial Orbital Fat Loss in Selected Patients.

PURPOSE: Dermatochalasis with lateral hooding and medial orbital fat loss are common signs of aging in the upper eyelid. Removing the excess skin in this area through infrabrow skin excision can effectively lift the loose skin of the upper eyelid and minimizes visible scarring. Additionally, we have identified three compartments of orbital fat prolapse based on orbital anatomy. Transferring volume from the lateral compartment to the intermediate region can flatten the lateral upper eyelid and create medial fullness, which ultimately rejuvenates the upper eyelid. This study presents an operative method for correcting age-related changes in the upper eyelid using this technique. METHODS: A total of 34 eyelids from 17 patients underwent a surgical procedure involving infrabrow skin excision, along with repositioning and lifting of lateral orbital fat. The inclusion criteria consisted of patients with moderate to severe upper eyelid dermatochalasis, coupled with middle fat loss and lateral hooding. To correct lateral hooding and restore midfacial fullness, lateral orbital fat was repositioned to an intermediate position, and the orbicularis oculi muscle was fold-sutured to the corrugator supercilii muscle. RESULTS: The mean age of the patients was 55.59 ± 3.20 years, with a range of 48 to 61 years. The mean follow-up period was 9.94 ± 1.35 months, ranging from 8 to 12 months. Patients were evaluated at 1-month, 3-month, and 6-month intervals. The Strasser system was used to evaluate the surgical outcomes at 3 months. All patients achieved good surgical outcomes, expressed through satisfactory cosmetic improvements, and improved visual field. The procedure effectively corrected lateral hooding and loss of middle orbital fat through infrabrow skin excision. No complications, such as wound dehiscence, lagophthalmos, noticeable scarring, ocular dyskinesia, or sensory changes, were observed. CONCLUSIONS: The combination of infrabrow skin excision, repositioning of lateral orbital fat, and lifting of the orbicularis oculi muscle effectively addresses moderate to severe dermatochalasis, lateral hooding, medial fat loss, and improves elasticity of the anterior wall of the upper lid in our patients. This procedure can produce satisfactory and long-lasting aesthetic results with an inconspicuous scar beneath the brow.

The optimal introversion angle and length of pedicle screw to avoid L1-S1 vascular damage.

BACKGROUND: posterior pedicle screw fixation is common method, one of the most severe complications is iatrogenic vascular damage, no report investigated association of different introversion angles (INTAs) and length of pedicle screw. The aims were to investigate the optimal introversion angle and length of pedicle screw for improving the safety of the operation, and to analyze the differences of vascular damage types at L1-S1. METHODS: Lumbar CT imaging data from110 patients were analyzed by DICOM software, and all parameters were measured by new Cartesian coordinate system, INTAs (L1-L5:5°,10°,15°,S1: 0°, 5°,10°,15°), DO-AVC (the distance between the origin (O) with anterior vertebral cortex (AVC)), DAVC-PGVs (the distance between AVC and the prevertebral great vessels (PGVs)), DO-PGVs (the distance between the O and PGVs). At different INTAs, DAVC-PGVs were divided into four grades: Grade III: DAVC-PGVs ≤ 3 mm, Grade II: 3 mm < DAVC-PGVs ≤ 5 mm, Grade I: DAVC-PGVs > 5 mm, and N: the not touching PGVs. RESULTS: The optimal INTA was 5° at L1-L3, the left was 5° and the right was 15° at L4, and screw length was less than 50 mm at L1-L4. At L5, the left optimal INTA was 5° and the right was 10°, and screw length was less than 45 mm. The optimal INTA was 15° at S1, and screw length was less than 50 mm. However, screw length was less than 40 mm when the INTA was 0° or 5° at S1. CONCLUSIONS: At L5-S1, the risk of vascular injury is the highest. INTA and length of the pedicle screw in lumbar operation are closely related. 3 mm interval of screw length may be more preferable to reduce vascular damage.

Inflammatory cytokines and their potential role in kidney stone disease: a Mendelian randomization study.

PURPOSE: Previous studies have reported a complex relationship between inflammatory cytokines and kidney stone disease (KSD). The purpose of this paper is to investigate the potential causal impact of inflammatory cytokines on KSD by Mendelian randomization (MR) analysis. METHODS: In our study, a thorough two-sample Mendelian randomization (MR) analysis was performed by us to determine the potential causal relationship between inflammatory cytokines and kidney stone disease. Utilizing GWAS summary data of inflammatory cytokines and KSD, we performed the first two-sample MR analysis. Genetic variants in GWASs related to inflammatory cytokines were employed as instrumental variables (IVs). The data on cytokines were derived from 14,824 participants and analyzed by utilizing the Olink Target-96 Inflammation Panel. GWAS summary data related to KSD (9713 cases and 366,693 controls) were obtained from the FinnGen consortium. The primary MR analysis method was Inverse variance weighted. Reverse MR analysis, Cochran's Q test, MR Egger, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were used to assess the stability of the results. RESULTS: 91 cytokines were enrolled in the MR analysis after strict quality control of IV. The IVW analysis revealed 2 cytokines as risk factors for KSD: Cystatin D (OR 1.06, 95% CI 1.01-1.11), Fibroblast growth factor 5 (OR 1.06, 95% CI 1.00-1.12), suggesting they are positively associated with the occurrence of kidney stones. We also found 3 protective associations between cytokines and KSD: Artemin (OR 0.86, 95% CI 0.78-0.96), T-cell surface glycoprotein CD6 isoform (OR 0.92, 95% CI 0.88-0.98), STAM-binding protein (OR 0.83, 95% CI 0.69-0.99). There was no horizontal pleiotropy or significant heterogeneity in our MR analysis, as determined by the p-value results of our MR Egger's intercept test, Cochrane Q-test, and MR-PRESSO, which were all > 0.05. CONCLUSIONS: Our study explored a variety of inflammatory cytokines related to KSD through MR analysis, which validated several previous findings and provided some new potential biomarkers for KSD. However, the findings require further investigation to validate their exact functions in the pathogenesis and evolution of KSD.

Imaging and Liquid Biopsy for Distinguishing True Progression From Pseudoprogression in Gliomas, Current Advances and Challenges.

RATIONALE AND OBJECTIVES: Gliomas are aggressive brain tumors with a poor prognosis. Assessing treatment response is challenging because magnetic resonance imaging (MRI) may not distinguish true progression (TP) from pseudoprogression (PsP). This review aims to discuss imaging techniques and liquid biopsies used to distinguish TP from PsP. MATERIALS AND METHODS: This review synthesizes existing literature to examine advances in imaging techniques, such as magnetic resonance diffusion imaging (MRDI), perfusion-weighted imaging (PWI) MRI, and liquid biopsies, for identifying TP or PsP through tumor markers and tissue characteristics. RESULTS: Advanced imaging techniques, including MRDI and PWI MRI, have proven effective in delineating tumor tissue properties, offering valuable insights into glioma behavior. Similarly, liquid biopsy has emerged as a potent tool for identifying tumor-derived markers in biofluids, offering a non-invasive glimpse into tumor evolution. Despite their promise, these methodologies grapple with significant challenges. Their sensitivity remains inconsistent, complicating the accurate differentiation between TP and PSP. Furthermore, the absence of standardized protocols across platforms impedes the reliability of comparisons, while inherent biological variability adds complexity to data interpretation. CONCLUSION: Their potential applications have been highlighted, but gaps remain before routine clinical use. Further research is needed to develop and validate these promising methods for distinguishing TP from PsP in gliomas.

Xylooligosaccharides ameliorate insulin resistance by increasing Akkermansia muciniphila and improving intestinal barrier dysfunction in gestational diabetes mellitus mice.

Little is known regarding the effects of xylooligosaccharides (XOS) on insulin resistance (IR) in gestational diabetes mellitus (GDM). We aimed to investigate this issue and its mechanism. Sixty female mice were randomly allotted to 4 groups (n = 15): control, high fat diet (HFD), GDM, and GDM + XOS. The control mice were fed an AIN-93 diet, while the mice in the other groups were fed 45% HFD. After pregnancy, mice in GDM and GDM + XOS groups were intraperitoneally injected with 30 mg kg-1 streptozocin for 3 days from the first day of pregnancy. Mice in the GDM + XOS group were then fed an HFD containing 2% XOS. Fasting glucose and insulin levels were monitored. The fecal Akkermansia muciniphila (Akk. muciniphila) and Bifidobacterium were measured by qPCR. The Chiu scores were calculated from hematoxylin-eosin (HE)-stained ileal tissues. Phosphorylated Akt in the liver and occludin and ZO-1 in the intestinal tissues were determined by western blotting. XOS reduced (p < 0.05) fasting blood glucose and insulin and HOMA-IR, and increased (p < 0.05) Akt phosphorylation in the livers of GDM mice. Moreover, XOS decreased (p < 0.05) TNFα, IL-1ß, IL-15 and LPS in the serum, increased (p < 0.05) fecal Akk. muciniphila abundance, lowered (p < 0.05) Chiu's scores, and enhanced (p < 0.05) occludin and ZO-1 expression. XOS ameliorate IR by increasing Akk. muciniphila and improving intestinal barrier dysfunction in GDM mice.

Preparation, characterization of basil essential oil liposomes unidirectional single-conducting water sustained-release pads and their preservation properties to Lateolabrax japonicus fillets.

The juice exudation of aquatic products oozes out during storage can influence storage quality. Herein, a novel basil essential oil liposome unidirectional water-conducting sustained-release preservation pads (BEOL/UCSP) were prepared with nylon mesh as water-conducting layer, basil essential oil liposome (BEOL) as sustained-release preservation layer, and diatomite and absorbent-cotton as water-absorbing layer. EL/UCSP, ß-CL/UCSP, and BEO/UCSP were prepared after BEOL was replaced by eugenol liposome, ß-caryophyllene liposome, and BEO. BEOL are microspheres with bilayer structure, had good storage stability, centrifugal stability, thermal stability, embedding capacity, sustained-release, and oxidation resistance, and the main components of preservatives had a synergistic effect on antibacterial properties. The pads without preservative can initially slow down quality deterioration. BEOL/UCSP can directionally absorb exudate and realize long-term sustained-release of preservative, has excellent antibacterial and antioxidant effect, and extended shelf life of Lateolabrax japonicus fillets from 6.0 days to 12.8 days. The BEOL/UCSP can provide technical theoretical support for preservation materials.

A Novel Hydrodynamic Design Greatly Improves the Debris Clearance Rate of Flexible Ureteroscopy.

Objectives: To introduce a novel hydrodynamic design for a flexible ureteroscope that can increase stone debris clearance. Methods: Based on hydrodynamics, the new design allowed the ureteroscope to have six water jets. Fluid gushed from the six jets and would ultimately converge into an eddy. The safety and stone debris clearance efficiency were tested in a 3D-printed kidney model. Stone fragments between 0.5 and 1 mm were used to mimic the debris. A ureteroscope already approved for marketing was used as a control. Results: The new design did not change the local renal pressure and did not raise the whole renal pressure under irrigation at 80 or 100 mL/min but slightly raised it under irrigation at 120 mL/min. The pressures in the 2 g stone clearance procedures were 26.0, 33.1, and 37.5 cmH2O for the new design and 25.1, 30.2, and 39.3 cmH2O for the current design; in the 4 g stone clearance procedures, the pressures were 30.1, 37.2, and 40.0 cmH2O for the new design and 26.9, 30.8, and 39.8 cmH2O for the current design, all under conditions of 80, 100, and 120 mL/min irrigation, respectively. The new design significantly improved the stone clearance rate by ∼10-fold. It effectively cleared 2 and 4 g stones within 900 seconds under the three irrigation rates. In contrast, the current design cleared <10% of the stone debris in all tests. Conclusion: The new hydrodynamic design significantly improved the stone debris clearance rate without causing obviously increased renal pressure, and the improvement was maintained under different irrigation pressures and stone burdens.

Long non-coding RNA CCHE1 modulates LDHA-mediated glycolysis and confers chemoresistance to melanoma cells.

Melanoma is considered as the most common metastatic skin cancer with increasing incidence and high mortality globally. The vital roles of long non-coding RNAs (lncRNAs) in the tumorigenesis of melanoma are elucidated by emerging evidence. The lncRNA cervical carcinoma high-expressed 1 (CCHE1) was overexpressed and acted as an oncogene in a variety of cancers, while the function of CCHE1 in melanoma remains unclear. Here, we found that CCHE1 was highly expressed in melanoma and correlated with the poorer survival of melanoma patients. Depletion of CCHE1 inhibited the proliferation, induced cell apoptosis and suppressed in vivo tumor growth. To further understand the functional mechanism of CCHE1, the interacting partners of CCHE1 were identified via RNA pull-down assay followed by mass spectrometry. CCHE1 was found to bind lactate dehydrogenase A (LDHA) and acted as a scaffold to enhance the interaction of LDHA with the fibroblast growth factor receptor type 1 (FGFR1), which consequently enhanced LDHA phosphorylation and activity of LDHA. Inhibiting CCHE1 strikingly suppressed the glycolytic flux of melanoma cells and lactate generation in vivo. Further study demonstrated that CCHE1 desensitized melanoma cells to dacarbazine and inhibition of glycolysis reversed CCHE1-induced chemoresistance. These results uncovered the novel function of CCHE1 in melanoma by reprogramming the glucose metabolism via orchestrating the activity of LDHA.

AFP deletion leads to anti-tumorigenic but pro-metastatic roles in liver cancers with concomitant CTNNB1 mutations.

HCC remains one of the most prevalent and deadliest cancers. Serum AFP level is a biomarker for clinical diagnosis of HCC, instead the contribution of AFP to HCC development is clearly highly complex. Here, we discussed the effect of AFP deletion in the tumorigenesis and progression of HCC. AFP deletion in HepG2 cells inhibited the cell proliferation by inactivating PI3K/AKT signaling. Surprisingly, AFP KO HepG2 cells appeared the increasing metastatic capacity and EMT phenotype, which was attributed to the activation of WNT5A/ß-catenin signal. Further studies revealed that the activating mutations of CTNNB1 was closely related with the unconventional pro-metastatic roles of AFP deletion. Consistently, the results of DEN/CCl4-induced HCC mouse model also suggested that AFP knockout suppressed the growth of HCC primary tumors, but promoted lung metastasis. Despite the discordant effect of AFP deletion in HCC progression, a drug candidate named OA showed the potent suppression of HCC tumor growth by interrupting AFP-PTEN interaction and, importantly, reduced the lung metastasis of HCC via angiogenesis suppression. Thus, this study demonstrates an unconventional effect of AFP in HCC progression, and suggests a potent candidate strategy for HCC therapy.

Efficacy and safety of Water Vapor Thermal Therapy in the treatment of benign prostate hyperplasia: a systematic review and single-arm Meta-analysis.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common chronic condition among men aged 50 or older, causing voiding and obstructive lower urinary tract symptoms. Water vapor thermal therapy (WVTT) using the Rezum® system is a new minimally invasive surgical technique that is increasingly reported as a treatment for BPH. METHODS: The protocol was submitted to the PROSPERO registry. We searched PubMed, Web of Science, Embase, Cochrane Library and ClinicalTrials.gov up to July 29, 2022. Quality assessment was carried out by a 20-item checklist form prepared by the Institute of Health Economics (IHE). Double arcsine transformation was performed to stabilize the variance of the original ratio. When I2 > 50%, the random effect model was used to calculate the pooled parameters. Otherwise, the fixed effect model was used. 95% confidence intervals (CIs) were calculated. A leave-one-out sensitivity analysis was performed to evaluate the impact of each study on the pooled outcomes, and finally, Egger's test was used to assess publication bias. RESULTS: A total of seven single-arm observational studies and one random controlled trial, including 1015 patients, were included. One year after WVTT, the International Prostate Symptom Score decreased by 11.37 (95% CI: -12.53, -10.21), the IPSS Quality of Life scale decreased by 2.59 (95% CI: -2.92, -2.26), the maximum urine flow rate increased by 5.26 ml/s (95% CI: 4.53, 5.99), and the postvoid residual decreased by 13.18 ml (95% CI: -24.32, -2.03). The most common complication was dysuria, with a pooled incidence of 21% (95% CI: 14%, 29%), and the second most common complication was hematuria, with a pooled incidence of 14% (95% CI: 10%, 18%). The pooled incidence of retreatment was 3% (95% CI: 2%, 5%). CONCLUSIONS: WVTT is an attractive alternative to medication or more invasive surgical procedures and can serve as first-line therapy for men with BPH.

Wettability effect on oil recovery using rock-structured microfluidics.

Surface wettability has a crucial impact on drop splashing, emulsion dynamics, slip flow for drag reduction, fluid-fluid displacement, and various microfluidic applications. Targeting enhanced oil recovery (EOR) applications, we experimentally investigate the effect of matrix wettability on the invasion morphology and sweep efficiency of viscous oil displaced by different aqueous floods using microfluidics, whose porous network mimics a sandstone structure. For comparison, systematic experiments of the same oil-flood pair are done in both hydrophilic and hydrophobic microfluidic chips. The results show that the hydrophilic microfluidic rock has a remarkable increase in oil recovery by a factor of ≈1.44, compared to the hydrophobic case. In addition, we observe a more pronounced lateral growth of the displacing pattern of aqueous flood for the hydrophilic surface. Finally, we quantitatively explain the increasing factor in the recovery rate and finger width for the hydrophilic vs. hydrophobic rock-liked porous networks by incorporating the contact angle into a scaling analysis.

First Report of 'Candidatus Phytoplasma aurantifolia' Associated with the Invasive Weed Eclipta prostrata (L.) in Taiwan.

Eclipta prostrata (L.), commonly known as false daisy of the family Asteraceae, is an erect or prostrate annual herb that grows 5 to 45 cm tall. It is widespread mainly in tropical and subtropical regions like India, China, Taiwan, Thailand, and Brazil (Chung et al., 2017). E. prostrata has very wide medicinal properties accounted by several phytochemicals like thiophene derivatives, steroids, flavonoids, and polypeptides (Feng et. al., 2019). It is also used as a traditional herbal medicine for the treatment of bleeding, hemoptysis and itching, hepatitis diarrhea, and even hair loss (Timalsina et al., 2021). In September 2021, E. prostrata displaying branch proliferation and phyllody symptoms with about 30% (6 were symptomatic and 14 were healthy) incidence rate was observed in Mailiao, Yunlin, Taiwan where phytoplasma disease is permeating and has affected many crops and non-crop species including peanut, mungbean, curl-leaved tobacco, false amaranth, etc. Compared to healthy E. prostrata bearing white ray florets and cream or dull white disk florets, symptomatic ones developed phyllody which is more pronounced on the severely infected ones. Further examination by transmission electron microscope revealed a pleomorphic (circular, elliptical, and bell-shaped) phytoplasma-like organisms accumulated in the sieve elements of the symptomatic leaves. Phytoplasma infection was further confirmed by nested polymerase chain reaction using universal primers P1/P7 (carried out for 12 cycles), followed by R16F2n/R16R2 (carried out for 35 cycles) on the genomic DNA extracted by Plant Genomic DNA Purification Kit (DP022-150, GeneMark) (Lee et al. 1993). Results revealed that the conserved 16S rRNA gene with a 1.2 kb fragment size was amplified only by the symptomatic samples. Furthermore, western blotting was done using the polyclonal antibody raised against the immunodominant membrane protein (Imp) of peanut witches'-broom (PnWB) phytoplasma, a 'Candidatus Phytoplasma aurantifolia' in Taiwan that belongs group to 16SrII (Chen et al. 2021). Consistent with the nested PCR, only the symptomatic samples revealed a specific Imp signal with a size of 19 kDa. To classify the phytoplasma associated with the symptomatic E. prostrata, the DNA sequence (No. OM397418) of the P1/P7 primer pair-amplified DNA fragment was obtained using P1 and a nested primer (5'-GGGTCTTTACTGACGCTGAGG-3'), which shares 100% identity with that of GenBank accession NZ_AMWZ01000008 (complement [31109 to 32640]) of PnWB phytoplasma. Further analysis of the virtual RFLP pattern of OM397418 by iPhyClassifier confirmed that the phytoplasma identified in the symptomatic E. prostrata belongs 16SrII-V subgroup. To the best of our knowledge, this is the first report of phytoplasma disease in E. prostrata associated with the 'Ca. P. aurantifolia' in Taiwan.

Detection, Identification, and Molecular Characterization of a 16SrII-V Subgroup Phytoplasma Associated with Nicotiana plumbaginifolia.

Nicotiana plumbaginifolia Viviani, commonly known as curl-leaved tobacco, is an annual herbaceous plant belonging to Solanaceae family. This plant is native to Mexico, South America, and parts of the Caribbean and has been reported to be present in Taiwan since 2006. In March 2021, N. plumbaginifolia Viviani, found in Yunlin County, Taiwan, was observed to have phyllody, virescence, and witches'-broom, which is consistent with the disease symptoms caused by phytoplasma infection. Samples of the healthy and symptomatic plants were collected for analysis of the causal agent associated with the diseased N. plumbaginifolia Viviani. Under transmission electron microscopy, the phytoplasma-like pleomorphic bodies were found in the sieve tubes of the diseased plants. The 16S ribosomal RNA (rRNA)-based phylogenetic analysis and the iPhyClassifier-based virtual restriction fragment length polymorphism study demonstrated that the phytoplasma identified in this study can be classified into the 16SrII-V subgroup, which is similar to the peanut witches'-broom phytoplasma, a 'Candidatus phytoplasma aurantifolia'-related strain. Further identification of SAP54/PHYL1 and SAP11 homologs in the phytoplasma explain the disease symptoms of phyllody, virescence, and witches'-broom observed in diseased N. plumbaginifolia Viviani. The discovery of new phytoplasma plant hosts has gained scientific importance in light of the attempt to unravel an efficient strategy to fight the rapid spread of this disease, which poses a threat to the agricultural sector and food security in Taiwan.

Physicochemical Characterization and Biopharmaceutical Evaluation of ZWF: A Novel Anticancer Drug for the Treatment of Non-small Cell Lung Cancer.

The orally available novel small molecule drug ZWF is under preclinical development for an anticancer purpose. The present study aimed to assess the viability of developing ZWF as a form of oral formulation for clinical application based on the principles of biopharmaceutics and pharmacokinetics. The crucial physicochemical properties of ZWF were determined by in vitro assays. The in situ gastrointestinal absorption characteristics and in vivo pharmacokinetic behaviors of ZWF in rats were characterized. The solubility of ZWF showed a highly pH-dependent profile, decreasing from 25,392.89 to 20.48 µg/mL as the solution pH increased from 1.0 to 5.8. In PBS with a pH of 1.0 to 5.8, the LogP value of ZWF ranged from -2.35 to 2.20 and was gradually increased as the pH value increased. ZWF was partially absorbed in the stomach, and the favorable absorption sites were the duodenum, jejunum, and ileum. Pharmacokinetic studies showed that the AUC(0-t) and Cmax values of ZWF after its oral administration as a suspension prepared with 0.5% CMC-Na were increased by 18.97% and 40% than that with normal saline, providing a model oral formulation of ZWF with ideal bioavailability and system exposure in rats. From the perspective of oral absorption, ZWF possessed appealing qualities as a drug candidate and could be prepared as an oral preparation for clinical application. The present study has established a fundamental foundation for the development and quality evaluation of the ZWF oral formulations.

Pharmacokinetics and tissue distribution study of hupehenenine in rats: A novel isosteroid alkaloid isolated from Bulbus Hupehensis Fritillariae.

Hupehenenine is a novel isosteroid alkaloid that was first isolated from Bulbus Hupehensis Fritillariae. The inhibitory proliferation effect of hupehenenine and its three related alkaloid derivatives, including o-caproyl-hupehenenine, o-(2-furanoyl)-hupehenenine, and Δ5(6) -isopeimine on human lung cancer cell line, human chronic myeloid leukemia cell line, and human thyroid duct cancer cell line in vitro, has been identified. This study first developed a sensitive HPLC-MS/MS method for the simultaneous quantification of hupehenenine and three alkaloid derivatives in rat plasma and tissues. The developed method was validated, and it was linear over the concentration range of 1-800 ng/mL for all analytes with R2 ≥ 0.9939 and 0.9972, respectively, in rat plasma and rat liver homogenate. The lower limit of quantitation was 1 ng/mL for all analytes. The intra-day and inter-day precision and accuracy were satisfactory. This validated method was successfully applied to investigate the pharmacokinetics and tissue distribution of hupehenenine in rats. In pharmacokinetic study, the maximum plasma concentration of rats exists gender difference. Tissue distribution study showed that hupehenenine has good affinity for multiple tissues but is unable to cross the blood-brain barrier. These results may provide a useful reference for further research of hupehenenine and its three related alkaloid derivatives.

Elucidation of the core betalain biosynthesis pathway in Amaranthus tricolor.

Amaranthus tricolor L., a vegetable Amaranthus species, is an economically important crop containing large amounts of betalains. Betalains are natural antioxidants and can be classified into betacyanins and betaxanthins, with red and yellow colors, respectively. A. tricolor cultivars with varying betalain contents, leading to striking red to green coloration, have been commercially produced. However, the molecular differences underlying betalain biosynthesis in various cultivars of A. tricolor remain largely unknown. In this study, A. tricolor cultivars with different colors were chosen for comparative transcriptome analysis. The elevated expression of AmCYP76AD1 in a red-leaf cultivar of A. tricolor was proposed to play a key role in producing red betalain pigments. The functions of AmCYP76AD1, AmDODAα1, AmDODAα2, and AmcDOPA5GT were also characterized through the heterologous engineering of betalain pigments in Nicotiana benthamiana. Moreover, high and low L-DOPA 4,5-dioxygenase activities of AmDODAα1 and AmDODAα2, respectively, were confirmed through in vitro enzymatic assays. Thus, comparative transcriptome analysis combined with functional and enzymatic studies allowed the construction of a core betalain biosynthesis pathway of A. tricolor. These results not only provide novel insights into betalain biosynthesis and evolution in A. tricolor but also provide a basal framework for examining genes related to betalain biosynthesis among different species of Amaranthaceae.

Oliceridine for the Management of Acute Postoperative Pain.

OBJECTIVE: To review the pharmacological characteristics, clinical evidence, and place in the management of acute postoperative pain severe enough to require an intravenous opioid. DATA SOURCES: A comprehensive literature search was conducted in PubMed (January 2000 to December 1, 2020). Key search terms included oliceridine or acute postoperative pain. Other sources were derived from product labeling and ClinicalTrials.gov. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were reviewed and evaluated. Phase I, II, and III clinical trials were included. DATA SYNTHESIS: Oliceridine is a novel selective µ-receptor G-protein pathway modulator. It has the property of activating G-protein signaling while causing low ß-arrestin recruitment to the µ-receptor. Intravenous oliceridine showed statistically superior analgesia than placebo in patients with moderate or severe pain after surgery, with a favorable safety and tolerability profile regarding respiratory and gastrointestinal adverse effects, compared with morphine. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The analgesic capacity of oliceridine is at least comparable to that of morphine at clinically relevant dosages, with a rapid onset of action. Also, it may be associated with a lower incidence of adverse events at dosing regimens associated with comparable analgesia. These data suggest that oliceridine may provide an important new treatment option for the management of moderate to severe postoperative pain where an intravenous opioid is warranted. CONCLUSION: Oliceridine has obvious analgesic effects in patients with moderate or severe pain after surgery; additionally, it has a favorable safety and tolerability profile.

Effect and mechanism of asiatic acid on autophagy in myocardial ischemia-reperfusion injury in vivo and in vitro.

Myocardial ischemia-reperfusion injury (MIRI) is a major cause of heart failure in patients with coronary heart disease. The excessive accumulation of reactive oxygen species (ROS) during MIRI induces the overactivation of an autophagic response, which aggravates myocardial cell damage. Asiatic acid (AA) is a triterpenoid compound, which is extracted from Centella asiatica and exhibits a variety of pharmacological effects such as hepatoprotective, neuroprotective and antioxidant. However, the association of AA with autophagy in MIRI is not fully understood. In the present study, the positive effects of AA in MIRI injury were determined via establishing a MIRI mouse model. Pre-treatment with AA was indicated to improve cardiac function and decrease cardiomyocyte autophagy in mice subjected to MIRI. To examine the protective effects of AA and the underlying mechanisms in MIRI, a cardiomyocyte glucose deprivation/reperfusion (OGD) model was established. The administration of AA decreased the levels of ROS and malondialdehyde and increased the levels of superoxide dismutase activity in OGD-treated cells. Using western blotting, it was demonstrated that treatment with AA decreased the phosphorylation of p38 and increased the expression of Bcl-2 in OGD-treated cells. Additionally, the expression of autophagy markers, including beclin-1 and the microtubule-associated proteins 1A/1B light chain 3B II/I ratio, were also decreased in AA treated cells compared with OGD-treated cells. These results demonstrated that AA pretreatment protected cardiomyocytes from ROS-mediated autophagy via a p38 mitogen-activated protein kinase/Bcl-2/beclin-1 signaling pathway in MIRI.

Bempedoic acid for the treatment of hypercholesterolemia.

INTRODUCTION: Although several lipid-lowering drugs are available, they are not sufficient for some patients. Bempedoic acid is a small molecule adenosine triphosphate-citrate lyase inhibitor indicated for the treatment of adults with hypercholesterolemia. AREAS COVERED: We performed a systematic review of the literature using PubMed database, and the following keywords were used: 'bempedoic acid,' 'hypercholesterolemia,' and 'adenosine triphosphate citrate lyase.' The chemical property, mechanism of action, pharmacokinetics, clinical efficacy, and safety of bempedoic acid are introduced in this paper. EXPERT OPINION: Bempedoic acid can modulate the metabolism of cholesterol. Clinical trials indicated that bempedoic acid could significantly reduce low-density lipoprotein cholesterol levels. Bempedoic acid was well tolerated.

Polymer/lipid interplay in altering in vitro supersaturation and plasma concentration of a model poorly soluble drug.

Supersaturation drug delivery system (SDDS) based on amorphous solid dispersion (ASD) is a widely used strategy to improve oral absorption of poorly water-soluble drugs by achieving a supersaturated state where drug concentration is significantly higher than drug solubility. However, dissolved drugs tend to recrystallize in gastrointestinal (GI) tract if without effective stabilizing excipients. In this paper, well-recognized polymer (polyvinylpyrrolidone, PVP) and lipid (phosphatidylcholine, PC) excipients are combined as ASD carrier, aiming at investigating the effects on evolution of in vitro supersaturation and in vivo plasma concentration of a model poorly soluble drug indomethacin (IND). Fundamental aspects including polymer/lipid composition ratio, drug loading (DL) degree and administration dose were investigated. The in vitro dissolution profiles of ASDs were assessed by supersaturation degree, duration, maximum achievable drug concentration and dose-normalized efficiency, and correlated with in vivo pharmacokinetic data. Results showed that both in vitro and in vivo concentration-time profiles of IND were significantly varying with abovementioned factors. Solution viscosity, solid-state properties and morphology of ASDs were related to the results. This study revealed fundamental mechanisms of PVP/PC mixture effect on IND supersaturation and oral bioavailability, demonstrating that polymer/lipid mixture could be used as a promising carrier to alter supersaturation profile and oral bioavailability of SDDS products.