Floral volatile benzenoids/phenylpropanoids: biosynthetic pathway, regulation and ecological value.

Benzenoids/phenylpropanoids, the second most diverse group of plant volatiles, exhibit significant structural diversity and play crucial roles in attracting pollinators and protecting against pathogens, insects, and herbivores. This review summarizes their complex biosynthetic pathways and regulatory mechanisms, highlighting their links to plant growth, development, hormone levels, circadian rhythms, and flower coloration. External factors like light, humidity, and temperature also influence their biosynthesis. Their ecological value is discussed, offering insights for enhancing floral scent, pollinator attraction, pest resistance, and metabolic engineering through genetic modification.

Photoelectron-transfer-effect grafting: Validation of a generalized strategy for fluorescence and photoelectrochemical dual-mode detection of hydrogen sulfide.

BACKGROUND: The progress of modern research is constantly fueled by the convergence of multiple technologies. Despite the enormous potential of both fluorescence (FL) and photoelectrochemical (PEC) technologies, the development of synergistic PEC-FL sensing platforms that combine the advantages of both is still in its early stages due to their relatively recent inception. Hydrogen sulfide (H2S), possessing dual irritant and asphyxiating traits, poses challenges for environmental preservation and human health. The development of the PEC-FL detection methodology for H2S in complex environmental settings is imperative. RESULTS: Combining FL and PEC sensing techniques, this work presented a new concept of photoinduced electron-transfer (PET) effect grafting for dual-mode fluorescence and PEC analysis. Briefly, a well-designed fluorescent molecule (BTFM-DNP) featuring the PET effect was synthesized and implemented to modulate the photoelectric response of the indium tin oxide (ITO)/BiOI photocathode electrode. After reacting with H2S, the thiolysis of dinitrophenyl ether eliminated the intramolecular PET effect and recovered the significant fluorescence of the probe. Remarkably, the newly formed 2,4-dinitrobenzenethiol (DBT) with strong electron-withdrawing groups was then grafted to the ITO/BiOI photoelectrode and achieved the successful transfer of the PET process, resulting in a sharp decrease in photocurrent. The as-developed dual-mode protocol exhibited good performance in terms of ultra-sensitivity, high selectivity, fast response, and a wide detection range from 1 pM to 80 µM. SIGNIFICANCE: The newly developed PEC-FL sensing platform can be applied to detect H2S levels in both the environment and food. This study demonstrates a promising synergy between fluorescent probes and PEC sensors, offering a novel perspective on the advancement of multi-mode analysis techniques. This approach has the potential to significantly enhance detection accuracy and reliability.

Viral load dynamics in asymptomatic and symptomatic patients during Omicron BA.2 outbreak in Shanghai, China, 2022: a longitudinal cohort study.

The SARS-CoV-2 virus, particularly the Omicron BA.2 variant, led to a significant surge in Shanghai, 2022. However, the viral load dynamic in Omicron infections with varying clinical severities remain unclear. This prospective cohort included 48,830 hospitalized coronavirus disease 2019 (COVID-19) patients across three hospitals in Shanghai, China, between 23 March and 15 May 2022. Systematic nucleic acid testing was performed using RT-PCR Cycle threshold (Ct) value as a proxy of viral load. We analyzed the kinetic characteristics of viral shedding by clinical severity and identified associated risk factors. The study comprised 31.06% asymptomatic cases, 67.66% mild-moderate cases, 1.00% severe cases, 0.29% critical and fatal cases. Upon admission, 57% of patients tested positive, with peak viral load observed at 4 days (median Ct value 27.5), followed by a decrease and an average viral shedding time (VST) of 6.1 days (Interquartile range, 4.0-8.8 days). Although viral load exhibited variation by age and clinical severity, peak Ct values occurred at similar times. Unvaccinated status, age exceeding 60, and comorbidities including hypertension, renal issues kidney dialysis and kidney transplantation, neurological disorders, rheumatism, and psychotic conditions were found to correlate with elevated peak viral load and extended VST. Asymptomatic cases demonstrated a 40% likelihood of contagiousness within 6 days of detection, while mild-moderate and severe cases exhibited post-symptom resolution infectious probabilities of 27% and over 50%, respectively. These findings revealed that the initial Ct values serve as a predictive indicator of severe outcomes. Unvaccinated elderly individuals with particular comorbidities are at high-risk for elevated viral load and prolonged VST.

The transcription factor MYC2 positively regulates terpene trilactone biosynthesis through activating GbGGPPS expression in Ginkgo biloba.

Terpene trilactones (TTLs) have important medicinal value, but their low content in Ginkgo biloba leaves makes their exploitation extremely costly, thereby limiting the development of TTL-related industries. It was found that exogenous methyl jasmonate (MeJA) treatment increased the accumulation of TTLs, but the molecular mechanism is still unclear. Here, we identified two bHLH transcription factors in G. biloba, with the protein subcellular localizations in the nucleus. Expression of GbMYC2s was strongly induced by MeJA treatment, and the interactions between GbJAZs and GbMYC2s were demonstrated by yeast two-hybrid and bimolecular fluorescence complementation experiments. Overexpression of GbMYC2_4 and GbMYC2_5 enhanced Arabidopsis root sensitivity and significantly increased TTL content. In addition, GbGGPPS was found to be a common target of GbMYC2_4 and GbMYC2_5 by yeast one-hybrid, electrophoretic mobility shift, and dual-luciferase reporter assays and DAP-seq, and they achieved regulation of GbGGPPS by binding to the G-box. Further findings revealed that GbMYC2_4 and GbMYC2_5 bind the G-box not universally but selectively. Our study revealed that jasmonic acid signaling mediates TTL biosynthesis through the GbJAZ-GbMYC2-GbGGPPS module, which enriches the terpenoid biosynthesis regulatory networks and provides a research basis and target genes for enhancing TTL content through genetic engineering.

Research status and hotspots in the field of endoplasmic reticulum stress and liver disease: A bibliometric study.

Recently, the study of endoplasmic reticulum stress (ERS) and liver disease has attracted much attention, but bibliometric analysis on this field is scarce. Therefore, to address this gap, we conducted a bibliometric analysis to explore the research status, hotspots, and trends in this field. We searched the Web of Science Core Collection database for publications on ERS and liver disease from 2007 to 2022. Bibliometric online analysis platform, VOSviewer, and CiteSpace were used to perform bibliometric analysis. Two thousand seven hundred fifty-one publications were retrieved form the Web of Science Core Collection database. The USA was the most productive and influential country. Seoul National University, International Journal of Molecular Sciences, and Kaufman RJ were the most productive institution, journal, and author. "Endoplasmic reticulum stress," "nonalcoholic fatty liver disease," "inflammation," "oxidative stress" and "insulin resistance" were the high-frequency keywords, "necrosis factor alpha" was the keywords with the strongest citation bursts, and "nonalcoholic fatty liver," "fibrosis" and "lipid droplet" were the keywords that were still bursting in 2022. The number of publications on ERS and liver disease has increased over the past years. The USA was the most productive and influential country. China has become the country with the largest number of annual publications, but it still needs to work on the quality. ERS and nonalcoholic fatty liver disease, especially the insulin resistance and lipotoxicity in hepatocytes may be the research hotspots and trends in this field of ERS and liver disease.

Autophagy in benign prostatic hyperplasia: insights and therapeutic potential.

Autophagy is a cellular homeostatic mechanism characterized by cyclic degradation. It plays an essential role in maintaining cellular quality and survival by eliminating dysfunctional cellular components. This process is pivotal in various pathophysiological processes. Benign prostatic hyperplasia (BPH) is a common urological disorder in middle-aged and elderly men. It frequently presents as lower urinary tract symptoms due to an increase in epithelial and stromal cells surrounding the prostatic urethra. The precise pathogenesis of BPH is complex. In recent years, research on autophagy in BPH has gained significant momentum, with accumulating evidence indicating its crucial role in the onset and progression of the disease. This review aims to outline the various roles of autophagy in BPH and elucidate potential therapeutic strategies targeting autophagy for managing BPH.

Biologically active franchetine-type diterpenoid alkaloids: Isolation, synthesis, anti-inflammatory, agalgesic activities, and molecular docking.

In this study, four franchetine-type diterpenoid alkaloids (1-4) were isolated from Aconitum sinoaxillare, and fourteen diverse franchetine analogs (5-18) were synthesized. Compounds 1, 2, 7 and 16 exhibited stronger inhibitory effects on NO production when compared to celecoxib. Among them, compound 1 had the best inhibitory effect on iNOS and COX-2 inflammatory proteins. The in vitro studies displayed that the anti-inflammatory effect of the most active compound 1 was ascribed to the inhibition of the TLR4-MyD88/NF-κB/MAPKs signalling pathway. Consequently, this led to a inhibition in the expression of inflammatory factors or mediators including NO, ROS, TNF-α, IL-6, IL-1ß, iNOS, and COX-2. Additionally, compound 1 had low toxicity (LD50 > 20 mg/kg) in mice, and it had notable analgesic effects on acetic acid-induced visceral pain (ED50 = 2.15 ± 0.07 mg/kg). Moreover, compound 1 exhibited a distinct reduction in the NaV1.7 and NaV1.8 channel currents during both resting and half-inactivated states at 50 µM. The present study enriches the pharmacological activities of franchetine derivatives and provides valuable insights for the development of novel anti-inflammatory and analgesic agents.

Selective Generation of Reactive Oxygen Species in Photocatalytic Oxidation by Tuning Porphyrin-Based COFs' Dimensionality.

Regulating the selective generation of reactive oxygen species (ROS) is a significant challenge in the field of photocatalytic oxidation, with successful approaches still being limited. Herein, we present a strategy to selectively generate singlet oxygen (1O2) and superoxide radicals (O2•-) by tuning the dimensionality of porphyrin-based covalent organic frameworks (COFs). The transformation of COFs from three-dimensional (3D) solids to two-dimensional (2D) sheets was achieved through the reversible protonation of the imine bond. Upon irradiation, both bulk and thin-layer COF-367 can transfer energy to O2 to generate 1O2. However, thin-layer COF-367 exhibited a superior performance compared to its bulk counterpart in activating O2 to form the O2•- radicals via electron transfer. After excluding the influences of the band structure, O2 adsorption energy, and frontier orbital composition attributed to the dimensionality of the COFs, it is reasonably speculated that the variance in ROS generation arises from the differential exposure ratios of the active surfaces, leading to distinct reaction pathways between the carrier and O2. This study is the first to explore the modulation mechanism of COF dimensionality on the activation of the O2 pathway, underscoring the importance of considering COF dimensionality in photocatalytic reactions.

The activation of the HIF-1α-VEGFA-Notch1 signaling pathway by Hydroxysafflor yellow A promotes angiogenesis and reduces myocardial ischemia-reperfusion injury.

Hydroxyl Safflower Yellow A (HSYA) is the primary bioactive compound derived from Safflower, which has been scientifically proven to possess anti-inflammatory, anti-apoptotic, and ameliorative properties against mitochondrial damage during acute myocardial ischemia-reperfusion injury (MIRI); however, its effects during the recovery stage remain unknown. Angiogenesis plays a crucial role in the rehabilitation process. AIM OF THE STUDY: The objective of this study was to investigate the long-term angiogenic effect of HSYA and its contribution to recovery after myocardial ischemia, as well as explore its underlying mechanism using non-targeted metabolomics and network pharmacology. MATERIALS AND METHODS: The MIRI model in rat was established by ligating the left anterior descending branch of the coronary artery. The effect of HSYA was assessed based on myocardial infarction volume and histopathology. Immunofluorescence staining was employed to evaluate angiogenesis, while ELISA was used to detect markers of myocardial injury. Additionally, a rat myocardial microvascular endothelial cell (CMECs) injury model was established using oxygen-glucose deprivation/reoxygenation (OGD/R), followed by scratch assays, migration assays, and tube formation experiments to assess angiogenesis. Western blot analysis was conducted to validate the underlying mechanism. RESULTS: Our findings provide compelling evidence for the therapeutic efficacy of HSYA in reducing myocardial infarction size, facilitating cardiac functional recovery, and reversing pathological alterations within the heart. Furthermore, we elucidate that HSYA exerts its effects on promoting migration and generation of myocardial microvascular endothelial cells through activation of the HIF-1α-VEGFA-Notch1 signaling pathway. CONCLUSION: These results underscore how HSYA enhances cardiac function via angiogenesis promotion and activation of the aforementioned signaling cascade.

CPT2-mediated Fatty Acid Oxidation Is Dispensable for Humoral Immunity.

B cell activation is accompanied by dynamic metabolic reprogramming, supported by a multitude of nutrients that include glucose, amino acids, and fatty acids. Although several studies have indicated that fatty acid mitochondrial oxidation is critical for immune cell functions, contradictory findings have been reported. Carnitine palmitoyltransferase II (CPT2) is a critical enzyme for long-chain fatty acid oxidation in mitochondria. In this study, we test the requirement of CPT2 for humoral immunity using a mouse model with a lymphocyte-specific deletion of CPT2. Stable [13C] isotope tracing reveals highly reduced fatty acid-derived citrate production in CPT2-deficient B cells. Yet, CPT2 deficiency has no significant impact on B cell development, B cell activation, germinal center formation, and Ab production upon either thymus-dependent or -independent Ag challenges. Together, our findings indicate that CPT2-mediated fatty acid oxidation is dispensable for humoral immunity, highlighting the metabolic flexibility of lymphocytes.

Trend of gastrointestinal and liver diseases in China: Results of the Global Burden of Disease Study, 2019.

BACKGROUND: China is one of the countries with the largest burden of gastrointestinal and liver diseases (GILD) in the world. The GILD constitutes various causes of mortality and disability. The study aimed to investigate the trend of GILD in China using the Global Burden of Diseases Study 2019 (GBD 2019) data resources from 1990 to 2019. METHODS: The data on the age-standardized mortality rates (ASMR) and disability-adjusted life years (DALYs) for GILD in China from 1990 to 2019 were collected from the GBD 2019 data resources. Furthermore, the ranking of the main causes of deaths and DALYs, as well as the trends of ASMR, DALYs, years of life lost (YLLs), and years of life lost due to disability (YLDs) per 1,000,000 in GILD were reported. RESULTS: The ASMR and DALYs for stomach cancer, liver cancer, and esophageal cancer, which ranked top three among the GILDs from 1990 to 2019, were gradually decreasing. Significant decreases in the ASMR and DALYs were found in diarrheal diseases and acute hepatitis (A, E, and C). However, noteworthy increases were found in those of colon and rectum cancer (CRC) and pancreatic cancer. Trend of DALYs, mortality, and YLLs rates for most of GILD were decreasing from 1990 to 2019, except the burden of CRC and pancreatic cancer with an increasing trend. The DALYs, mortality and YLLs of most GILD diseases showed decreasing trends from 1990 to 2019, except the burden of CRC and pancreatic cancer with an increasing trends. CONCLUSIONS: The result of the GBD 2019 showed that the rates of most GILDs decreased in China; however, gastrointestinal and liver cancer, such as stomach cancer still held the top ranking. Furthermore, the shift from infectious diseases to non-communicable causes among GILD burden is occurring and is likely to continue with many public health strategies implications.

A new perspective on the regulation of glucose and cholesterol transport by mitochondria-lysosome contact sites.

Mitochondria and lysosomes play a very important role in maintaining cellular homeostasis, and the dysfunction of these organelles is closely related to many diseases. Recent studies have revealed direct interactions between mitochondria and lysosomes, forming mitochondria-lysosome contact sites that regulate organelle network dynamics and mediate the transport of metabolites between them. Impaired function of these contact sites is not only linked to physiological processes such as glucose and cholesterol transport but also closely related to the pathological processes of metabolic diseases. Here, we highlight the recent progress in understanding the mitochondria-lysosome contact sites, elucidate their role in regulating metabolic homeostasis, and explore the potential implications of this pathway in metabolic disorders.

Mesoporous metal-organic framework NH2-MIL-101(Cr) as an efficient photocatalyst for the epoxidation of styrene.

Oxidation of styrene is a key reaction in the synthesis of pharmaceuticals and fine chemicals, and therefore oxidizing styrene with selective, efficient, and recyclable heterogeneous catalysts is significant from an environmental and economic standpoint. In this study, we report the transition Cr-based metal-organic framework [NH2-MIL-101(Cr)] as a heterogeneous photocatalyst, which efficiently promotes styrene epoxidation using H2O2 as a green oxidant, achieving high conversion efficiency (98%) and excellent selectivity (82%) under ambient conditions. Radical detection and quenching experiments reveal that the superoxide radical anion (O2˙-) acts as an active oxygen species, selectively promoting the oxidation of styrene to its oxidized form. This work provides insight into the development of a sustainable and cost-effective method for producing styrene oxide.

Targeting mechanistic target of rapamycin complex 2 attenuates immunopathology in Systemic Lupus Erythematosus.

Objective: We aim to explore the role of mechanistic target of rapamycin complex (mTORC) 2 in systemic lupus erythematosus (SLE) development, the in vivo regulation of mTORC2 by type I interferon (IFN) signaling in autoimmunity, and to use mTORC2 targeting therapy to ameliorate lupus-like symptoms in an in vivo lupus mouse model and an in vitro coculture model using human PBMCs. Method: We first induced lupus-like disease in T cell specific Rictor, a key component of mTORC2, deficient mice by topical application of imiquimod (IMQ) and monitored disease development. Next, we investigated the changes of mTORC2 signaling and immunological phenotypes in type I IFNAR deficient Lpr mice. We then tested the beneficial effects of anti-Rictor antisense oligonucleotide (Rictor-ASO) in a mouse model of lupus: MRL/lpr mice. Finally, we examined the beneficial effects of RICTOR-ASO on SLE patients' PBMCs using an in vitro T-B cell coculture assay. Results: T cell specific Rictor deficient mice have reduced age-associated B cells, plasma cells and germinal center B cells, and less autoantibody production than WT mice following IMQ treatment. IFNAR1 deficient Lpr mice have reduced mTORC2 activity in CD4+ T cells accompanied by restored CD4+ T cell glucose metabolism, partially recovered T cell trafficking, and reduced systemic inflammation. In vivo Rictor-ASO treatment improves renal function and pathology in MRL/lpr mice, along with improved immunopathology. In human SLE (N = 5) PBMCs derived T-B coculture assay, RICTOR-ASO significantly reduce immunoglobulin and autoantibodies production (P < 0.05). Conclusion: Targeting mTORC2 could be a promising therapeutic for SLE.

Effects of personalized music listening on post-stroke cognitive impairment: A randomized controlled trial.

BACKGROUND AND PURPOSE: Previous studies have suggested that music listening has the potential to positively affect cognitive functions and mood in individuals with post-stroke cognitive impairment (PSCI), with a preference for self-selected music likely to yield better outcomes. However, there is insufficient clinical evidence to suggest the use of music listening in routine rehabilitation care to treat PSCI. This randomized control trial (RCT) aims to investigate the effects of personalized music listening on mood improvement, activities of daily living (ADLs), and cognitive functions in individuals with PSCI. MATERIALS AND METHODS: A total of 34 patients with PSCI were randomly assigned to either the music group or the control group. Patients in the music group underwent a three-month personalized music-listening intervention. The intervention involved listening to a personalized playlist tailored to each individual's cultural, ethnic, and social background, life experiences, and personal music preferences. In contrast, the control group patients listened to white noise as a placebo. Cognitive function, neurological function, mood, and ADLs were assessed. RESULTS: After three months of treatment, the music group showed significantly higher Montreal Cognitive Assessment (MoCA) scores compared to the control group (p=0.027), particularly in the domains of delayed recall (p=0.019) and orientation (p=0.023). Moreover, the music group demonstrated significantly better scores in National Institutes of Health Stroke Scale (NIHSS) (p=0.008), Barthel Index (BI) (p=0.019), and Zarit Caregiver Burden Interview (ZBI) (p=0.008) compared to the control group. No effects were found on mood as measured by the Hamilton Anxiety Rating Scale (HAMA) and the Hamilton Depression Rating Scale (HAMD). CONCLUSION: Personalized music listening promotes the recovery of cognitive and neurological functions, improves ADLs, and reduces caregiver burden in patients with PSCI.

Retinal microvascular changes in patients with pancreatitis and their clinical significance.

Acute pancreatitis, a common exocrine inflammatory disease affecting the pancreas, is characterized by intense abdominal pain and multiple organ dysfunction. However, the alterations in retinal blood vessels among individuals with acute pancreatitis remain poorly understood. This study employed optical coherence tomography angiography (OCTA) to examine the superficial and deep retinal blood vessels in patients with pancreatitis. Sixteen patients diagnosed with pancreatitis (32 eyes) and 16 healthy controls (32 eyes) were recruited from the First Affiliated Hospital of Nanchang University for participation in the study. Various ophthalmic parameters, such as visual acuity, intraocular pressure, and OCTA image for retina consisting of the superficial retinal layer (SRL) and the deep retinal layer (DRL), were recorded for each eye. The study observed the superficial and deep retinal microvascular ring (MIR), macrovascular ring (MAR), and total microvessels (TMI) were observed. Changes in retinal vascular density in the macula through annular partitioning (C1-C6), hemispheric quadrant partitioning (SR, SL, IL, and IR), and early diabetic retinopathy treatment studies (ETDRS) partitioning methods (R, S, L, and I). Correlation analysis was employed to investigate the relationship between retinal capillary density and clinical indicators. Our study revealed that in the superficial retinal layer, the vascular density of TMI, MIR, MAR, SR, IR, S, C2, C3 regions were significantly decreased in patients group compared with the normal group. For the deep retinal layer, the vascular density of MIR, SR, S, C1, C2 regions also reduced in patient group. The ROC analysis demonstrated that OCTA possesses significant diagnostic performance for pancreatitis. In conclusion, patients with pancreatitis may have retinal microvascular dysfunction, and OCTA can be a valuable tool for detecting alterations in ocular microcirculation in pancreatitis patients in clinical practice.

Association of fatigue with disease activity and clinical manifestations in patients with Crohn's disease and ulcerative colitis: an observational cross-sectional study in the United States.

BACKGROUND: Fatigue imposes a socioeconomic burden on patients with Crohn's disease (CD) and ulcerative colitis (UC). We assessed the prevalence of fatigue among patients with CD or UC and identified disease activity measures associated with fatigue. METHODS: Data from the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease (SPARC IBD) were analyzed separately for CD and UC. Fatigue was defined based on a subjective and dichotomic questionnaire. Patients indicated if they experienced fatigue within the last week. The overall prevalence of fatigue was analyzed using descriptive and contingency tables. Demographics, clinical characteristics, disease activity (measures include Physician's Global Assessment for both CD and UC, short CD Activity Index for CD, and Ulcerative Colitis Disease Activity Index for UC), symptoms, and patient-reported outcomes were compared between patients with and without fatigue. Multivariable logistic regression models were constructed to identify symptoms and disease activity measures associated with fatigue. RESULTS: The study included 903 patients with CD and 443 patients with UC. Fatigue was reported in 47.7% of patients with CD and 40.9% of patients with UC. In patients with CD, abdominal pain, bowel incontinence, depressive symptoms, reduced general well-being, and night-time bowel movements were associated with fatigue. In patients with UC, depressive symptoms, reduced general well-being, moderate or severe disease activity by the physician's global assessment, and night-time bowel movements were significantly associated with fatigue. CONCLUSIONS: Fatigue is a common symptom among patients with CD or UC and is associated with higher levels of disease activity and reduced general well-being.

Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), can lead to fatigue in many patients regardless of their disease severity. Fatigue not only affects patients' quality-of-life but also their ability to work and their mental health. However, research specific to the IBD related symptoms that contribute to fatigue in these patients is not currently available, especially in the United States (US). To address this gap, real-world data was analyzed to understand how common fatigue is among patients with CD and UC in the US and clinical symptoms that co-occur with fatigue. We found that fatigue affects more than 40% of the patients. Our results suggest that fatigue is correlated with more severe disease symptoms and overall lower well-being among patients with CD and UC.

Triplinones A-H: Anti-Inflammatory Arylalkenyl α,ß-Unsaturated-δ-Lactones Isolated from the Leaves of Australian Rainforest Plant Cryptocarya triplinervis (Lauraceae).

Our ongoing exploration of Australian rainforest plants for the biodiscovery of anti-inflammatory agents led to the isolation and structural elucidation of eight new arylalkenyl α,ß-unsaturated-δ-lactones, triplinones A-H (1-8), from the leaves of the Australian rainforest plant Cryptocarya triplinervis B. Hyland (Lauraceae). The chemical structures of these compounds were established by NMR spectroscopic data analysis, while their relative and absolute configurations were established using a combination of Mosher ester analysis utilizing both Riguera's and Kishi's methods, ECD experiments, and X-ray crystallography analysis. Compounds 1-8 exhibited good inhibitory activities toward nitric oxide (NO) production in lipopolysaccharide (LPS) and interferon (IFN)-γ induced RAW 264.7 macrophages, in particular compounds 1-3 and 5, with IC50 values of 7.3 ± 0.5, 6.0 ± 0.3, 5.6 ± 0.3, and 5.4 ± 2.5 µM, respectively.

Discovery of 4-(isopentyloxy)-3-nitrobenzamide derivatives as xanthine oxidase inhibitors through a non-anthraquinone exploration.

In our previous study, we reported a series of N-(9,10-anthraquinone-2-carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug-like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure-activity relationship (SAR) studies, we identified a series of 4-(isopentyloxy)-3-nitrobenzamide derivatives exhibiting excellent in vitro potency against XO. The optimized compound, 4-isopentyloxy-N-(1H-pyrazol-3-yl)-3-nitrobenzamide (6k), demonstrated exceptional in vitro potency with an IC50 value of 0.13 µM. Compound 6k showed favorable drug-like characteristics with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.41 and 3.73, respectively. In comparison to the initial compound 1d, 6k exhibited a substantial 24-fold improvement in IC50, along with a 1.6-fold enhancement in LE and a 3.7-fold increase in LLE. Molecular modeling studies provided insights into the strong interactions of 6k with critical amino acid residues within the active site. Furthermore, in vivo hypouricemic investigations convincingly demonstrated that 6k significantly reduced serum uric acid levels in rats. The MTT results revealed that compound 6k is nontoxic to healthy cells. The gastric and intestinal stability assay demonstrated that compound 6k exhibits good stability in the gastric and intestinal environments. In conclusion, compound 6k emerges as a promising lead compound, showcasing both exceptional in vitro potency and favorable drug-like characteristics, thereby warranting further exploration.

Cytokine Storm in COVID-19: Insight into Pathological Mechanisms and Therapeutic Benefits of Chinese Herbal Medicines.

Cytokine storm (CS) is the main driver of SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) in severe coronavirus disease-19 (COVID-19). The pathological mechanisms of CS are quite complex and involve multiple critical molecular targets that turn self-limited and mild COVID-19 into a severe and life-threatening concern. At present, vaccines are strongly recommended as safe and effective treatments for preventing serious illness or death from COVID-19. However, effective treatment options are still lacking for people who are at the most risk or hospitalized with severe disease. Chinese herbal medicines have been shown to improve the clinical outcomes of mild to severe COVID-19 as an adjunct therapy, particular preventing the development of mild to severe ARDS. This review illustrates in detail the pathogenesis of CS-involved ARDS and its associated key molecular targets, cytokines and signalling pathways. The therapeutic targets were identified particularly in relation to the turning points of the development of COVID-19, from mild symptoms to severe ARDS. Preclinical and clinical studies were reviewed for the effects of Chinese herbal medicines together with conventional therapies in reducing ARDS symptoms and addressing critical therapeutic targets associated with CS. Multiple herbal formulations, herbal extracts and single bioactive phytochemicals with or without conventional therapies demonstrated strong anti-CS effects through multiple mechanisms. However, evidence from larger, well-designed clinical trials is lacking and their detailed mechanisms of action are yet to be well elucidated. More research is warranted to further evaluate the therapeutic value of Chinese herbal medicine for CS in COVID-19-induced ARDS.