Processing Speed and Attentional Shift/Mental Flexibility in Patients with Stroke: A Comprehensive Review on the Trail Making Test in Stroke Studies.

The Trail Making Test (TMT) is one of the most commonly administered tests in clinical and research neuropsychological settings. The two parts of the test (part A (TMT-A) and part B (TMT-B)) enable the evaluation of visuoperceptual tracking and processing speed (TMT-A), as well as divided attention, set-shifting and cognitive flexibility (TMT-B). The main cognitive processes that are assessed using TMT, i.e., processing speed, divided attention, and cognitive flexibility, are often affected in patients with stroke. Considering the wide use of TMT in research and clinical settings since its introduction in neuropsychological practice, the purpose of our review was to provide a comprehensive overview of the use of TMT in stroke patients. We present the most representative studies assessing processing speed and attentional shift/mental flexibility in stroke settings using TMT and applying scoring methods relying on conventional TMT scores (e.g., time-to-complete part A and part B), as well as derived measures (e.g., TMT-(B-A) difference score, TMT-(B/A) ratio score, errors in part A and part B). We summarize the cognitive processes commonly associated with TMT performance in stroke patients (e.g., executive functions), lesion characteristics and neuroanatomical underpinning of TMT performance post-stroke, the association between TMT performance and patients' instrumental activities of daily living, motor difficulties, speech difficulties, and mood statue, as well as their driving ability. We also highlight how TMT can serve as an objective marker of post-stroke cognitive recovery following the implementation of interventions. Our comprehensive review underscores that the TMT stands as an invaluable asset in the stroke assessment toolkit, contributing nuanced insights into diverse cognitive, functional, and emotional dimensions. As research progresses, continued exploration of the TMT potential across these domains is encouraged, fostering a deeper comprehension of post-stroke dynamics and enhancing patient-centered care across hospitals, rehabilitation centers, research institutions, and community health settings. Its integration into both research and clinical practice reaffirms TMT status as an indispensable instrument in stroke-related evaluations, enabling holistic insights that extend beyond traditional neurological assessments.

Are the Dietary-Nutritional Recommendations Met? Analysis of Intake in Endurance Competitions.

BACKGROUND: In recent decades the number of endurance events has increased, as well as the number of athletes participating in them. Adequate nutritional and water planning is essential to maintain optimal sports performance and to reduce the incidence of gastrointestinal problems. The main objective of this study is to determine the dietary intake and compliance with nutritional recommendations of athletes in two endurance competitions, as well as to assess the incidence of gastrointestinal complaints. METHODS: An observational and cross-sectional study was carried out on the consumption of liquids, food, and supplements in 42 triathletes and mountain runners (MRs) participating in a Vi-Half-Gasteiz triathlon and the Ultra Sierra de Cazorla trail run. At the completion of the trials, participants completed a validated questionnaire (NIQEC). RESULTS: The mean caloric intake during the test of the participants in this study was 192.17 kcal/h, while the mean carbohydrate intake was 43.67 g/h, the mean sodium intake was 267.43 mg/h, and the mean caffeine intake was 15.53 mg/h, with no significant differences between the two sports. The amount of liquids consumed by the participants was 421.21 mL/h, with no significant differences between the triathletes and MRs. As for gastrointestinal problems, it was observed that the participants presented gastrointestinal discomfort in 61.9% of the cases. CONCLUSIONS: The intakes of energy, carbohydrates, water, sodium, and caffeine were lower than the current recommendations. There were no differences in the energy, carbohydrate, water, sodium, and caffeine intakes between the triathletes and mountain runners. Gastrointestinal problems showed a high prevalence in these athletes.

The Promise of Piperine in Cancer Chemoprevention.

Cancer, characterized by the unregulated growth and dissemination of malignantly transformed cells, presents a significant global health challenge. The multistage process of cancer development involves intricate biochemical and genetic alterations within target cells. Cancer chemoprevention has emerged as a vital strategy to address this complex issue to mitigate cancer's impact on healthcare systems. This approach leverages pharmacologically active agents to block, suppress, prevent, or reverse invasive cancer development. Among these agents, piperine, an active alkaloid with a wide range of therapeutic properties, including antioxidant, anti-inflammatory, and immunomodulatory effects, has garnered attention for its potential in cancer prevention and treatment. This comprehensive review explores piperine's multifaceted role in inhibiting the molecular events and signaling pathways associated with various stages of cancer development, shedding light on its promising prospects as a versatile tool in cancer chemoprevention. Furthermore, the review will also delve into how piperine enhances the effectiveness of conventional treatments such as UV-phototherapy and TRAIL-based therapy, potentially synergizing with existing therapeutic modalities to provide more robust cancer management strategies. Finally, a crucial perspective of the long-term safety and potential side effects of piperine-based therapies and the need for clinical trials is also discussed.

Tubeimoside-1 Enhances TRAIL-Induced Apoptotic Cell Death through STAMBPL1-Mediated c-FLIP Downregulation.

Tubeimoside-1 (TBMS-1), a traditional Chinese medicinal herb, is commonly used as an anti-cancer agent. In this study, we aimed to investigate its effect on the sensitization of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Our results revealed that even though monotherapy using TBMS-1 or TRAIL at sublethal concentrations did not affect cancer cell death, combination therapy using TBMS-1 and TRAIL increased apoptotic cell death. Mechanistically, TBMS-1 destabilized c-FLIP expression by downregulating STAMBPL1, a deubiquitinase (DUB). Specifically, when STAMBPL1 and c-FLIP bound together, STAMBPL1 deubiquitylated c-FLIP. Moreover, STAMBPL1 knockdown markedly increased sensitivity to TRAIL by destabilizing c-FLIP. These findings were further confirmed in vivo using a xenograft model based on the observation that combined treatment with TBMS-1 and TRAIL decreased tumor volume and downregulated STAMBPL1 and c-FLIP expression levels. Overall, our study revealed that STAMBPL1 is essential for c-FLIP stabilization, and that STAMBPL1 depletion enhances TRAIL-mediated apoptosis via c-FLIP downregulation.

Evaluation of clinical trials of ethnomedicine used for the treatment of diabetes: A systematic review.

Diabetes mellitus (DM) is a widespread metabolic disorder with a yearly 6.7 million deaths worldwide. Several treatment options are available but with common side effects like weight gain, cardiovascular diseases, neurotoxicity, hepatotoxicity, and nephrotoxicity. Therefore, ethnomedicine is gaining the interest of researchers in the treatment of DM. Ethnomedicine works by preventing intestinal absorption and hepatic production of glucose as well as enhancing glucose uptake in muscles and fatty tissues and increasing insulin secretion. A variety of plants have entered clinical trials but very few have gained approval for use. This current study provides an evaluation of such clinical trials. For this purpose, an extensive literature review was performed from a database using keywords like "ethnomedicine diabetes clinical trial", "clinical trials", "clinical trial in diabetes", "diabetes", "natural products in diabetes", "ethno-pharmacological relevance of natural products in diabetes", etc. Clinical trials of 20 plants and natural products were evaluated based on eligibility criteria. Major limitations associated with these clinical trials were a lack of patient compliance, dose-response relationship, and an evaluation of biomarkers with a small sample size and treatment duration. Measures in terms of strict regulations can be considered to achieve quality clinical trials. A specific goal of this systematic review is to discuss DM treatment through ethnomedicine based on recent clinical trials of the past 7 years.

Indirubin Inhibits TRAIL-Induced Activation of Death Receptor 5 in Jurkat Cells.

Death receptor 5 (DR5) is an apoptosis-inducing membrane receptor that mediates cell death in several life-threatening conditions. There is a crucial need for the discovery of DR5 antagonists for the therapeutic intervention of conditions in which the overactivation of DR5 underlies the pathophysiology. DR5 activation mediates cell death in non-alcoholic fatty liver disease (NAFLD) and neurodegenerative processes including amyloid-beta (Aß) accumulation, spinal cord injury (SCI), and brain ischemia. In the current work, we used fluorescence resonance energy transfer (FRET) to monitor the conformational dynamics of DR5 that mediate death signaling. We used a time-resolved FRET screening platform to screen the Selleck library of 2863 U.S. Food and Drug Administration (FDA)-approved compounds. The high-throughput screen (HTS) identified 13 compounds that modulated the FRET between DR5 monomers beyond 5 median absolute deviations (MADs) from the DMSO controls. Of these 13 compounds, indirubin was identified to specifically inhibit tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced caspase-8 activity without modulating DR5 surface expression or TRAIL binding. Indirubin inhibited Fas-associated death domain (FADD) oligomerization and increased cellular FLICE-inhibitory protein (c-FLIP) expression; both are molecular mechanisms involved in inhibiting the DR5 signaling cascade. This study has elucidated previously unknown properties of indirubin that make it a promising candidate for therapeutic investigation of diseases in which overactivation of DR5 underlies pathology.

[Effect of penetrative needling of "Zhibian" (BL54) through "Shuidao" (ST28) on expression of TRAIL and its receptors in rats with premature ovarian insufficiency].

OBJECTIVE: To observe the effect of penetrative needling of "Zhibian" (BL54) through "Shuidao" (ST28) on the expressions of death receptor pathway-related protein tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors, as death receptor 4 (DR4), death receptor 5 (DR5), decoy receptor 1 (DcR1) and decoy receptor 2 (DcR2) in premature ovarian insufficiency (POI) rats, so as to explore its mechanisms underlying improvement of POI. METHODS: Forty female SD rats were randomly divided into blank control, model, penetrative needling and medication (estradiol valerate) groups, with 10 rats in each group. The POI model was established by intraperitoneal injection of cyclophosphamide (D1: 50 mg·kg-1·d-1, D2 to D15: 8 mg·kg-1·d-1, for a total of 15 d). After successful modeling, the rats in the penetrative needling group received penetrative needling of BL54 through ST28, with the needle retained for 30 min, once a day for a total of 4 weeks. Rats of the medication group received gavage of estradiol valerate (0.09 mg·kg-1·d-1) once daily for 4 weeks. After the intervention, the content of serum follicles of stimulation hormone (FSH),lateinizing hormone (LH),estradiol (E2) and vascular endothelial growth factor (VEGF) were assayed using enzyme-linked immunosorbent assay, and histopathological changes of ovarian tissue and the number of follicles were observed under light microscope after H.E. staining. The expression levels of TRAIL, DR4, DR5, DcR1, DcR2, and Fas-associated death domain (FADD) in ovarian tissues were detected using quantitative real-time PCR, and the immunoactivity of ovarian TRAIL, DR4 and DR5 detected using immunohistochemistry. The body weight and the damp weight of ovary were measured for calculating the ovarian coefficient. RESULTS: Compared with the blank control group, the E2 and VEGF contents, ovarian coefficient, and the number of the primary, secondary and sinus follicles were significantly decreased (P<0.01) in the model group, whereas FSH and LH contents, the atretic follicle number, TRAIL, DR4 and DR5 immunoactivity, and the expression levels of TRAIL, DR4, DR5 and FADD mRNAs considerably increased in the model group (P<0.01). In comparison with the model group, the decrease of the VEGF content, ovarian coefficient, and the number of the primary, secondary and sinus follicles, and the increase of the atretic follicle number, TRAIL, DR4 and DR5 immunoactivity, and expression levels of TRAIL, DR4, DR5 and FADD mRNAs were reversed in both penetrative needling and medication groups (P<0.01, P<0.05). The number of primary follicles was significantly more in the medication group than in the penetrative needling group (P<0.01). CONCLUSION: Penetrative needling of BL54 and ST28 can improve ovarian weight and promote follicular development in POI rats, which may be associated with its function in down-regulating the expression of pro-apoptotic proteins TRAIL, DR4, DR5 and FADD of the death receptor pathway to inhibit apoptosis of ovarian granulosa cells.

Dissipation kinetics of co-formulation with two herbicides, clodinafop-propargyl and oxyfluorfen, in/on onion (Allium cepa) samples.

Supervised field trail on dissipation of co-formulation with herbicides clodinafop-propargyl and oxyfluorfen in spring onion showed similar pattern of dissipation during two different seasons. Residues of clodinafop-propargyl reached ≤ limit of quantitation (LOQ, 0.05 mg kg-1) on 3rd day after application at both standard and double dose during both the seasons. Oxyfluorfen residues followed first-order kinetics in both the doses during first season with half-life of 0.81 to 3.14 days. The residues of clodinafop-propargyl were detected in soil at both the doses during first season. However, residues were ≤ LOQ (0.05 mg kg-1) during second season. The residues of oxyfluorfen were detected only in double dose during first season in soil. In all other cases and in onion bulb, residues were ≤ LOQ (0.05 mg kg-1) at the time of harvest. As the residues were either ≤ LOQ (0.05 mg kg-1) on 3rd day or have a half-life of 3.14 days, the co-formulation can be used safely, provided a pre harvest interval (PHI) of 3 days is followed. On the basis of maximum residue limits (MRLs) in other commodities and from the data of present study, a default MRL of 0.05 mg kg-1 is proposed for both the pesticides.

Effects of acupoint application therapy combined with chinese herbal medicine on perimenopausal syndrome: A systematic review and meta-analysis of randomized controlled trails.

BACKGROUND: An increasing number of women suffer from perimenopausal syndrome (PMS) and the global burden of this disease has been steadily rising. Acupoint application therapy and Chinese herbal medicine (CHM) are widely used as effective methods for treating PMS, but the efficacy was inconsistent and the evidence should be summarized by quantitively analysis. OBJECTIVE: The purpose of this systematic review and meta-analysis was to evaluate the clinical efficacy and safety of the acupoint application combined with the CHM for the treatment of PMS. METHODS: We searched eight databases from their inception to August 2022 to identify relevant studies. Only randomized controlled trials (RCTs) focusing on acupoint application combined with CHM for the treatment of PMS were included in this study. To assess the clinical efficacy and safety, meta-analysis was used to quantitively synthesize the effect estimates. Subgroup analysis, publication bias assessment and sensitivity analysis were also performed. We further assessed whether the included studies had reported on the purity and potency of the CHM used in their trials. RESULTS: A total of 8 RCTs with 560 participants were included in the systematic review and meta-analysis, of which none of them included a description of an independent testing of purity or potency of the CHM product used. There were significant differences between the acupoint application combined with CHM and CHM alone in terms of Kupperman Menopausal Index (KMI) score (MD = -2.91, 95%CI: -3.91 to -1.91), total effective rate (RR = 1.22, 95% CI: 1.11-1.34), Pittsburgh Sleep Quality Interview (PSQI) score (MD = -2.86, 95% CI: -3.61 to -2.10) and reduction in the serum level of luteinizing hormone (LH) (MD = -2.52, 95% CI: -4.70 to -0.34), whereas there were no differences between the two groups regarding lowering serum level of follicle-stimulating hormone (FSH) (MD = -1.66, 95% CI: -3.98-0.67) and elevating serum level of oestradiol (E2) (MD = 2.41, 95% CI: -0.70-5.52). For the comparation between the acupoint application combined with CHM and western medicine (WM), the KMI score (MD = -6.80, 95%CI: -7.95 to -5.65) was substantially different, while the PSQI score (MD = -0.60, 95% CI: -1.88-0.68) was not substantially different. The total effective rate in the combined group (91.7%) was higher than the western medicine group (83.49%). CONCLUSION: Acupoint application combined with CHM may enhance the efficacy and safety of patients with PMS. However, due to the lack of description of an independent testing of purity or potency of the CHM product used in the trials, as well as blinding of participants and investigators, these results should be interpreted with caution.

A new 1,2-diketone physalin isolated from Physalis minima and TRAIL-resistance overcoming activity of physalins.

A new 1,2-diketone physalin, physalin XII (1), and 13 known compounds were isolated from the methanol extract of Physalis minima whole plant collected in Thailand. Among them, five physalins (2-6) had tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistance overcoming activity, and physalin F (3) was the most active with an IC50 value of 0.39 µM against human gastric adenocarcinoma cell line AGS in the presence of TRAIL (100 ng/mL). An investigation of the TRAIL-resistance overcoming activity of physalins using western blot analysis showed that 3 promoted TRAIL-induced apoptosis by suppressing anti-apoptotic proteins c-FLIP and Bcl-2.

A nutritional intervention for moderate altitude endurance preparation: A case report.

Background: Moderate altitudes carry physiological and metabolic changes that can dampen exercise performance. Fortunately, these changes can be modulated by an optimal nutritional intervention. This case study represents the first nutritional intervention of a moderate altitude athlete. These results may help to establish well-designed nutritional guidelines for moderate altitude sports athletes. Case presentation: This case study examined the effects of a 11-week nutritional intervention on body composition, muscle strength, cardiorespiratory fitness, resting and exercise nutrient oxidation, and subjective sleep quality, in a male high-level moderate altitude athlete with a very light non-exercise activity thermogenesis. During the 11-week of nutritional intervention, 2800-3500 kcal/day, 6.8-8.9 g/kg/day of carbohydrates, 1.2-1.7 g/kg/day of protein, and 1-2.5 g/kg/day of fat were prescribed. Different specific considerations were also included, such as: iron supplementation, antioxidants increment in different phases, and ergogenic aids (i.e. creatine and beta-alanine). Our results demonstrated a decrease in adiposity and an increase in fat-free mass. In parallel, the athlete improved muscle strength, and therefore endurance adaptations after a maximal effort test (i.e. enhancement of the heart rate recovery). After the intervention, the athlete not only increased the carbohydrate oxidation during exercise and resting conditions but also improved his subjective sleep quality. Conclusions: Our results suggest that a nutritional intervention based on the endurance nutritional recommendations and adapted to the altitude physiological peculiarities can induce body re-composition, improve physiological adaptations to effort, and upgrade the substrate oxidation in a moderate altitude high-level athletes.

Exploration of acupuncture therapy in the treatment of mild cognitive impairment based on the brain-gut axis theory.

Background: Mild cognitive impairment (MCI) is an intermediary state between normal aging and dementia. Early intervention for MCI may be a key opportunity in managing dementia. Recent studies have demonstrated the alterations in the gut microbial communities associated with MCI. This study aims to evaluate if acupuncture can improve cognitive function in subjects with MCI and explore the possible mechanism of acupuncture by better defining the interactions of gut microbiota. Methods: A randomized assessor-blind controlled study is proposed. A total of 62 subjects will be recruited and randomly allocated into two groups in a 1:1 ratio: the treatment and control groups. Participants in the treatment group will receive active acupuncture and exercise/cognitive training (conventional treatment). The control group will receive sham acupuncture and exercise/cognitive training. Each participant will receive active or sham acupuncture for 12 weeks. The primary outcome will be the Montreal Cognitive Assessment (MoCA) score and intestinal flora. Secondary outcomes will include mini-mental state examination (MMSE) and activity of daily living (ADL) scores. Various scales will be collected at baseline, during the treatment (weeks 4 and 8), week 12, and months 4 and 6 after the intervention. Feces will be collected before and after the treatment based on 16S rRNA gene sequencing technology for each participant to characterize the intestinal flora. Adverse events will be recorded by monthly follow-up. Results: The trial is expected to show that cognitive function can be improved by acupuncture and produce reliable clinical outcomes in MCI patients. It will also provide preliminary data on the possible mechanism based on the changes in the intestinal flora. Collected data will be used to support future large-scale fundamental studies. Conclusion: Acupuncture is an effective method to improve cognitive function for MCI. This study will provide data on the relationship between gut microbiota and the effectiveness of acupuncture in patients with MCI from a new angle. Clinical trial registration: [www.ClinicalTrials.gov], identifier [MR-33-22-002376].

Production of Soluble Murine TRAILs in Escherichia coli with Zn2+ Supplementation.

BACKGROUND: Accumulating evidence has demonstrated the immunomodulatory effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in rheumatoid arthritis and the tumor microenvironment, besides its known capacity of specifically inducing the apoptosis of cancer cells. Mice are common available animal models for studying the roles of TRAIL. However, mice express only a single TRAIL receptor (mTRAILR) with an intracellular death domain, in contrast to the two TRAIL receptors (TRAILR1 and TRAILR2) in humans. Moreover, human TRAIL binds weakly to mTRAILR, whereas mouse TRAIL has a high affinity for human TRAIL-Rs. Therefore, we considered that murine TRAIL would be more suitable than human TRAIL for exploring the immunoregulatory effect of TRAIL in immunocompetent mice or when using mouse cells as the target. To our knowledge, the detailed method for the production of recombinant murine TRAIL has not been reported. OBJECTIVE: In this study, we aimed to design and express two soluble forms of murine TRAIL and verify the properties of the protein. METHODS: Recombinant murine TRAILs were expressed in Escherichia coli BL21 (DE3, and Nichelating affinity chromatography was used for protein purification. SDS-PAGE, GDS-PAGE and HPLC were applied to analyze the protein structure. The cytotoxicity of our purified murine TRAILs was evaluated in the TRAIL-sensitive human breast cancer ZR-75-30 cells and murine breast cancer 4T1 cells. Finally, validation of the tumor-killing ability of the murine protein in vivo. RESULTS: Two soluble forms of murine TRAILs (mT_N99 and mT_N188) were purified and demonstrated with high purity and trimeric structure. In addition, Zn2+ supplement was essential to produce soluble murine TRAILs in E.coli BL21 (DE3). The two purified soluble mTRAILs showed similar cytotoxicity to cancer cells, moreover, mT_N99 also showed a good anti-tumor effect in vivo and is more suitable for the treatment of murine tumor models. CONCLUSION: A production approach for recombinant murine TRAIL was determined, which covered the design of shortened forms, expression, purification and characterization.

Oral ketone monoester supplementation does not accelerate recovery of muscle force or modulate circulating cytokine concentrations after muscle-damaging eccentric exercise in healthy males and females.

NEW FINDINGS: What is the central question of this study? Does acute ketone monoester supplementation enhance the recovery of muscle force and modulate circulating cytokine concentrations after muscle-damaging eccentric exercise? What is the main finding and its importance? Ketone monoester supplementation increased plasma ß-hydroxybutyrate concentrations but did not attenuate the reduction in muscle force or the increase in plasma inflammatory cytokine concentrations that occurred after eccentric exercise. Notably we report novel data demonstrating a reduction in plasma TRAIL concentrations after eccentric exercise, highlighting TRAIL signalling as a possibly novel regulator of muscle recovery. ABSTRACT: Muscle-damaging eccentric exercise is associated with inflammation and impaired muscle force. ß-Hydroxybutyrate (ß-OHB) reduces muscle protein breakdown during inflammation but whether oral ketone monoester supplementation accelerates recovery of muscle force after eccentric exercise is unknown. Sixteen healthy males and females consumed thrice daily ketone monoester (27 g per dose; n = 8; six females; KES) or isocaloric maltodextrin placebo (n = 8; four females; PLA) drinks (randomized, double-blind, parallel group design) for 3 days beginning immediately after 300 unilateral eccentric quadriceps contractions during complete eucaloric dietary control (1.2 ± 0.1 g/kg BM/day standardized protein). Bilateral muscle force measurements and venous blood sampling were performed before and 3, 6, 24, 48 and 72 h after eccentric exercise. Plasma ß-OHB concentrations were greater in KES compared with PLA at 3 h (0.56 ± 0.13 vs. 0.22 ± 0.04 mM, respectively; P = 0.080) and 6 h (0.65 ± 0.41 vs. 0.23 ± 0.02 mM, respectively; P = 0.031) post-eccentric exercise. Relative to the control leg, isokinetic work (by 20 ± 21% in PLA and 21 ± 19% in KES; P = 0.008) and isometric torque (by 23 ± 13% in PLA and 20 ± 18% in KES; P < 0.001) decreased from baseline at 3 h in the eccentrically exercised leg, and remained below baseline at 48 and 72 h, with no significant group differences. Of eight measured plasma cytokines, interleukin-6 (P = 0.008) and monocyte chemoattractant protein-1 (P = 0.024) concentrations increased after 6 h, whereas tumour necrosis factor-related apoptosis-inducing ligand concentrations decreased after 3 h (P = 0.022) and 6 h (P = 0.011) post-exercise with no significant group differences. Oral ketone monoester supplementation elevates plasma ß-OHB concentrations but does not prevent the decline in muscle force or alter plasma inflammatory cytokine profiles induced by eccentric exercise.

Licochalcone B induces DNA damage, cell cycle arrest, apoptosis, and enhances TRAIL sensitivity in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is a highly fatal disease recognized as a growing global health crisis. Traditional Chinese herbal medicines have been used to treat patients with cancer for many years in China. This study investigated the effects of licochalcone B (LCB), a flavonoid compound isolated from the root of Glycyrrhiza uralensis Fisch., on cell proliferation, DNA damage and TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in HCC cells. Our results showed that LCB inhibited cell proliferation and induced DNA damage, cell cycle arrest and apoptosis. Treatment with LCB significantly inhibited the Akt/mTOR pathway and activated endoplasmic reticulum (ER) stress and mitogen-activated protein kinase (MAPK) signaling pathway. Moreover, combined treatment with LCB and TRAIL yielded evident enhancements in the viability reduction and apoptosis. LCB upregulated death receptor 4 (DR4) and death receptor 5 (DR5) protein in a concentration- and time-dependent manner. The knockdown of DR5 significantly suppressed TRAIL-induced cleavage of PARP, which was enhanced by LCB. Treatment with an extracellular-regulated kinase (ERK) inhibitor (PD98059) or c-Jun N-terminal kinase (JNK) inhibitor (SP600125) markedly reduced the LCB-induced upregulation of DR5 expression and attenuated LCB-mediated TRAIL sensitization. In summary, LCB exhibits cytotoxic activity through modulation of the Akt/mTOR, ER stress and MAPK pathways in HCC cells and effectively enhances TRAIL sensitivity through the upregulation of DR5 expression in ERK- and JNK-dependent manner. Combination therapy with LCB and TRAIL may be an alternative treatment strategy for HCC.

Experimental and clinical trial investigations of phyto-extracts, phyto-chemicals and phyto-formulations against oral lichen planus: A systematic review.

ETHNOPHARMACOLOGICAL RELEVANCE: Bio-assay guided phytoextracts and derived phytoconstituents reported having multipotent biological activities and nearly 60-80% of the global population still using natural regimens as an alternative therapeutic source. This study focused on the ethnopharmacological and experimental evidence of natural remedies that are effective in treating oral lichen planus (OLP), a chronic T-cell mediated autoimmune disease that is associated with oral cancer transmission. AIM OF THE REVIEW: A number of studies have shown that antioxidants and antiinflammatory phytoextracts and phyto-constituents are effective against OLP. In this systematic review, we summarize the details of experimentally assessed ancient Traditional Chinese Medicine (TCM), Indian Ayurveda or Ayurvedic Medicine, and Japanese Kampo Medicine (JKM) regimens (crude extracts, individual phytochemicals, and phyto-formulations) that reduce oral lesion, severity index and pain associated with OLP based on studies conducted in vivo, in vitro, and in randomized controlled trials (RCTs). MATERIALS AND METHODS: Experimental, clinical and RCT investigation reports were gathered and presented according to PRISMA-2020 format. Briefly, the information was obtained from PubMed, ScienceDirect, Wiley journal library, Scopus, Google Scholar with ClinicalTrials.gov (a clinical trial registry database operated by the National Library of Medicine in the United States). Further, individual phytochemical structures were verified from PubChem and ChemSpider databases and visualized by ChemDraw 18.0 software. RESULTS: We summarized 11 crude phytoextracts, 7 individual phytochemicals, 9 crude formulations, 8 specific TCM and JKM herbal cocktails, and 6 RCTs/patents corroborated by multiple in vitro, in vivo and enzyme assay methods. Briefly, plants and their family name, used plant parts, reported phytochemicals and their chemical structure, treatment doses, and duration of each experiment were presented more concisely and scientifically. CONCLUSION: Documentation of evidence-based natural ethnomedicines or remedies could be useful for promoting them as potential, cost-effective and less toxic alternatives or as complementary to commonly prescribed steroids towards the control of OLP.

Does hypnotizability affect neurovascular coupling during cognitive tasks?

Susceptibility to hypnosis is a very pervasive psychophysiological trait characterized by different attentional abilities, information processing, and cardiovascular control. Since near infrared spectroscopy is a good index of neurovascular coupling, we used it during mental computation (MC) and trail making task (TMT) in 13 healthy low-to-medium (med-lows) and 10 healthy medium-to-high (med-highs) hypnotizable participants classified according to the Stanford Hypnotic Susceptibility Scale, form A, and characterized for the level of proneness to be deeply absorbed in related experiences by the Tellegen Absorption Scale. The med-highs reported greater absorption than med-lows. The tissue hemoglobin index (THI) and the tissue oxygenation index (TOI) increased across the tasks only in med-highs who displayed also different time courses of THI and TOI during MC and TMT, which indicates different tasks processing despite the two groups' similar performance. The findings suggest that med-highs' tissue oxygenation is more finely adjusted to metabolic demands than med-lows'.

Thannilignan glucoside and 2-(ß-glucopyranosyl)-3-isoxazolin-5-one derivative, two new compounds isolated from Terminalia bellirica.

Two new compounds, thannilignan 9-O-ß-glucoside (1) and 2-(ß-glucopyranosyl)-3-isoxazolin-5-one derivative (2), and seven known compounds were isolated from the methanol extract of Terminalia bellirica leaves, collected in Bangladesh. The structures of the compounds were elucidated using spectroscopic analysis. Among these isolated compounds, corilagin (3) was cytotoxic against human gastric adenocarcinoma cell line AGS at an IC50 of 20.8 µM, and ß-D-glucopyranose 1,3,6-trigallate (4) exhibited the ability to overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance.

Antitumor effect of acanthoic acid against primary effusion lymphoma via inhibition of c-FLIP.

Acanthoic acid (AA) is an active substance that is extracted from Croton oblongifolius Roxb., a traditional plant in Thailand. The antiinflammatory effect of AA on NF-κB pathway has been exclusively reported, however, its anticancer effect is still lacking. PEL is a B cell lymphoma that is mostly found in HIV patients. The prognosis and progression of PEL patients are terribly poor with a median survival time less than 6 months, so the new effective treatment is urgently needed. In this study, we found that AA effectively inhibited PEL cell proliferation with IC50s at 120-130 µM in well-representative cells, while the IC50s of AA in PBMC were higher (>200 µM). AA increased percentages of Annexin V/PI positive cells, whereas adding of caspase inhibitor (Q-VD-OPh) prevented AA-induced cell death. The antiapoptotic protein, c-FLIP, was downregulated by AA which leading to the activation of caspase-8 and -3. Combination of AA and TRAIL dramatically enhanced apoptotic cell death. In PEL xenograft model, AA at the dose of 250 mg/kg effectively inhibited PEL tumor growth without detectable toxicities assessed by mice weight and appearance.

BAP1 and YY1 regulate expression of death receptors in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare, aggressive, and incurable cancer arising from the mesothelial lining of the pleura, with few available treatment options. We recently reported that loss of function of the nuclear deubiquitinase BRCA1-associated protein 1 (BAP1), a frequent event in MPM, is associated with sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. As a potential underlying mechanism, here we report that BAP1 negatively regulates the expression of TRAIL receptors: death receptor 4 (DR4) and death receptor 5 (DR5). Using tissue microarrays of tumor samples from MPM patients, we found a strong inverse correlation between BAP1 and TRAIL receptor expression. BAP1 knockdown increased DR4 and DR5 expression, whereas overexpression of BAP1 had the opposite effect. Reporter assays confirmed wt-BAP1, but not catalytically inactive BAP1 mutant, reduced promoter activities of DR4 and DR5, suggesting deubiquitinase activity is required for the regulation of gene expression. Co-immunoprecipitation studies demonstrated direct binding of BAP1 to the transcription factor Ying Yang 1 (YY1), and chromatin immunoprecipitation assays revealed BAP1 and YY1 to be enriched in the promoter regions of DR4 and DR5. Knockdown of YY1 also increased DR4 and DR5 expression and sensitivity to TRAIL. These results suggest that BAP1 and YY1 cooperatively repress transcription of TRAIL receptors. Our finding that BAP1 directly regulates the extrinsic apoptotic pathway will provide new insights into the role of BAP1 in the development of MPM and other cancers with frequent BAP1 mutations.