Antidepressant and anxiolytic potential of Citrus reticulata Blanco essential oil: a network pharmacology and animal model study.

Background: Citrus reticulata Blanco essential oil (CBEO) has attracted increasing attention as a potential treatment for depression and anxiety in recent years. However, there is limited evidence regarding the active compounds responsible for its therapeutic effects. In addition, substantial amounts of CBEO and prolonged therapy are often required. This study aims to investigate the rapid acting antidepressant and anxiolytic effects of CBEO, identify the underlying composition as well as optimize its dosage and duration. Methods: CBEO composition was determined using gas chromatography-mass spectrometry (GC-MS), and the corresponding targets were obtained from the SwissTargetPrediction database. Depression-related targets were collected from DisGeNET, GeneCards, Therapeutic Target Database, and Online Mendelian Inheritance in Man. Subsequently, the overlap between CBEO and depression targets was utilized to build a network diagram depicting the relationship between the active ingredients and targets using Cytoscape software. The STRING database facilitated the construction of a protein-protein interaction network, and the Ma'ayan Laboratory Enrichment tool was employed for Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Wiki pathway analyses. Molecular docking was conducted using AutoDock Vina and Discovery Studio Visualizer. Topological analysis predicted the main antidepressant active ingredients in CBEO. A mixture of these compounds was prepared based on their relative GC-MS ratios. Tail suspension test, elevated plus maze, corticosterone-induced PC12 cells, and lipopolysaccharide (LPS)-induced BV2 cells were used to validate the antidepressant and anxiolytic potential of CBEO and CBEO's main bioactive constituents. Results: CBEO contains 18 components that target 121 proteins. We identified 595 targets associated with depression; among them, 29 targets were located between essential oils and depression. Topological results revealed that linalool, p-cymene, α-terpinene, terpinen-4-ol, and α-terpineol were the major active compounds of CBEO in the management of depression. GO analysis identified G protein-coupled opioid receptor activity, phospholipase C-activating G protein-coupled receptor, and neuron projections that were mostly related to molecular functions, cellular components, and biological processes. Neuroactive ligand-receptor interactions, chemical carcinogenesis, and calcium signaling pathways were the major pathways identified in KEGG analysis. Molecular docking showed that the main bioactive ingredients of CBEO had favorable binding affinities for Protein-Protein Interaction's hub proteins, including OPRM1, PTGS2, ESR1, SLC6A4, DRD2, and NR3C1. These five compounds were then mixed at 0.8:5:0.6:2:1 (w/w) ratio to form a CBEO antidepressant active compound mixture. An acute intranasal treatment of CBEO (25 mg/kg) only demonstrated an antidepressant effect, whereas the main bioactive compounds combination (12.5 mg/kg) illustrated both antidepressant and anxiolytic effects in mice. Linalool, p-cymene, and terpinene-4-ol exhibited neuroprotective and anti-neuroinflammation in the in vitro study, while these effects were not observed for α-terpinene and α-terpineol. Conclusion: Linalool, p-cymene, α-terpinene, terpinen-4-ol, and α-terpineol cymene might be mainly contributing to CBEO's antidepressant effect by regulating neuroactive ligand-receptor interaction, neuron projection, and receptor signaling pathway. A mixture of these compounds showed rapid antidepressant potential via intranasal administration, which was comparable to that of CBEO. The mixture also exhibited an anxiolytic effect while not seen in CBEO.

Intranasal delivery of herbal medicine for disease treatment: A systematic review.

BACKGROUND: Intranasal administration has been adopted in traditional medicine to facilitate access to the bloodstream and central nervous system (CNS). In modern medicine, nasal drug delivery systems are valuable for disease treatment because of their noninvasiveness, good absorption, and fast-acting effects. OBJECTIVE: This study aimed to systematically organize preclinical and clinical studies on intranasal herbal medicines to highlight their potential in drug development. METHODS: A comprehensive search for literature until February 2023 was conducted on PubMed and the Web of Science. From the selected publications, we extracted key information, including the types of herbal materials, target diseases, intranasal conditions, methods of toxicity evaluation, main outcomes, and mechanisms of action, and performed quality assessments for each study. RESULTS: Of the 45 studies, 13 were clinical and 32 were preclinical; 28 studies used herbal extracts, 9 used prescriptions, and 8 used natural compounds. The target diseases were rhinosinusitis, influenza, fever, stroke, migraine, insomnia, depression, memory disorders, and lung cancer. The common intranasal volumes were 8-50 µl in mice, 20-100 µl in rats, and 100-500 µl in rabbits. Peppermint oil, Ribes nigrum folium, Melia azedarach L., Elaeocarpus sylvestris, Radix Bupleuri, Da Chuan Xiong Fang, Xingnaojing microemulsion, and Ginsenoside Rb1 emerged as potential candidates for rapid intranasal therapy. The in vivo toxicity assessments were based on mortality, body weight, behavioral changes, mucociliary activity, histopathology, and blood tests. Most intranasal treatments were safe, except for Cyclamen europaeum, Jasminum sambac, Punica granatum L., and violet oil, which caused mild adverse effects. At lower doses, intranasal herbal treatments often show greater effects than oral administration. The actions of intranasal herbal medicine mainly involve regulating inflammation and neurotransmission, with the olfactory bulb and anterior cingulate cortex to be relevant brain regions. CONCLUSION: Intranasal delivery of herbal materials holds promise for enhancing drug delivery efficacy and reducing treatment duration, offering a potential future perspective for developing intranasal therapies for various diseases.

mFOLFIRINOX versus mFOLFOX 6 as adjuvant treatment for high-risk stage III colon cancer - the FROST trial: study protocol for a multicenter, randomized controlled, phase II trial.

BACKGROUND: High-risk stage III colon cancer has a considerably poorer prognosis than stage II and low-risk stage III colon cancers. Nevertheless, most guidelines recommend similar adjuvant treatment approaches for all these stages despite the dearth of research focusing on high-risk stage III colon cancer and the potential for improved prognosis with intensive adjuvant treatment. Given the the proven efficacy of triplet chemotherapy in metastatic colorectal cancer treatment, the goal of this study is to evaluate the oncologic efficacy and safety of mFOLFIRINOX in comparison to those of the current standard of care, mFOLFOX 6, as an adjuvant treatment for patients diagnosed with high-risk stage III colon cancer after radical resection. METHODS: This multicenter, randomized (1:1), open-label, phase II trial will assess and compare the effectiveness and toxicity of mFOLFIRINOX and mFOLFOX 6 in patients with high-risk stage III colon cancer after radical resection. The goal of the trial is to enroll 312 eligible patients, from 11 institutes, aged between 20 and 70 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, or between 70 and 75 with an ECOG performance status of 0. Patients will be randomized into two arms - Arm A, the experimental arm, and Arm B, the reference arm - and will receive 12 cycles of mFOLFIRINOX and mFOLFOX 6 every 2 weeks, respectively. The primary endpoint of this study is the 3-year disease-free survival, and secondary endpoints include the 3-year overall survival and treatment toxicity. DISCUSSION: The Frost trial would help determine the oncologic efficacy and safety of adjuvant triplet chemotherapy for high-risk stage III colon cancers and ultimately improve prognoses. TRIAL REGISTRATION: ClinicalTrials.gov NCT05179889, registered on 17 December 2021.

Essential oil of Pterocarpus santalinus L. alleviates behavioral impairments in social defeat stress-exposed mice by regulating neurotransmission and neuroinflammation.

BACKGROUND: Pterocarpus santalinus L. essential oil (PSEO) is traditionally employed for treating fever and mental aberrations. We aim to explore the antidepressant potential of intranasal PSEO in social defeat stress (SDS)-expose mice and identify its mechanisms and components. METHODS: PSEO components were analyzed using gas chromatography-mass spectrometry (GC-MS). C57BL/6 mice underwent a 10-day SDS with intranasal PSEO (10, 20 mg/kg) for 21 days. Efficacy was evaluated through changes in behaviors and serum corticosterone (CORT), hippocampal neurotransmitter, and inflammatory cytokine levels. In vitro effects were examined using primary hippocampal neurons, PC12 and BV2 cells. RESULTS: GC-MS identified 22 volatile compounds in PSEO, and (+)-ledene (16.7%), cedrol (13.5%), and isoaromadendrene epoxide (7.0%) as major components. PSEO (20 mg/kg) significantly reversed SDS-induced social withdrawal, increased open-area explorations in the open field test (OFT) and elevated plus maze (EPM) test, and reduced immobility time in the tail suspension test (TST) and forced swimming test (FST). PSEO downregulated serum CORT and hippocampal interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α levels, while increasing hippocampal gamma-aminobutyric acid (GABA), norepinephrine (NE), and serotonin (5-HT) levels. PSEO (0.1, 1, 10 µg/mL) reduced neurotoxicity and neuroinflammation in PC12 and BV2 cells, respectively. PSEO (10 µg/mL) enhanced glutamic acid decarboxylase 6 (GAD6)- and GABA B receptor 1 (GABABR1)-positive puncta in the hippocampal neurons and FM1-43 fluorescence intensity. CONCLUSION: Intranasal PSEO exhibited antidepressant-like effects on SDS-exposed mice, potentially through modulating stress hormone, neurotransmission, and neuroinflammation. Further investigation into the pharmacokinetics, bioavailability, and mechanisms of (+)-ledene, cedrol, and isoaromadendrene epoxide is needed.

Intranasal administration of the essential oil from Perillae Folium ameliorates social defeat stress-induced behavioral impairments in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Perillae Folium, the leaves and twigs of Perilla frutescens (L.) Britton, has been included in many traditional Chinese medicine herbal formulas to treat depression. However, the precise antidepressant mechanism of the essential oil from Perillae Folium (PFEO) has not been fully investigated. AIM OF THE STUDY: To assess the effects and potential mechanisms of PFEO on depression using animal models and network pharmacology analysis. MATERIALS AND METHODS: PFEO was intranasally administered to a mouse model of social defeat stress (SDS). The antidepressant effects of PFEO on SDS-induced mice were evaluated using behavioral tests. Enzyme-linked immunosorbent assay (ELISA) and western blot were performed to measure the levels of depression-related biomarkers in the hippocampus and serum of the mice. The chemical compounds of PFEO were determined using gas chromatography-mass spectrometry (GC-MS). Network pharmacology and molecular docking analyses were conducted to investigate the potential bioactive components of PFEO and the mechanisms underlying the antidepressant effects. To validate the mechanisms of the bioactive compounds, in vitro models using PC12 and BV2 cells were established and the blood-brain barrier (BBB) permeability was evaluated. RESULTS: The intranasal administration of PFEO suppressed SDS-induced depression in mice by increasing the time spent in the social zone and the social interactions in the social interaction test and by decreasing the immobility time in the tail suspension and forced swimming tests. Moreover, the PFEO treatment reduced the SDS-induced anxiety-like behavior, as inferred from the increased activity in the central zone observed in the open field test and in the open arms observed in the elevated plus maze test. PFEO administration recovered the SDS-induced decrease in the levels of 5-HT, NE, gamma-aminobutyric acid (GABA), and p-ERK in the hippocampus of mice. Furthermore, the increased serum corticosterone level was also attenuated by the PFEO treatment. A total of 21 volatile compounds were detected in PFEO using GC-MS, among which elemicin (15.52%), apiol (15.16%), and perillaldehyde (12.79%) were the most abundant ones. The PFEO compounds targeted 32 depression-associated genes, which were mainly related to neural cells and neurotransmission pathways. Molecular docking indicated good binding affinities between the bioactive components of PFEO (apiol, ß-caryophyllene, elemicin, and myristicin) and the key targets, including ACHE, IL1B, IL6, MAOB, SLC6A2, SLC6A3, SLC6A4, and tumor necrosis factor. Among the four compounds, ß-caryophyllene, elemicin, and myristicin were more effective in reducing neurotoxicity and neuroinflammation. Elemicin showed the highest BBB permeability rate. CONCLUSIONS: This study shows the antidepressant activities of PFEO in an SDS-induced mouse model and suggests its potential mechanisms of action: regulation of the corticosterone levels, hippocampal neurotransmitters, and ERK signaling. Apiol, ß-caryophyllene, elemicin, and myristicin may be the main contributors to the observed effects induced by PFEO. Further studies are needed to fully elucidate the underlying mechanisms and the main PFEO bioactive components.

Efficacy of a 1 day Rifaximin and Metronidazole Regimen and Mechanical Bowel Preparation for Preventing Surgical Site Infection in Minimally Invasive Colorectal Cancer Surgery: A Prospective Observational Study.

BACKGROUND: A combination of oral antibiotics and mechanical bowel preparation is recommended for patients scheduled to undergo elective colorectal surgery on the basis of recent large trials that have reported the superiority of this approach in preventing surgical site infections (SSIs). However, there are no standard recommendations for this approach. Therefore, in this study, we evaluated the efficacy of rifaximin and metronidazole and mechanical bowel preparation for preventing SSIs in cases of minimally invasive surgery for colorectal cancer. METHODS: This single-arm prospective observational study included 256 individuals. The primary end point was the rate of SSI. Rifaximin 400 mg and metronidazole 500 mg were administered twice daily (10 am and 10 pm), and mechanical bowel preparation was administered the day before the operation. RESULTS: After excluding 15 patients, 241 were enrolled. No adverse event occurred following the administration of oral antibiotics and mechanical bowel preparation; there was 100% compliance. The total SSI rate was 2.9%; the rates of incisional and organ/space SSIs were 1.2% and 1.7%, respectively. All patients were treated conservatively. Univariate analyses revealed preoperative anemia, hypoalbuminemia, and transfusion and postoperative transfusion were significantly associated with SSIs. DISCUSSION: A 1 day rifaximin and metronidazole regimen with mechanical bowel preparation for elective minimally invasive surgery for colorectal cancer was associated with a favorable SSI rate of 2.9%, safety, and high compliance. This approach is appropriate for inclusion in the current guidelines for perioperative management of patients scheduled to undergo minimally invasive surgery for colorectal cancer.

Anion Engineering for Stabilizing Li Interstitial Sites in Halide Solid Electrolytes for All-Solid-State Li Batteries.

Halide solid electrolytes (SEs) have been highlighted for their high-voltage stability. Among the halide SEs, the ionic conductivity has been improved by aliovalent metal substitutions or choosing a ccp-like anion-arranged monoclinic structure (C2/m) over hcp- or bcc-like anion-arranged structures. Here, we present a new approach, hard-base substitution, and its underlying mechanism to increase the ionic conductivity of halide SEs. The oxygen substitution to Li2ZrCl6 (trigonal, hcp) increased the ionic conductivity from 0.33 to 1.3 mS cm-1 at Li3.1ZrCl4.9O1.1 (monoclinic, ccp), while the sulfur and fluorine substitutions were not effective. A systematic comparison study revealed that the energetic stabilization of interstitial sites for Li migration plays a key role in improving the ionic conductivity, and the ccp-like anion sublattice is not sufficient to achieve high ionic conductivity. We further examined the feasibility of the oxyhalide SE for practical and all-solid-state battery applications.

Different oncological features of colorectal cancer codon-specific KRAS mutations: Not codon 13 but codon 12 have prognostic value.

BACKGROUND: Approximately 40% of colorectal cancer (CRC) cases are linked to Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. KRAS mutations are associated with poor CRC prognosis, especially KRAS codon 12 mutation, which is associated with metastasis and poorer survival. However, the clinicopathological characteristics and prognosis of KRAS codon 13 mutation in CRC remain unclear. AIM: To evaluate the clinicopathological characteristics and prognostic value of codon-specific KRAS mutations, especially in codon 13. METHODS: This retrospective, single-center, observational cohort study included patients who underwent surgery for stage I-III CRC between January 2009 and December 2019. Patients with KRAS mutation status confirmed by molecular pathology reports were included. The relationships between clinicopathological characteristics and individual codon-specific KRAS mutations were analyzed. Survival data were analyzed to identify codon-specific KRAS mutations as recurrence-related factors using the Cox proportional hazards regression model. RESULTS: Among the 2203 patients, the incidence of KRAS codons 12, 13, and 61 mutations was 27.7%, 9.1%, and 1.3%, respectively. Both KARS codons 12 and 13 mutations showed a tendency to be associated with clinical characteristics, but only codon 12 was associated with pathological features, such as stage of primary tumor (T stage), lymph node involvement (N stage), vascular invasion, perineural invasion, tumor size, and microsatellite instability. KRAS codon 13 mutation showed no associations (77.2% vs 85.3%, P = 0.159), whereas codon 12 was associated with a lower 5-year recurrence-free survival rate (78.9% vs 75.5%, P = 0.025). In multivariable analysis, along with T and N stages and vascular and perineural invasion, only codon 12 (hazard ratio: 1.399; 95% confidence interval: 1.034-1.894; P = 0.030) among KRAS mutations was an independent risk factor for recurrence. CONCLUSION: This study provides evidence that KRAS codon 13 mutation is less likely to serve as a prognostic biomarker than codon 12 mutation for CRC in a large-scale cohort.

Screening for Neuroprotective and Rapid Antidepressant-like Effects of 20 Essential Oils.

Depression is a serious psychiatric disorder with high prevalence, and the delayed onset of antidepressant effects remains a limitation in the treatment of depression. This study aimed to screen essential oils that have the potential for rapid-acting antidepressant development. PC12 and BV2 cells were used to identify essential oils with neuroprotective effects at doses of 0.1 and 1 µg/mL. The resulting candidates were treated intranasally (25 mg/kg) to ICR mice, followed by a tail suspension test (TST) and an elevated plus maze (EPM) after 30 min. In each effective essential oil, five main compounds were computationally analyzed, targeting glutamate receptor subunits. As a result, 19 essential oils significantly abolished corticosterone (CORT)-induced cell death and lactate dehydrogenase (LDH) leakage, and 13 reduced lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). From in vivo experiments, six essential oils decreased the immobility time of mice in the TST, in which Chrysanthemum morifolium Ramat. and Myristica fragrans Houtt. also increased time and entries into the open arms of the EPM. Four compounds including atractylon, α-curcumene, α-farnesene, and selina-4(14),7(11)-dien-8-one had an affinity toward GluN1, GluN2B, and Glu2A receptor subunits surpassed that of the reference compound ketamine. Overall, Atractylodes lancea (Thunb.) DC and Chrysanthemum morifolium Ramat essential oils are worthy of further research for fast-acting antidepressants through interactions with glutamate receptors, and their main compounds (atractylon, α-curcumene, α-farnesene, and selina-4(14),7(11)-dien-8-one) are predicted to underlie the fast-acting effect.

Effects of Essential Oils and Fragrant Compounds on Appetite: A Systematic Review.

Appetite dysregulation is one of the factors contributing to anorexia, bulimia nervosa, obesity, and diabetes. Essential oils or fragrant compounds have been proven to regulate food intake and energy expenditure; hence, this study aimed to summarize their effects on appetite and the underlying mechanisms. The PubMed and Web of Science databases were searched until July 2022. Only two of the 41 studies were performed clinically, and the remaining 39 used animal models. Oral administration was the most common route, and a dosage range of 100-2000 mg/kg for mice or 2-32 mg/kg for rats was applied, with a duration of 12 days to 4 weeks, followed by inhalation (10-6-10-3 mg/cage or 10-9-10-2 mg/cm3 within 1 h). Approximately 11 essential oil samples and 22 fragrant compounds were found to increase appetite, while 12 essential oils and seven compounds decreased appetite. These fragrant components can exert appetite-regulating effects via leptin resistance, the activity of sympathetic/parasympathetic nerves, or the mRNA expression of neuropeptide Y (NPY)/agouti-related protein (AgRP), cocaine- and amphetamine-regulated transcript (CART)/proopiomelanocortin (POMC) in the hypothalamus. Fragrance memory and cognitive processes may also play roles in appetite regulation. The findings of this study accentuate the potential of essential oils and fragrant compounds to regulate appetite and eating disorders.

Sericin mediated gold/silver bimetallic nanoparticles and exploration of its multi-therapeutic efficiency and photocatalytic degradation potential.

The current investigation aimed at bimetallic gold-silver nanoparticles (Au/Ag NPs), here called BM-GS NPs, synthesis using sericin protein as the reducing agent in an easy, cost-effective, and sustainable way. The obtained BM-GS NPs were characterized by UV-Visible spectroscopy, Transmission electron microscopy (TEM), energy dispersive X-ray analysis (EDS), atomic force microscopy (AFM), Dynamic light scattering (DLS) and Zeta potential, X-ray Powder Diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), and Thermogravimetric analysis followed by evaluation of its multitherapeutic and photocatalytic degradation potentials. The TEM analysis revealed its spherical nature and the EDS result displayed the presence of both Ag and Au elements, confirming the synthesis of BM-GS NPs. The XRD pattern verified the crystalline nature of the nanoparticles (NPs). The DLS analysis showed an average size of 86.08 d nm and the zeta potential showed a highly negative value (-26.3 mV) which specifies that the generated bimetallic NPs are stable. The BM-GS NPs exhibited positive wound healing potential (with 63.38% of wound closure rate at 25 µg/ml, as compared to 54.42% by the untreated control) with very negligible toxicity effect on the cell viability of the normal keratinocyte cells. It also demonstrated promising antioxidant properties with 65.00%, 69.23%, and 63.03% activity at 100 µg/ml concentration for ABTS (2, 2-azinobis) (3-ethylbenzothiazoline-6-sulfonic acid)), DPPH (1, 1 diphenyl-2-picrylhydrazyl) and SOD (superoxide dismutase enzyme) assays respectively, antidiabetic potential (with a significantly high α-glucosidase inhibition potential of 99.69% at 10µg/ml concentration and 62.11% of α-amylase enzyme inhibition at 100 µg/ml concentration) and moderate tyrosinase inhibitory potential (with 17.09% at 100 µg/ml concentration). Besides, it displayed reasonable antibacterial potential with the diameter of zone of inhibition ranging between 10.89 and 12.39 mm. Further, its antibacterial mode of action reveals that its effects could be due to being very smaller, the NPs could have penetrated inside the cellular membrane thereby causing rupture and damage to the interior materials leading to cellular lysis. The photocatalytic evaluation showed that synthesized BM-GS NPs have the efficiency of degrading methylene blue dye by 34.70% within 3 h of treatment. The above findings revealed the multi-therapeutic efficacy of the sericin globular protein-mediated BM-GS NPs and its potential future applications in the cosmetics and food sector and environmental contamination management industries.

Synthesis of Biogenic Gold Nanoparticles by Using Sericin Protein from Bombyx mori Silk Cocoon and Investigation of Its Wound Healing, Antioxidant, and Antibacterial Potentials.

Introduction: A number of biological wastes and factory waste materials have been tested recently for the eco-friendly biosynthesis of nanoparticles. Sericin protein (SSP) is usually removed from the silk cocoon during the degumming process in the process of making the silk, and this sericin protein is normally thrown away by the sericulture industries as waste materials. It is found that this sericin protein possesses a number of biological properties. Methods: Considering this, in the present study, an effort has been made to biosynthesize gold nanoparticles (SSP-AuNPs) using the waste sericin solution as the reducing and capping agent and investigate its biopotential in terms of its wound healing, antioxidant and antibacterial activities. Results: The synthesis of SSP-AuNPs was perceived by the visual color change and confirmed by UV-Vis spectroscopy with absorption maxima at 522 nm. Further characterization of SSP-AuNPs was done by TEM, EDS, XRD, FTIR, DLS, zeta potential, TGA, AFM, etc. The size of SSP-AuNPs was found out to be 54.82 nm as per the particle size analyzer and the zeta potential is -19.8 mV. The SSP-AuNPs displayed promising wound healing potential of 70.96 and 69.76% wound closure rate at 5 and 10 µg/mL respectively as compared to 74.91% by the Centella asiatica taken as a positive control. It also exhibited promising antioxidant potential in terms of the DPPH, ABTS free radical scavenging, reducing power potential, and total antioxidant capacity. Besides, the SSP-AuNPs also displayed significant antibacterial activities against the tested pathogenic bacterial with the diameter of inhibition zones ranging between 12.10 and 14.96 mm as compared to the positive control cephalexin that displayed inhibition zones ranging between 12.08 and 13.24 mm. Discussion: Taken together, SSP-AuNPs could serve as an interesting candidate for food, cosmetics, and biomedical fields in the applications of wound healing, cosmetics, antibacterial bandages, and ointments, etc.

Safety of early surgery after self-expandable metallic stenting for obstructive left-sided colorectal cancer.

BACKGROUND: Self-expanding metallic stenting (SEMS) is usual for the temporary resolution of obstructive left-sided colorectal cancer (CRC) as a bridge to elective surgery. However, there is no consensus regarding adequate time intervals from stenting to radical surgery. The aim of this study was to identify the optimal time interval that results in favorable short- and long-term outcomes. METHODS: Data on patients with obstructive left-sided CRC who underwent elective radical surgery after clinically successful SEMS deployment in five tertiary referral hospitals from 2004 to 2016 were analyzed, retrospectively. An inverse probability treatment-weighted propensity score analysis was used to minimize bias. Postoperative short- and long-term outcomes were compared between two groups: an early surgery (within 8 days) group and delayed surgery (after 8 days) group. RESULTS: Of 311 patients, 148 (47.6%) underwent early and 163 (52.4%) underwent delayed surgery. The median surgery interval was 9.0 days. After adjustment, the groups had similar patient and tumor characteristics. In terms of short-term outcomes, there was no difference in hospitalization length or postoperative complications. No deaths were observed. With a median follow-up of 71.0 months, no significant difference was observed between the groups in 5-year overall survival (early vs. delayed surgery: 79.6% vs. 71.3%, P = 0.370) and 5-year disease-free survival (early vs. delayed surgery: 59.1% vs. 60.4%, P = 0.970). CONCLUSIONS: In obstructive left-sided CRC, the time interval between SEMS and radical surgery did not significantly influence short- and long-term outcomes. Therefore, early surgery after SEMS could be suggested if there is no reason to postpone surgery for preoperative medical optimization.

Clinical impact of preoperative and postoperative sarcopenia on oncological outcomes in non-metastatic colorectal cancer.

AIM: This study investigated the association between preoperative and postoperative changes in skeletal muscle mass and long-term oncological outcomes in patients with non-metastatic colorectal cancer. METHOD: Patients who underwent surgery for Stages I-III colorectal cancer from January 2014 to December 2015 were included. Skeletal muscle mass was evaluated through preoperative and postoperative abdominopelvic CT scans. A multivariable analysis was conducted to determine the factors affecting disease-free survival rates. RESULTS: A total of 238 patients were analysed. Forty-nine (25.9%) patients had preoperative sarcopenia. Patients with preoperative sarcopenia showed lower 3-year disease-free survival (58.5% vs. 78.4%, P = 0.001). Patients with postoperative sarcopenia also showed significantly lower 3-year disease-free survival compared to postoperative patients without sarcopenia at 6, 12 and 18 months, respectively (53.9% vs. 77.8%; 69.7% vs. 81.8%; 69.1% vs. 87.7%, P = 0.004). In a subgroup analysis, patients with both preoperative and postoperative sarcopenia showed the lowest 3-year disease-free survival rates (50.9%). The incidence of tumour recurrence was higher among the patients who had lost more skeletal muscle mass at 12, 18 and 24 months (-14.3 cm2 /m2 vs. -1.5 cm2 /m2 , P < 0.001; -24.5 cm2 /m2 vs. -1.1 cm2 /m2 , P < 0.001; and -31.6 cm2 /m2 vs. -1.4 cm2 /m2 , P < 0.001, respectively). A multivariable analysis demonstrated that the factors associated with disease-free survival included tumour stage, venous invasion, adjuvant chemotherapy, and preoperative or postoperative sarcopenia. CONCLUSION: Not only preoperative but also postoperative sarcopenic changes adversely affect oncological outcomes following curative resection of colorectal cancer. Careful attention should be given to correcting sarcopenic status from the preoperative to the postoperative period.

Anti-Psoriatic Effect of Rheum palmatum L. and Its Underlying Molecular Mechanisms.

Psoriasis is a chronic, immune-mediated inflammatory skin disorder. Rheum palmatum L. is a common traditional medicinal herb with anti-inflammatory and immunomodulatory activities. This study aimed to investigate the anti-psoriatic effects of the ethanolic extract from R. palmatum L. (RPE) and its chemical constituents, as well as the mechanisms underlying their therapeutic significance. An imiquimod (IMQ)-induced psoriasis-like mouse model was used to examine the anti-psoriatic effect of RPE in vivo. Network pharmacological analysis was performed to investigate the potential targets and related pathways of the RPE components, including rhein, emodin, chrysophanol, aloe-emodin, and physcion. The anti-inflammatory effects and underlying mechanisms of these components were examined using in vitro models. Topical application of RPE alleviated psoriasis-like symptoms and reduced levels of inflammatory cytokines and proliferation markers in the skin. Network pharmacological analysis revealed that RPE components target 20 genes that are linked to psoriasis-related pathways, such as IL-17, MAPK, and TNF signaling pathways. Among the five components of RPE, rhein and emodin showed inhibitory effects on TNF-α and IL-17 production in EL-4 cells, attenuated the production of CXCL8, CXCL10, CCL20, and MMP9, and reduced proliferation in HaCaT cells. Chrysophanol, aloe-emodin, and physcion were less effective than rhein and emodin in suppressing inflammatory responses and keratinocyte proliferation. The effects of these compounds might occur through the inhibition of the ERK, STAT3, and NF-κB signaling pathways. This study suggested the anti-psoriatic effect of RPE, with rhein and emodin as the main contributors that regulate multiple signaling pathways.

Network Pharmacology and Experimental Validation to Investigate the Antidepressant Potential of Atractylodes lancea (Thunb.) DC.

Atractylodes lancea (Thunb.) DC. (AL) has been indicated in traditional prescriptions for the treatment of depression. However, the mechanism of action of AL in the treatment of depression is still unclear. This study aimed to investigate the antidepressant potential of AL using network pharmacology, molecular docking, and animal experiments. The active components of AL were retrieved from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP), and the depression-related targets were screened through the DisGeNET database. Overlapping targets of AL and depression were selected and analyzed. Ten active compounds of AL showed anti-depressant potential, including stigmasterol, 3ß-acetoxyatractylone, wogonin, ß-sitosterol, selina-4(14),7(11)-dien-8-one, atractylenolide I, atractylenolide II, atractylenolide III, patchoulene, and cyperene. These compounds target 28 potential antidepressant genes/proteins. Gene Ontology (GO) enrichment analysis revealed that the potential targets might directly influence neural cells and regulate neuroinflammation and neurotransmitter-related processes. The potential Kyoto Encyclopedia Genes and Genomes (KEGG) pathways for the antidepressant effects of AL include neuroactive ligand-receptor interactions, calcium signaling pathways, dopaminergic synapse, interleukin (IL)-17 signaling pathways, and the pathways of neurodegeneration. IL-6, nitric oxide synthase 3 (NOS), solute carrier family 6 member 4 (SLC6A4), estrogen receptor (ESR1), and tumor necrosis factor (TNF) were the most important proteins in the protein-protein interaction network and these proteins showed high binding affinities with the corresponding AL compounds. AL showed an antidepressant effect in mice by decreasing immobility time in the tail suspension test and increasing the total contact number in the social interaction test. This study demonstrated the antidepressant potential of AL, which provides evidence for pursuing further studies to develop a novel antidepressant.

Anxiolytic-like Effect of Inhaled Cinnamon Essential Oil and Its Main Component Cinnamaldehyde in Animal Models.

Aromatherapy is one of the most common safer alternative treatments for psychiatric disorders with fewer side effects than conventional drugs. Here, we investigated the effects of cinnamon essential oil (CIEO) inhalation on mouse behaviors by performing different behavioral tests. CIEO inhalation showed anxiolytic effects in the elevated plus maze test, as inferred from increased time spent in open arms and decreased time spent in closed arms. Moreover, the CIEO treatment enhanced social behavior by increasing the total contact number, time spent in the center, distance traveled in the center, and total distance in the social interaction test. However, CIEO inhalation did not have any effect on performance in the open field test, tail suspension test, forced swimming test, and Y maze tests. The microarray analysis indicated that the CIEO treatment downregulated 17 genes and upregulated 15 genes in the hippocampus. Among them, Dcc, Egr2, and Fos are the most crucial genes that are involved in anxiety-related biological processes and pathways, including the regulation of neuronal death and neuroinflammation. Gas chromatography/mass spectrometry analysis revealed that cinnamaldehyde is the main component of CIEO. Cinnamaldehyde recovered MK-801-induced anxiety-related changes in the electroencephalogram power spectrum in zebrafish. Taken together, our findings suggest that CIEO and its main component cinnamaldehyde have an anxiolytic effect through the regulation of the expression of genes related to neuroinflammatory response and neuronal death.

Clinical impact of inferior mesenteric vein preservation during left hemicolectomy with low ligation of the inferior mesenteric artery for distal transverse and descending colon cancers: A comparative study based on computed tomography.

Purpose: Presence of a long remnant sigmoid colon after left hemicolectomy with inferior mesenteric vein (IMV) ligation for distal transverse and descending colon cancers may be a risk factor for venous ischemia. This study aimed to evaluate the clinical impact of IMV preservation in patients who underwent left hemicolectomy with inferior mesenteric artery (IMA) preservation. Methods: We included 155 patients who underwent left hemicolectomy with IMA preservation for distal transverse and descending colon cancers from 2003 to 2020. Technical success of IMV preservation was determined by assessing pre- and post-operative patency of the IMV on computed tomography (CT) by an abdominal radiologist. Intestinal complications comprising ulceration, stricture, venous engorgement, and colitis in remnant colon were compared between the IMV preservation and ligation groups. Results: IMV was preserved in 22 (14.2%) and ligated in 133 (85.8%) patients. Surgical time, postoperative recovery outcomes, and number of harvested lymph nodes were similar in both groups. The technical success of IMV preservation was 81.8%. Intestinal complications were less common in the preservation group than in the IMV ligation group (4.5% vs. 23.3%, P=0.048). The complications in the IMV ligation group were anastomotic ulcer (n=2), anastomotic stricture (n=4), venous engorgement of the remnant distal colon (n=4), and colitis in the distal colon (n=21). Conclusions: IMV preservation may be beneficial after left hemicolectomy with IMA preservation for distal transverse and descending colon cancers. We suggest that IMV preservation might be considered when long remnant sigmoid colon is expected during left hemicolectomy with low ligation of IMA.

Efficacy of geriatric multidisciplinary oncology clinic in the surgical treatment decision-making process for frail elderly patients with colorectal cancer.

Purpose: Multidisciplinary care has become a cornerstone of colorectal cancer management. To evaluate the clinical efficacy of a geriatric multidisciplinary oncology clinic (GMOC), we analyzed the surgical treatment decision-making process and outcomes. Methods: This retrospective single-center study reviewed the data of patients aged ≥65 years who participated in the GMOC at a tertiary referral hospital between 2015 and 2021. The clinical adherence rate, comprehensive geriatric assessment, and a multidimensional frailty score (MFS) were obtained. The groups that were recommended and not recommended for surgery were compared, analyzing the factors impacting the decision and 1-year survival outcomes. Furthermore, the postoperative complications of patients who underwent surgery were evaluated. Results: A total of 165 patients visited the GMOC, and 74 had colorectal cancer (mean age, 85.5 years [range, 81.2-89.0 years]). Among patients with systemic disease (n = 31), 7 were recommended for surgery, and 5 underwent surgery. Among patients with locoregional disease (n = 43), 18 were recommended for surgery, and 12 underwent surgery. Patients recommended and not recommended for surgery had significantly different activities of daily living (ADL) (P = 0.024), instrumental ADL (P = 0.001), Mini-Mental State Examination (P = 0.014), delirium risk (P = 0.039), and MFS (P = 0.001). There was no difference in the 1-year overall survival between the 2 groups (P = 0.980). Of the 17 patients who underwent surgery, the median (interquartile range) of operation time was 165.0 minutes (120.0-270.0 minutes); hospital stay, 7.0 days (6.0-8.0 days); and 3 patients had wound complications. Conclusion: Proper counseling of patients through the GMOC could lead to appropriate management and favorable outcomes.