A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease.

Stem cells are ubiquitously found in various tissues and organs in the body, and underpin the body's ability to repair itself following injury or disease initiation, though repair can sometimes be compromised. Understanding how stem cells are produced, and functional signaling systems between different niches is critical to understanding the potential use of stem cells in regenerative medicine. In this context, this review considers kynurenine pathway (KP) metabolism in multipotent adult progenitor cells, embryonic, haematopoietic, neural, cancer, cardiac and induced pluripotent stem cells, endothelial progenitor cells, and mesenchymal stromal cells. The KP is the major enzymatic pathway for sequentially catabolising the essential amino acid tryptophan (TRP), resulting in key metabolites including kynurenine, kynurenic acid, and quinolinic acid (QUIN). QUIN metabolism transitions into the adjoining de novo pathway for nicotinamide adenine dinucleotide (NAD) production, a critical cofactor in many fundamental cellular biochemical pathways. How stem cells uptake and utilise TRP varies between different species and stem cell types, because of their expression of transporters and responses to inflammatory cytokines. Several KP metabolites are physiologically active, with either beneficial or detrimental outcomes, and evidence of this is presented relating to several stem cell types, which is important as they may exert a significant impact on surrounding differentiated cells, particularly if they metabolise or secrete metabolites differently. Interferon-gamma (IFN-γ) in mesenchymal stromal cells, for instance, highly upregulates rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO-1), initiating TRP depletion and production of metabolites including kynurenine/kynurenic acid, known agonists of the Aryl hydrocarbon receptor (AhR) transcription factor. AhR transcriptionally regulates an immunosuppressive phenotype, making them attractive for regenerative therapy. We also draw attention to important gaps in knowledge for future studies, which will underpin future application for stem cell-based cellular therapies or optimising drugs which can modulate the KP in innate stem cell populations, for disease treatment.

Sex- and suicide-specific alterations in the kynurenine pathway in the anterior cingulate cortex in major depression.

Major depressive disorder (MDD) is a serious psychiatric disorder that in extreme cases can lead to suicide. Evidence suggests that alterations in the kynurenine pathway (KP) contribute to the pathology of MDD. Activation of the KP leads to the formation of neuroactive metabolites, including kynurenic acid (KYNA) and quinolinic acid (QUIN). To test for changes in the KP, postmortem anterior cingulate cortex (ACC) was obtained from the National Institute of Health NeuroBioBank. Gene expression of KP enzymes and relevant neuroinflammatory markers were investigated via RT-qPCR (Fluidigm) and KP metabolites were measured using liquid chromatography-mass spectrometry in tissue from individuals with MDD (n = 44) and matched nonpsychiatric controls (n = 36). We report increased IL6 and IL1B mRNA in MDD. Subgroup analysis found that female MDD subjects had significantly decreased KYNA and a trend decrease in the KYNA/QUIN ratio compared to female controls. In addition, MDD subjects that died by suicide had significantly decreased KYNA in comparison to controls and MDD subjects that did not die by suicide, while subjects that did not die by suicide had increased KYAT2 mRNA, which we hypothesise may protect against a decrease in KYNA. Overall, we found sex- and suicide-specific alterations in the KP in the ACC in MDD. This is the first molecular evidence in the brain of subgroup specific changes in the KP in MDD, which not only suggests that treatments aimed at upregulation of the KYNA arm in the brain may be favourable for female MDD sufferers but also might assist managing suicidal behaviour.

Normative Data on Serum and Plasma Tryptophan and Kynurenine Concentrations from 8089 Individuals Across 120 Studies: A Systematic Review and Meta-Analysis.

In this systematic review and meta-analysis, a normative dataset is generated from the published literature on the kynurenine pathway in control participants extracted from case-control and methodological validation studies. Study characteristics were mapped, and studies were evaluated in terms of analytical rigour and methodological validation. Meta-analyses of variance between types of instruments, sample matrices and metabolites were conducted. Regression analyses were applied to determine the relationship between metabolite, sample matrix, biological sex, participant age and study age. The grand mean concentrations of tryptophan in the serum and plasma were 60.52 ± 15.38 µM and 51.45 ± 10.47 µM, respectively. The grand mean concentrations of kynurenine in the serum and plasma were 1.96 ± 0.51 µM and 1.82 ± 0.54 µM, respectively. Regional differences in metabolite concentrations were observed across America, Asia, Australia, Europe and the Middle East. Of the total variance within the data, mode of detection (MOD) accounted for up to 2.96%, sample matrix up to 3.23%, and their interaction explained up to 1.53%; the latter of which was determined to be negligible. This review was intended to inform future empirical research and method development studies and successfully synthesised pilot data. The pilot data reported in this study will inform future precision medicine initiatives aimed at targeting the kynurenine pathway by improving the availability and quality of normative data.

A randomized, double-blind, placebo-controlled, parallel-group 12-week pilot phase II trial of SaiLuoTong (SLT) for cognitive function in older adults with mild cognitive impairment.

INTRODUCTION: This study primarily aimed to evaluate the efficacy and safety of SaiLuoTong (SLT) on cognition in mild cognitive impairment (MCI). METHODS: Community-dwelling people with MCI aged ≥60 years were randomly assigned to 180 mg/day SLT or placebo for 12 weeks. RESULTS: Thirty-nine participants were randomized to each group (N = 78); 65 were included in the final analysis. After 12 weeks, the between-groups difference in Logical Memory delayed recall scores was 1.40 (95% confidence interval [CI]: 0.22 to 2.58; P = 0.010); Delis-Kaplan Executive Function System Trail Making Test Condition 4 switching and contrast scaled scores were 1.42 (95% CI: -0.15 to 2.99; P = 0.038) and 1.56 (95% CI: -0.09 to 3.20; P = 0.032), respectively; Rey Auditory Verbal Learning Test delayed recall was 1.37 (95% CI: -0.10 to 2.84; P = 0.034); and Functional Activities Questionnaire was 1.21 (95% CI: -0.21 to 2.63; P = 0.047; P < 0.001 after controlling for baseline scores). DISCUSSION: SLT is well tolerated and may be useful in supporting aspects of memory retrieval and executive function in people with MCI. Highlights: SaiLuoTong (SLT) improves delayed memory retrieval and executive function in people with mild cognitive impairment (MCI).SLT is well tolerated in people ≥ 60 years.The sample of community dwellers with MCI was well characterized and homogeneous.

[Pathological study on the relationship between nucleic acid oxidative stress and heart failure with preserved ejection fraction in patients aged over 85 years].

Objective: To investigate the level of nucleic acid oxidation in myocardial tissue of patients aged over 85 with heart failure with preserved ejection fraction (HFpEF) and the correlation with myocardial amyloid deposition. Methods: This was a retrospective case-control study. Data of patients≥85 years old who underwent systematic pathological autopsy in Beijing Hospital from 2003 to 2017 were retrospectively collected. Twenty-six patients were included in the HFpEF group and 13 age-and sex-matched patients who had not been diagnosed with heart failure and died of non-cardiovascular diseases served as the control group. The left ventricular myocardium slices of both groups were semi-quantitatively analyzed using immunohistochemical staining of 8-oxidized guanine riboside (8-oxo-G) and 8-oxidized guanine deoxyriboside (8-oxo-dG) to evaluate the oxidation of RNA and DNA in cardiomyocytes. Using the median of the mean absorbance value of 8-oxo-G immunohistochemical staining as the cut-off value, patients were divided into high-absorbance group and low-absorbance group. Congo red staining was used to compare myocardial amyloid deposition between the two groups. Results: The mean age of patients in HFpEF group was (91.8±3.7) years, 24 (92.3%) were males. The mean age of patients in control group was (91.7±3.7) years old, 11 (84.6%) were males. The median mean optical absorbance value of 8-oxo-G immunohistochemical staining of myocardium was significantly higher in HFpEF patients than in control group (0.313 8 (0.302 2, 0.340 6) vs. 0.289 2 (0.276 7, 0.299 4), Z=-3.245, P=0.001). The median mean absorbance value of 8-oxo-dG immunohistochemical staining of myocardial tissue was similar between the two groups (0.300 0 (0.290 0, 0.322 5) vs. 0.300 0 (0.290 0, 0.320 0), Z=-0.454, P=0.661). Proportion of patients with moderate and severe cardiac amyloid deposition was significantly higher in the high-absorbance group than in the low-absorbance group ((85.0%, 17/20) vs. (31.6%, 6/19), P=0.001). Conclusion: The RNA oxidation degree of myocardium in HFpEF patients is higher than that in elderly people without heart failure. Degree of myocardial amyloid deposits is higher in patients with high levels of RNA oxidation.

Disease-modifying therapies do not affect sleep quality or daytime sleepiness in a large Australian MS cohort.

BACKGROUND: Poor sleep is common in multiple sclerosis (MS) and may impact daily functioning. The extent to which disease-modifying therapies (DMTs) contribute to sleep outcomes is under-examined. OBJECTIVE: To compare the effects of DMTs on sleep outcomes in an Australian cohort of people with MS and investigate associations between DMT use and beliefs about sleep problems and daily functioning (social functioning and activity engagement). METHODS: Sleep outcomes were assessed using the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. DMT use and functioning were self-reported. RESULTS: Of 1,715 participants, 64% used a DMT. No differences in sleep outcomes were detected between participants who did and did not use DMTs, the type of DMT used (lower vs higher efficacy, interferon-ß vs other DMTs), the timing of administration, or adherence to standard administration recommendations. Beliefs that DMT use worsened sleep were associated with poorer sleep quality and perceptions that sleep problems interfered with daily functioning. CONCLUSION: The use of a DMT does not appear to affect self-reported sleep outcomes in people with MS. However, beliefs that DMT use makes sleep worse were associated with poorer sleep quality and increased interference in daily functioning, suggesting a need for education to diminish negative perceptions of DMT use.

Association between Preexisting Sarcopenia and Stroke in Patients with Type 2 Diabetes Mellitus.

OBJECTIVES: This propensity score-matched population-based cohort study compared stroke risk between patients with type 2 diabetes mellitus with and without preexisting sarcopenia. RESEARCH DESIGN AND METHODS: We used data from Taiwan's National Health Insurance Research Database for the period from January 2008 to December 2019. We recruited patients with type 2 diabetes mellitus and categorized them into two groups at a ratio of 1:1 on the basis of diagnosed sarcopenia. The matching variables were age, sex, income level, urbanization level, diabetes severity (adapted Diabetes Complications Severity Index [aDCSI Scores]), Charlson Comorbidity Index (CCI), other comorbidities associated with stroke, smoking status, medication use, and types of antidiabetic medications. The matching process yielded a final cohort of 104,120 patients (52,060 and 52,060 in the sarcopenia and nonsarcopenia groups, respectively) who were eligible for inclusion in subsequent analyses. RESULTS: In the multivariate Cox regression analysis, the adjusted hazard ratio (aHR; 95% CI) of stroke for the sarcopenia diabetes group compared with the control group was 1.13 (1.10, 1.16; P < 0.001), after controlling for age, sex, CCI, and aDCSI scores. The incidence rates of stroke for the sarcopenia and nonsarcopenia groups were 295.98 and 260.68 per 10,000 person-years, respectively. The significant IRR (95% CI) of stroke was 1.14 (1.09, 1.17) for the sarcopenia diabetes group compared with the nonsarcopenic diabetes group. CONCLUSION: Preexisting sarcopenia increased the risk of stroke in patients with type 2 diabetes mellitus.

Kynurenic acid as a biochemical factor underlying the association between Western-style diet and depression: A cross-sectional study.

Consumption of a Western-style diet (WS-diet), high in saturated fat and added sugar, is associated with increased depression risk. However, the physiological mechanisms underlying the relationship requires elucidation. Diet can alter tryptophan metabolism along the kynurenine pathway (KP), potentially linking inflammation and depression. This study aimed to examine whether urinary inflammatory markers and KP metabolites differed according to WS-diet consumption and depression severity. Depression symptoms and habitual WS-diet consumption were assessed in 169 healthy adults aged 17-35 recruited from two experimental studies. Targeted metabolomics profiling of seven KP metabolites, ELISA-based assays of interleukin-6 (IL-6) and C-reactive protein (CRP) were performed using urine samples collected from the participants. Parametric tests were performed for group comparison and associations analysis. Multilevel mixed-effect modelling was applied to control for biases. Higher intake of WS-diet was associated with lower levels of neuroprotective kynurenic acid (KA; R = -0.17, p = 0.0236). There were no differences in IL-6 or CRP across diet groups (p > 0.05). Physical activity had negative associations with most KP metabolites. Mixed-effects regression analysis showed the glutamatergic inhibitor, KA, was the only biomarker to have a significant association with depression symptoms in a model adjusted for demographic and lifestyle variables: a unit increase in KA was associated with 0.21 unit decrease in Depression Anxiety and Stress Scale-21 depression score (p = 0.009). These findings suggest that urinary KA is associated with both habitual WS-diet intake, and levels of depression symptoms, independent of inflammation. Findings support the role of neuroprotection and glutamatergic modulation in depression. We propose that KA may act as endogenous glutamatergic inhibition in regulating depression severity in the absence of inflammation. Further comparison with blood-based markers will assist in validating the utility of non-invasive urine samples for measuring KP metabolites.

[Recommendations for management of antiphospholipid syndrome in China].

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder with vascular, obstetric, and hematological manifestations associated with thrombotic and inflammatory mechanisms orchestrated by antiphospholipid (aPLs) antibodies. Current clinical practice in APS is highly variable duo to lack of high quality of evidence. Here, Chinese Rheumatology Association developed recommendations for management of APS in China. The recommendations cover the early diagnosis, disease evaluation, thrombotic risk assessment, and treatment.

Kynurenine-3-monooxygenase expression is activated in the pancreatic endocrine cells by diabetes and its blockade improves glucose-stimulated insulin secretion.

Type 2 diabetes is associated with an inflammatory phenotype in the pancreatic islets. We previously demonstrated that proinflammatory cytokines potently activate the tryptophan/kynurenine pathway (TKP) in INS-1 cells and in normal rat islets. Here we examined: (1) the TKP enzymes expression in the diabetic GK islets; (2) the TKP enzymes expression profiles in the GK islets before and after the onset of diabetes; (3) The glucose-stimulated insulin secretion (GSIS) in vitro in GK islets after KMO knockdown using specific morpholino-oligonucleotides against KMO or KMO blockade using the specific inhibitor Ro618048; (4) The glucose tolerance and GSIS after acute in vivo exposure to Ro618048 in GK rats. We report a remarkable induction of the kmo gene in GK islets and in human islets exposed to proinflammatory conditions. It occurred prominently in beta cells. The increased expression and activity of KMO reflected an acquired adaptation. Both KMO knockdown and specific inhibitor Ro618048 enhanced GSIS in vitro in GK islets. Moreover, acute administration of Ro618048 in vivo improved glucose tolerance, GSIS and basal blood glucose levels in GK rats. These results demonstrate that targeting islet TKP is able to correct defective GSIS. KMO inhibition could represent a potential therapeutic strategy for type 2 diabetes.

The Cytokines CXCL10 and CCL2 and the Kynurenine Metabolite Anthranilic Acid Accurately Predict Patients at Risk of Developing Dengue With Warning Signs.

BACKGROUND: The resolution or aggravation of dengue infection depends on the patient's immune response during the critical phase. Cytokines released by immune cells increase with the worsening severity of dengue infections. Cytokines activate the kynurenine pathway (KP) and the extent of KP activation then influences disease severity. METHODS: KP metabolites and cytokines in plasma samples of patients with dengue infection (dengue without warning signs [DWS-], dengue with warning signs [DWS+], or severe dengue) were analyzed. Cytokines (interferon gamma [IFN-É£], tumor necrosis factor, interleukin 6, CXCL10/interferon-inducile protein 10 [IP-10], interleukin 18 [IL-18], CCL2/monocyte chemoattractant protein-1 [MCP-1], and CCL4/macrophage inflammatory protein-1beta [MIP-1ß] were assessed by a Human Luminex Screening Assay, while KP metabolites (tryptophan, kynurenine, anthranilic acid [AA], picolinic acid, and quinolinic acid) were assessed by ultra-high-performance liquid chromatography and Gas Chromatography Mass Spectrophotometry [GCMS] assays. RESULTS: Patients with DWS+ had increased activation of the KP where kynurenine-tryptophan ratio, anthranilic acid, and picolinic acid were elevated. These patients also had higher levels of the cytokines IFN-É£, CXCL10, CCL4, and IL-18 than those with DWS-. Further receiver operating characteristic analysis identified 3 prognostic biomarker candidates, CXCL10, CCL2, and AA, which predicted patients with higher risks of developing DWS+ with an accuracy of 97%. CONCLUSIONS: The data suggest a unique biochemical signature in patients with DWS+. CXCL10 and CCL2 together with AA are potential prognostic biomarkers that discern patients with higher risk of developing DWS+ at earlier stages of infection.

Systemic perturbations of the kynurenine pathway precede progression to dementia independently of amyloid-ß.

Increasing evidence suggests that kynurenine pathway (KP) dyshomeostasis may promote disease progression in dementia. Studies in Alzheimer's disease (AD) patients confirm KP dyshomeostasis in plasma and cerebrospinal fluid (CSF) which correlates with amyloid-ß and tau pathology. Herein, we performed the first comprehensive study assessing baseline levels of KP metabolites in participants enrolling in the Australian Imaging Biomarkers Flagship Study of Aging. Our purpose was to test the hypothesis that changes in KP metabolites may be biomarkers of dementia processes that are largely silent. We used a cross-sectional analytical approach to assess non-progressors (N = 73); cognitively normal (CN) or mild cognitive impairment (MCI) participants at baseline and throughout the study, and progressors (N = 166); CN or MCI at baseline but progressing to either MCI or AD during the study. Significant KP changes in progressors included increased 3-hydroxyanthranilic acid (3-HAA) and 3-hydroxyanthranilic acid/anthranilic acid (3-HAA/AA) ratio, the latter having the largest effect on the odds of an individual being a progressor (OR 35.3; 95% CI between 14 and 104). 3-HAA levels were hence surprisingly bi-phasic, high in progressors but low in non-progressors or participants who had already transitioned to MCI or dementia. This is a new, unexpected and interesting result, as most studies of the KP in neurodegenerative disease show reduced 3-HAA/AA ratio after diagnosis. The neuroprotective metabolite picolinic acid was also significantly decreased while the neurotoxic metabolite 3-hydroxykynurenine increased in progressors. These results were significant even after adjustment for confounders. Considering the magnitude of the OR to predict change in cognition, it is important that these findings are replicated in other populations. Independent validation of our findings may confirm the utility of 3-HAA/AA ratio to predict change in cognition leading to dementia in clinical settings.

Observation of ionic conductivity on PUA-TBAI-I2 gel polymer electrolyte.

Jatropha oil-based polyurethane acylate gel polymer electrolyte was mixed with different concentrations of tetrabutylammonium iodide salt (TBAI). The temperature dependences of ionic conductivity, dielectric modulus and relaxation time were studied in the range of 298 to 393 K. The highest ionic conductivity of (1.88 ± 0.020) × 10-4 Scm-1 at 298 K was achieved when the gel contained 30 wt% of TBAI and 2.06 wt% of I2. Furthermore, the study found that conductivity-temperature dependence followed the Vogel-Tammann Fulcher equation. From that, it could be clearly observed that 30 wt% TBAI indicated the lowest activation energy of 6.947 kJ mol-1. By using the fitting method on the Nyquist plot, the number density, mobility and diffusion coefficient of the charge carrier were determined. The charge properties were analysed using the dielectric permittivity, modulus and dissipation factor. Apart from this, the stoke drag and capacitance were determined.

Exploring the roles of tryptophan metabolism in MS beyond neuroinflammation and neurodegeneration: A paradigm shift to neuropsychiatric symptoms.

The metabolism of tryptophan through the kynurenine pathway (KP) has been increasingly recognised in contributing to disease progression in the autoimmune and inflammatory disease multiple sclerosis (MS). In this review, the roles of inflammation and the KP are recontextualised to better understand the aetiology of the neuropsychiatric symptoms (depression, postpartum depression, suicidality, fatigue and cognitive dysfunction) in MS. These symptoms will be discussed in the context of cytokine-induced sickness behaviours, KP activation and levels of neurotoxicity and neuroprotection in MS. In particular, there will be emphasis on how neuropsychiatric symptoms in MS occur against the shared background of inflammation and KP dysregulation. The discourse of this review aims to promote future research in elucidating KP mechanisms in MS that would inevitably lead to more targeted treatment options for neuropsychiatric symptoms and disease progression.

Innate immunity impacts social-cognitive functioning in people with multiple sclerosis and healthy individuals: Implications for IL-1ra and urinary immune markers.

Social-cognitive difficulties can negatively impact interpersonal communication, shared social experience, and meaningful relationships. This pilot investigation examined the relationship between social-cognitive functioning and inflammatory markers in people with multiple sclerosis (MS) and demographically-matched healthy individuals. Additionally, we compared the immune marker profile in serum and urine-matched samples. Social cognitive functioning was objectively assessed using The Awareness of Social Inference Test - Short (TASIT-S) and subjectively assessed using self-reports of abilities in emotion recognition, emotional empathy, and cognitive theory of mind. In people with MS and healthy individuals, there were moderate-to-large negative relationships between pro-inflammatory biomarkers (serum IL-1ß, IL-17, TNF-α, IP-10, MIP-1α, and urine IP-10, MIP-1ß) of the innate immune system and social-cognitive functioning. In MS, a higher serum concentration of the anti-inflammatory marker IL-1ra was associated with better social-cognitive functioning (i.e., self-reported emotional empathy and TASIT-S sarcasm detection performance). However, there were mixed findings for anti-inflammatory serum markers IL-4 and IL-10. Overall, our findings indicate a relationship between pro-inflammatory cytokines and social-cognitive abilities. Future studies may provide greater insight into biologically-derived inflammatory processes, sickness behaviour, and their connection with social cognition.

Renal denervation does not affect hypertension or the renin-angiotensin system in a rodent model of juvenile-onset polycystic kidney disease: clinical implications.

We examined the effect of total and afferent renal denervation (RDN) on hypertension and the renin-angiotensin system (RAS) in a rodent model of juvenile-onset polycystic kidney disease (PKD). Lewis Polycystic Kidney (LPK) and control rats received total, afferent or sham RDN by periaxonal application of phenol, capsaicin or normal saline, respectively, and were monitored for 4-weeks. Afferent RDN did not affect systolic blood pressure (SBP) determined by radiotelemetry in either strain (n = 19) while total RDN significantly reduced SBP in Lewis rats 4-weeks post-denervation (total vs. sham, 122 ± 1 vs. 130 ± 2 mmHg, P = 0.002, n = 25). Plasma and kidney renin content determined by radioimmunoassay were significantly lower in LPK vs. Lewis (plasma: 278.2 ± 6.7 vs. 376.5 ± 11.9 ng Ang I/ml/h; kidney: 260.1 ± 6.3 vs. 753.2 ± 37.9 ng Ang I/mg/h, P < 0.001, n = 26). These parameters were not affected by RDN. Intrarenal mRNA expression levels of renin, angiotensinogen, angiotensin-converting enzyme (ACE)2, and angiotensin II receptor type 1a were significantly lower, whereas ACE1 expression was significantly higher in the LPK vs. Lewis (all P < 0.05, n = 26). This pattern of intrarenal RAS expression was not changed by RDN. In conclusion, RDN does not affect hypertension or the RAS in the LPK model and indicates RDN might not be a suitable antihypertensive strategy for individuals with juvenile-onset PKD.

The Effects of Cannabinoids on Pro- and Anti-Inflammatory Cytokines: A Systematic Review of In Vivo Studies.

Introduction: Some cannabinoids have been identified as anti-inflammatory agents; however, their potential therapeutic or prophylactic applications remain controversial. The aim of this systematic review was to provide a timely and comprehensive insight into cannabinoid-mediated pro- and anti-inflammatory cytokine responses in preclinical in vivo studies. Methods and Materials: A systematic search was conducted using PubMed, Web of Science, EMBASE, and Scopus. Eligible studies where cannabinoids had been evaluated for their effect on inflammation in animal models were included in the analysis. Data were extracted from 26 of 4247 eligible full text articles, and risk of bias was assessed using the SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) tool. Studies examined cannabidiol (CBD; n=20); cannabigerol (CBG; n=1); delta 9-tetrahydrocannabinol (THC; n=2); THC and CBD separately (n=1); and THC and CBD in combination (n=2). Results: Tumor necrosis factor alpha, interleukin (IL)-1ß, IL-6, and interferon gamma were the most commonly studied pro-inflammatory cytokines and their levels were consistently reduced after treatment with CBD, CBG, or CBD+THC, but not with THC alone. The association between cannabinoid-induced anti-inflammatory response and disease severity was examined. In 22 studies where CBD, CBG, or CBD in combination with THC were administered, a reduction in the levels of at least one inflammatory cytokine was observed, and in 24 studies, some improvements in disease or disability were apparent. THC alone did not reduce pro-inflammatory cytokine levels (n=3), but resulted in improvements in neuropathic pain in one study. Conclusions: This review shows that CBD, CBG, and CBD+THC combination exert a predominantly anti-inflammatory effect in vivo, whereas THC alone does not reduce pro-inflammatory or increase anti-inflammatory cytokines. It is anticipated that this information could be used to inform human clinical trials of cannabinoids, focusing on CBD and CBG to reduce inflammation across a range of pathophysiological processes.

[A comparative study of transperitoneal transmesenteric approach versus paracolic sulci approach laparoscopic adrenal tumorectomy for treatment of primary hyperaldosteronism on left side].

Objective: To compare the therapeutic effect of transperitoneal transmesenteric approach versus paracolic sulci approach laparoscopic adrenal tumorectomy for treatment of left-sided primary hyperaldosteronism. Methods: From January 2017 to July 2019, the clinical data of 70 patients with left-sided primary hyperaldosteronism (PHA) who underwent surgery in the First Hospital of Lanzhou University and five other hospitals in Gansu Province were retrospectively analyzed. There are 43 male and 27 female patients. Among them,28 patients were performed transperitoneal transmesenteric approach laparoscopic adrenal tumorectomy and 42 patients were performed transperitoneal paracolic sulci approach laparoscopic adrenal tumorectomy. The general information and perioperative data of the two groups were compared. Results: All 70 cases of surgery were successfully completed. As compared with the paracolic sulci approach group, the operation time was significantly shorter in the transmesenteric approach group[(26.7±8.8)vs (38.9±7.1)min,P<0.001)], and the estimated blood loss was less in the transmesenteric approach group[45(30,50) vs 50(40,60)ml,P=0.042]. There was no statistically significant difference in the postoperative hospitalization days between the two groups[(4.4±1.0)vs(4.5±1.0)d, P=0.669)]. The electrolytes and aldosterone to renin ratio returned to a healthy level in the postoperative one month, and the blood pressure also returned to a healthy level in 53 (75.7%) patients. Conclusion: Transperitoneal transmesenteric approach laparoscopic adrenal tumorectomy is safe and feasible, with a short operation time and relatively less estimated blood loss.