A Comprehensive Research Review of Herbal Textual Research, Phytochemistry, Pharmacology, Traditional Uses, Clinical Application, Safety Evaluation, and Quality Control of Trollius chinensis Bunge.

Trollius chinensis Bunge (TCB) is a perennial plant of the Ranunculaceae family with medicinal and edible values. It is widely distributed and commonly used in various regions, including Asia, Europe, and North America. The main chemical components of TCB include alkaloids, flavonoids, phenolic acids, and volatile oil compounds. TCB is renowned for its anti-inflammatory, heat-clearing, detoxifying, and eyesight-improving properties. Its dried flowers are commonly used as a traditional Chinese medicine indicated for the treatment of upper respiratory tract infections, chronic tonsillitis, pharyngitis, influenza, and bronchitis. Modern pharmacology has demonstrated the anti-cancer, anti-inflammatory, antihypertensive, and antioxidant effects of TCB. This study presents a comprehensive overview of various aspects of TCB, including herbal textual research, botany, phytochemistry, pharmacology, traditional uses, clinical application, and quality control, aiming to provide new ideas on the scientific application of TCB as well as the integration of modern research with traditional medicinal uses.

Prevalence and genetic diversity of Anaplasma and Ehrlichia in ticks and domesticated animals in Suizhou County, Hubei Province, China.

Anaplasma and Ehrlichia are tick-borne bacterial pathogens that cause anaplasmoses and ehrlichioses in humans and animals. In this study, we examined the prevalence of Anaplasma and Ehrlichia species in ticks and domesticated animals in Suizhou County, Hubei Province in the central China. We used PCR amplification and DNA sequencing of the 16S rRNA, groEL, and gltA genes to analyze. We collected 1900 ticks, including 1981 Haemaphysalis longicornis and 9 Rhipicephalus microplus, 159 blood samples of goats (n = 152), cattle (n = 4), and dogs (n = 3) from May to August of 2023. PCR products demonstrated that Anaplasma bovis, Anaplasma capra, and an Ehrlichia species were detected in the H. longicornis with the minimum infection rates (MIR) of 1.11%, 1.32%, and 0.05%, respectively; A. bovis, A. capra, and unnamed Anaplasma sp. were detected in goats with an infection rate of 26.31%, 1.31% and 1.97%, respectively. Anaplasma and Ehrlichia species were not detected from cattle, dogs and R. microplus ticks. The genetic differences in the groEL gene sequences of the Anaplasma in the current study were large, whereas the 16S rRNA and gltA gene sequences were less disparate. This study shows that ticks and goats in Suizhou County, Hubei Province carry multiple Anaplasma species and an Ehrlichia species, with relatively higher infection rate of A. bovis in goats. Our study indicates that multiple Anaplasma and Ehrlichia species exist in ticks and goats in the central China with potential to cause human infection.

Composition and diversity of soil microbial communities change by introducing Phallus impudicus into a Gastrodia elata Bl.-based soil.

BACKGROUND: The Gastrodia elata Bl. is an orchid, and its growth demands the presence of Armillaria species. The strong competitiveness of Armillaria species has always been a concern of major threat to other soil organisms, thus disrupting the equilibrium of soil biodiversity. Introducing other species to where G. elata was cultivated, could possibly alleviate the problems associated with the disequilibrium of soil microenvironment; however, their impacts on the soil microbial communities and the underlying mechanisms remain unclear. To reveal the changes of microbial groups associated with soil chemical properties responding to different cultivation species, the chemical property measurements coupled with the next-generation pyrosequencing analyses were applied with soil samples collected from fallow land, cultivation of G. elata and Phallus impudicus, respectively. RESULTS: The cultivation of G. elata induced significant increases (p < 0.05) in soil pH and NO3-N content compared with fallow land, whereas subsequent cultivation of P. impudicus reversed these G. elata-induced increases and was also found to significantly increase (p < 0.05) the content of soil NH4+-N and AP. The alpha diversities of soil microbial communities were significantly increased (p < 0.01) by cultivation of G. elata and P. impudicus as indicated with Chao1 estimator and Shannon index. The structure and composition of soil microbial communities differed responding to different cultivation species. In particular, the relative abundances of Bacillus, norank_o_Gaiellales, Mortierella and unclassified_k_Fungi were significantly increased (p < 0.05), while the abundances of potentially beneficial genera such as Acidibacter, Acidothermus, Cryptococcus, and Penicillium etc., were significantly decreased (p < 0.05) by cultivation of G. elata. It's interesting to find that cultivation of P. impudicus increased the abundances of these genera that G. elata decreased before, which contributed to the difference of composition and structure. The results of CCA and heatmap indicated that the changes of soil microbial communities had strong correlations with soil nutrients. Specifically, among 28 genera presented, 50% and 42.9% demonstrated significant correlations with soil pH and NO3-N in response to cultivation of G. elata and P. impudicus. CONCLUSIONS: Our findings suggested that the cultivation of P. impudicus might have potential benefits as result of affecting soil microorganisms coupled with changes in soil nutrient profile.

Establishment of a RAA-CRISPR Cas12a based diagnostic method for peste des petits ruminants virus N gene and M gene.

Peste des petis ruminants (PPR) is an acute, highly contagious fatal disease affecting both domestic and wild small ruminants, caused by Morbillivirus caprinae (also known as peste des petis ruminants virus (PPRV)). Herein, a rapid method based on recombinase aided amplification-clustered regularly interspaced short palindromic repeats-Cas12a (RAA-CRISPR Cas12a) to detect PPRV was developed. CRISPR RNAs and RAA primers for PPRV-N (nucleocapsid) and PPRV-M (matrix) fragments were designed. The reaction system was constructed following screening and optimization. Detection could be completed within in 50 minutes at 37°C. Detection of gradient dilutions of plasmids carrying of PPRV N and M gene fragments indicated a minimum limit of detection of 10 copies/µL. There were no cross-reactions with related viruses and all tested lineages of PPRV were detected successfully. The method also showed good repeatability. The detection of clinical samples (previously detected using reverse transcription polymerase chain reaction (RT-PCR)) indicated good consistency between the RAA-CRISPR Cas12a method and RT-PCR. Thus, the RAA-CRISPR Cas12a method for rapid PPRV diagnosis has strong specificity, high sensitivity, and stable repeatability. Moreover, the results can be observed visually under blue or UV light or using lateral flow strips without complex instruments.

Small Transjugular Intrahepatic Portosystemic Shunt Plus Variceal Embolization for Gastric Varices: A Multicenter Cohort Study.

BACKGROUND & AIMS: The effect of transjugular intrahepatic portosystemic shunt (TIPS) plus variceal embolization for treating gastric varices (GVs) remains controversial. This nationwide multicenter cohort study aimed to evaluate whether adding variceal embolization to a small diameter (8-mm) TIPS could reduce the rebleeding incidence in patients with different types of GVs. METHODS: This retrospective cohort study involved 629 patients who underwent 8-mm TIPS for gastric varices at 7 medical centers. The primary endpoint was all-cause rebleeding, and the secondary endpoints included overt hepatic encephalopathy (OHE) and all-cause mortality. RESULTS: A total of 629 patients were included. Among them, 429 (68.2%) had gastroesophageal varices type 1 (GOV1), 145 (23.1%) had gastroesophageal varices type 2 (GOV2), and 55 (8.7%) had isolated gastric varices type 1 (IGV1). In the entire cohort, adjunctive embolization reduced rebleeding (6.2% vs 13.6%; P = .005) and OHE (31.0% vs 39.4%; P = .02) compared with TIPS alone. However, no significant differences were found in mortality (12.0% vs 9.7%; P = .42). In patients with GOV2 and IGV1, TIPS plus variceal embolization reduced both rebleeding (GOV2: 7.8% vs 25.1%; P = .01; IGV1: 5.6% vs 30.8%; P = .03) and OHE (GOV2: 31.8% vs 51.5%; P = .008; IGV1: 11.6% vs 38.5%; P = .04). However, in patients with GOV1, adjunctive embolization did not reduce rebleeding (5.9% vs 8.7%; P = .37) or OHE (33.1% vs 35.3%; P = .60). CONCLUSIONS: Compared with TIPS alone, 8-mm TIPS plus variceal embolization reduced rebleeding and OHE in patients with GOV2 and IGV1. These findings suggest that patients with GOV2 and IGV1, rather than GOV1, could benefit from embolization with TIPS.

SFTSV nucleoprotein mediates DNA sensor cGAS degradation to suppress cGAS-dependent antiviral responses.

Cyclic GMP-AMP synthase (cGAS) is an important DNA pattern recognition receptor that senses double-stranded DNA derived from invading pathogens or self DNA in cytoplasm, leading to an antiviral interferon response. A tick-borne Bunyavirus, severe fever with thrombocytopenia syndrome virus (SFTSV), is an RNA virus that causes a severe emerging viral hemorrhagic fever in Asia with a high case fatality rate of up to 30%. However, it is unclear whether cGAS interacts with SFTSV infection. In this study, we found that SFTSV infection upregulated cGAS RNA transcription and protein expression, indicating that cGAS is an important innate immune response against SFTSV infection. The mechanism of cGAS recognizing SFTSV is by cGAS interacting with misplaced mitochondrial DNA in the cytoplasm. Depletion of mitochondrial DNA significantly inhibited cGAS activation under SFTSV infection. Strikingly, we found that SFTSV nucleoprotein (N) induced cGAS degradation in a dose-dependent manner. Mechanically, N interacted with the 161-382 domain of cGAS and linked the cGAS to LC3. The cGAS-N-LC3 trimer was targeted to N-induced autophagy, and the cGAS was degraded in autolysosome. Taken together, our study discovered a novel antagonistic mechanism of RNA viruses, SFTSV is able to suppress the cGAS-dependent antiviral innate immune responses through N-hijacking cGAS into N-induced autophagy. Our results indicated that SFTSV N is an important virulence factor of SFTSV in mediating host antiviral immune responses. IMPORTANCE: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne RNA virus that is widespread in East and Southeast Asian countries with a high fatality rate of up to 30%. Up to now, many cytoplasmic pattern recognition receptors, such as RIG-I, MDA5, and SAFA, have been reported to recognize SFTSV genomic RNA and trigger interferon-dependent antiviral responses. However, current knowledge is not clear whether SFTSV can be recognized by DNA sensor cyclic GMP-AMP synthase (cGAS). Our study demonstrated that cGAS could recognize SFTSV infection via ectopic mitochondrial DNA, and the activated cGAS-stimulator of interferon genes signaling pathway could significantly inhibit SFTSV replication. Importantly, we further uncovered a novel mechanism of SFTSV to inhibit innate immune responses by the degradation of cGAS. cGAS was degraded in N-induced autophagy. Collectively, this study illustrated a novel virulence factor of SFTSV to suppress innate immune responses through autophagy-dependent cGAS degradation.

Persistence of SARS-CoV-2 colonization and high expression of inflammatory factors in cardiac tissue 6 months after COVID-19 recovery: a prospective cohort study.

Background: The presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in myocardial autopsy tissues has been observed in certain individuals with coronavirus disease 2019 (COVID-19). However, the duration of cardiac involvement remains uncertain among recovered COVID-19 patients. Our study aims to evaluate the long-term persistence of SARS-CoV-2 within cardiac tissue. Methods: We prospectively and consecutively evaluated the patients undergoing mitral valve replacement (MVR) and left atrial (LA) volume reduction surgery from May 25 to June 10, 2023 at our center, who had been approximately 6 months of recovery after Omicron wave. Patients tested positive for SARS-CoV-2 upon admission were excluded. The surgical LA tissue was collected in RNA preservation solution and stored at -80 ℃ immediately. Then SARS-CoV-2, interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) RNA expression in LA tissues were assessed through thrice-repeated reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses. Categorical variables were assessed using the Chi-square or Fisher's exact tests, and continuous variables was analyzed using the Mann-Whitney U test. Results: Nine of 41 patients were enrolled, all of whom tested negative for SARS-CoV-2 upon admission (two antigen and PCR tests). In four of nine patients, SARS-CoV-2 RNA was detected in their LA tissue, indicating viral colonization. Among the four positive cases, the IL-6 and IL-1ß relative expression levels in the LA tissue of one patient were increased approximately 55- and 110-fold, respectively, compared to those of SARS-CoV-2 (-) patients. Increased expression of IL-6 and IL-1ß were observed in the myocardium of this patient. Another patient demonstrated a remarkable 7-fold increase in both IL-6 and IL-1ß expression, surpassing that of SARS-CoV-2 (-) patients. Additionally, no other cardiac inflammation-related diseases or conditions were presented in these two patients. The IL-6 and IL-1ß expression levels of the remaining two patients were not significantly different from those of SARS-CoV-2 (-) patients. The relative expression levels of IL-6 and IL-1ß in cardiac tissues of all SARS-CoV-2 (-) patients were relatively low. Interestingly, despite abnormally elevated levels of IL-6 and IL-1ß within their cardiac tissue, two patients did not show a significant increase in serum IL-6 and IL-1ß levels when compared to other patients. Conclusions: Our research suggests that certain COVID-19-recovered patients have persistent colonization of SARS-CoV-2 in their cardiac tissue, accompanied by a local increase in inflammatory factors.

In silico genome-wide analysis of homeodomain-leucine zipper transcription factors in Cannabis sativa L.

HD-Zip (Homeodomain-Leucine Zipper) is a family of transcription factors unique to higher plants and plays a vital role in plant growth and development. Increasing research results show that HD-Zip transcription factors are widely involved in many life processes in plants. However, the HD-Zip transcription factor for cannabis, a valuable crop, has not yet been identified. The sequence characteristics, chromosome localization, system evolution, conservative motif, gene structure, and gene expression of the HD-Zip transcription factor in the cannabis genome were systematically studied. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to verify its function. The results showed that cannabis contained 33 HD-Zip gene members. The number of amino acids is 136-849aa, the isoelectric point is 4.54-9.04, and the molecular weight is 23264.32-93147.87Da. Many cis-acting elements are corresponding to hormone and abiotic stress in the HD-Zip family promoter area of cannabis. Sequencing of the transcriptome at 5 tissue sites of hemp, stems, leaves, bracts, and seeds showed similar levels of expression of 33 members of the HD-Zip gene family at 5 tissue sites. Bioinformatics results show that HD-Zip expression is tissue-specific and may be influenced by hormones and environmental factors. This lays a foundation for further research on the gene function of HD-Zip.

Chiral Pyclen-Based Heptadentate Chelates as Highly Stable MRI Contrast Agents.

In recent years, pyclen-based complexes have attracted a great deal of interest as magnetic resonance imaging (MRI) contrast agents (CAs) and luminescent materials, as well as radiopharmaceuticals. Remarkably, gadopiclenol, a Gd(III) bishydrated complex featuring a pyclen-based heptadentate ligand, received approval as a novel contrast agent for clinical MRI application in 2022. To maximize stability and efficiency, two novel chiral pyclen-based chelators and their complexes were developed in this study. Gd-X-PCTA-2 showed significant enhancements in both thermodynamic and kinetic stabilities compared to those of the achiral parent derivative Gd-PCTA. 1H NMRD profiles reveal that both chiral gadolinium complexes (Gd-X-PCTA-1 and Gd-X-PCTA-2) have a higher relaxivity than Gd-PCTA, while variable-temperature 17O NMR studies show that the two inner-sphere water molecules have distinct residence times τMa and τMb. Furthermore, in vivo imaging demonstrates that Gd-X-PCTA-2 enhances the signal in the heart and kidneys of the mice, and the chiral Gd complexes exhibit the ability to distinguish between tumors and normal tissues in a 4T1 mouse model more efficiently than that of the clinical agent gadobutrol. Biodistribution studies show that Gd-PCTA and Gd-X-PCTA-2 are primarily cleared by a renal pathway, with 24 h residues of Gd-X-PCTA-2 in the liver and kidney being lower than those of Gd-PCTA.

Clinical characteristics and lateralization of the horizontal semicircular canal light cupula.

Introduction: Positional vertigo and nystagmus are the main symptoms and signs of dizziness, respectively. Despite the clinical utility of the supine roll test (SRT) and null point (NP) in diagnosing light cupula, a type of positional vertigo, there exists a notable gap in the literature concerning the comprehensive evaluation of lateralization values based on various nystagmus characteristics and the intensity of direction-changing positional nystagmus (DCPN) in the SRT, particularly in comparison to the NP. Additionally, limited data on abnormal canal paresis (CP) in light cupula patients underscores the need for further research with a larger patient population to elucidate this mechanism. This study aims to investigate the characteristics of positional nystagmus and lateralization of the horizontal semicircular canal (HSCC) light cupula, which is a type of positional vertigo and nystagmus that is poorly understood. Methods: Eighty-five patients (17 males, 68 females; mean age, 60.9 years) with light cupula were reviewed. We summarized the characteristics of spontaneous nystagmus and positional nystagmus, including supine positioning nystagmus, bow nystagmus, and lean nystagmus. Then, the side of the NP was identified as the affected side, and the values of the fast phase direction of the spontaneous nystagmus, supine positioning nystagmus, bow nystagmus, and lean nystagmus, as well as the intensity of the DCPN in the SRT, were used to diagnose the affected sides. Caloric testing was also performed for some patients. Results: Light cupula was observed in 5.7% of the patients with positional nystagmus. The frequencies of supine positioning nystagmus (88.2%), bow nystagmus (90.6%), and lean nystagmus (83.5%) were higher than spontaneous nystagmus (61.2%) (p < 0.001). The second NP (NP2) (92.9%) and third NP (NP3) (83.5%) were readily detected, affecting the left and right sides in 38 and 47 patients, respectively. Lateralization through the fast phase directions of bow nystagmus and lean nystagmus did not significantly differ from that of NP (all p > 0.05). However, the accuracy rate of lateralization through the sides with more vigorous DCPN in the SRT was 63.5%, significantly lower than through NP (p < 0.001). Particularly in patients with supine positioning nystagmus (n = 75), the rate was only 58.7% (p < 0.001). However, the rate was 100% in patients without supine positioning nystagmus (n = 10). Among the 70 patients who underwent caloric testing, 37 had abnormal CP, and the sides of the reduced caloric reaction were ipsilateral to the affected sides of the light cupula in 83.8% of the patients. Conclusion: Besides utilizing the NP to determine the affected side, the fast phase direction of the bow nystagmus or lean nystagmus can also aid in identification. However, a simple comparison of the intensity of DCPN in SRT cannot provide accurate lateralization, especially in patients with supine positioning nystagmus. There is a high incidence of CP on the affected side of the light cupula.

Using UV/peracetic acid as pretreatment for subsequent bio-treatment of antibiotic-containing wastewater treatment: Mitigating microbial inhibition and antibiotic resistance genes proliferation.

UV/peracetic acid (PAA) treatment presents a promising approach for antibiotic removal, but its effects on microbial community and proliferation of antibiotic resistance genes (ARGs) during the subsequent bio-treatment remain unclear. Thus, we evaluated the effects of the UV/PAA on tetracycline (TTC) degradation, followed by introduction of the treated wastewater into the bio-treatment system to monitor changes in ARG expression and biodegradability. Results demonstrated effective TTC elimination by the UV/PAA system, with carbon-centered radicals playing a significant role. Crucially, the UV/PAA system not only eliminated antibacterial activity but also inhibited potential ARG host growth, thereby minimizing the emergence and dissemination of ARGs during subsequent bio-treatment. Additionally, the UV/PAA system efficiently removed multi-antibiotic resistant bacteria and ARGs from the bio-treatment effluent, preventing ARGs from being released into the environment. Hence, we propose a multi-barrier strategy for treating antibiotic-containing wastewater, integrating UV/PAA pre-treatment and post-disinfection with bio-treatment. The inhibition of ARGs transmission by the integrated system was verified through actual soil testing, confirming its effectiveness in preventing ARGs dissemination in the surrounding natural ecosystem. Overall, the UV/PAA treatment system offers a promising solution for tackling ARGs challenges by controlling ARGs proliferation at the source and minimizing their release at the end of the treatment process.

Identification and expression analysis of TPS family gene in Cannabis sativa L.

Terpene synthases (TPSs) regulate plant growth, development, and stress response. TPS genes have been identified in Arabidopsis thaliana and Zea mays. Cannabis sativa TPS genes were identified and analyzed using bioinformatics. Genomic data were downloaded from Plant Transcription Factor Database and National Center for Biotechnology Information database, and TPS genes were predicted, analyzed, and visualized using ExPASy, PlantCare, and other online websites along with TBtools, MEGA software, and other software. To verify its role, quantitative real-time polymerase chain reaction (qRT-PCR) tests were conducted. The Cannabis sativa TPS family comprises 41 elements distributed over 8 chromosomes and a single scaffold segment. The isoelectric point varied between 4.96 and 7.03, while the molecular weight spanned from 20705.90 to 102324.64 Da. The majority of genes were found in the cytoplasm and chloroplasts, with the remainder situated in the peroxisome, nucleus, plasma membrane, and mitochondria. Several cis-acting components associated with stress response were present in the gene's upstream promoter region. Data from RNA sequencing and qRT-PCR revealed specific expression of TPS genes in all five organs of female Cannabis sativa plants. Collinearity analysis showed 4 homologous gene pairs between the Cannabis sativa and Arabidopsis thaliana, with many pairs of homologous genes in other species, which was consistent with the dicotyledons evolutionary relationship. Furthermore, some genes may participate in Cannabis sativa growth and development and play a role in secondary metabolite synthesis. Therefore, bioinformatics analysis of the Cannabis sativa TPS gene family provides a theoretical basis for future research on the volatile terpene compounds of Cannabis sativa.

Corrigendum: Safety issues of tirzepatide (pancreatitis and gallbladder or biliary disease) in type 2 diabetes and obesity: a systematic review and meta-analysis.

[This corrects the article DOI: 10.3389/fendo.2023.1214334.].

Xenograft and organoid models in developing precision medicine for gastric cancer (Review).

Gastric cancer (GC), a highly heterogeneous disease, has diverse histological and molecular subtypes. For precision medicine, well­characterized models encompassing the full spectrum of subtypes are necessary. Patient­derived tumor xenografts and organoids serve as important preclinical models in GC research. The main advantage of these models is the retention of phenotypic and genotypic heterogeneity present in parental tumor tissues. Utilizing diverse sequencing techniques and preclinical models for GC research facilitates accuracy in predicting personalized clinical responses to anti­cancer treatments. The present review summarizes the latest advances of these two preclinical models in GC treatment and drug response assessment.

Efficacy of TIPS plus extrahepatic collateral embolisation in real-world data: a validation study.

OBJECTIVES: The efficacy of transjugular intrahepatic portosystemic shunt (TIPS) plus extrahepatic collateral embolisation (TIPS+E) in reducing rebleeding and hepatic encephalopathy (HE) post-TIPS was recently reported in a meta-analysis, but further validation is essential. This study aims to confirm the effectiveness of TIPS+E using real-world data. METHODS: The multicentre retrospective cohort included 2077 patients with cirrhosis who underwent TIPS±E (TIPS: 631, TIPS+E: 1446) between January 2010 and December 2022. Regression and propensity score matching (PSM) were used to adjust for baseline characteristic differences. After PSM, clinical outcomes, including rebleeding, HE, survival and further decompensation (FDC), were analysed. Baseline data from all patients contributed to the construction of prognostic models. RESULTS: After PSM, 1136 matched patients (TIPS+E: TIPS=568:568) were included. TIPS+E demonstrated a significant reduction in rebleeding (HR 0.77; 95% CI 0.59 to 0.99; p=0.04), HE (HR 0.82; 95% CI 0.68 to 0.99; p=0.04) and FDC (HR 0.85; 95% CI 0.73 to 0.99; p=0.04), comparing to TIPS. Significantly, TIPS+E also reduced rebleeding, HE and FDC in subgroup of using 8 mm diameter stents and embolising of gastric varices+spontaneous portosystemic shunts (GV+SPSS). However, there were no differences in overall or subgroup survival analysis. Additionally, the random forest models showed higher accuracy and AUROC comparing to other models. Controlling post-TIPS portal pressure gradient (pPPG) within 7 mm Hg

Albiflorin Attenuates Neuroinflammation and Improves Functional Recovery After Spinal Cord Injury Through Regulating LSD1-Mediated Microglial Activation and Ferroptosis.

Spinal cord injury (SCI) is a serious, prolonged, and irreversible injury with few therapeutic options. Albiflorin (AF) possesses powerful pharmacodynamic properties and exerts protective effects against neuroinflammation. However, no research has examined the neuroprotective effect of AF following SCI. Rats were received laminectomy to establish SCI animal model and treated with AF (20 mg/kg and 40 mg/kg). Behavioral experiments were conducted to assess the impacts of AF on motor function after SCI in rats. Hematoxylin-eosin (HE) staining, Nissl staining, and Prussian Blue staining were performed to observe histological changes, neuronal damage, and iron deposition, respectively. Transmission electron microscope was adopted to observe the ultrastructure of spinal cord tissues. Immunofluorescence assay was performed to examine neurons and microglia. ELISA assay was used to examine the production of cytokines. Western blot assay was used to detect the expression level of ferroptosis-related proteins. Microglia BV-2 cells were induced by LPS to mimic the neuroinflammatory condition. Cell viability was assessed by CCK-8 assay, and lipid peroxidase level was measured by C11 BODIPY 581/591 staining. Molecular docking technology was utilized to confirm the relationship between AF and LSD1. AF improved the motor functional recovery after SCI in rats. Meanwhile, AF attenuated neuron apoptosis and microglia activation, reduced the production of pro-inflammatory cytokines and iron accumulation, and inhibited spinal cord ferroptosis following SCI in rats. LSD1 was verified to be a target protein of AF, and AF could concentration-dependently downregulate LSD1 expression in injured spinal cords in vivo and LPS-induced BV-2 cells in vitro. In addition, AF not only inhibited ferroptosis through reducing lipid peroxidase and iron levels and regulating ferroptosis-related proteins, but also inhibited microglial activation and reduced pro-inflammatory cytokines production in LPS-induced BV-2 cells; however, these changes were partly counteracted by LSD1 overexpression. AF could reduce microglial activation and ferroptosis, attenuate neuroinflammation, and improve functional recovery following SCI by downregulating LSD1, providing novel therapeutic strategies for the treatment of SCI.

Advances and future perspectives of intranasal drug delivery: A scientometric review.

Intranasal drug delivery is as a noninvasive and efficient approach extensively utilized for treating the local, central nervous system, and systemic diseases. Despite numerous reviews delving into the application of intranasal drug delivery across biomedical fields, a comprehensive analysis of advancements and future perspectives remains elusive. This review elucidates the research progress of intranasal drug delivery through a scientometric analysis. It scrutinizes several challenges to bolster research in this domain, encompassing a thorough exploration of entry and elimination mechanisms specific to intranasal delivery, the identification of drugs compatible with the nasal cavity, the selection of dosage forms to surmount limited drug-loading capacity and poor solubility, and the identification of diseases amenable to the intranasal delivery strategy. Overall, this review furnishes a perspective aimed at galvanizing future research and development concerning intranasal drug delivery.

Targeted Delivery of Geraniol via Hyaluronic Acid-Conjugation Enhances Its Anti-Tumor Activity Against Prostate Cancer.

Background: Targeted delivery systems have been developed to improve cancer treatment by reducing side effects and enhancing drug efficacy. Geraniol, a natural product, has demonstrated promising anti-cancer effects in various cancer types, including prostate cancer, which is the most commonly diagnosed cancer in men. Hyaluronic acid (HA), a natural carrier targeting CD44-positive prostate cancer cells, can be utilized in a targeted delivery system. Purpose: This study investigated the efficacy of a conjugate of HA and geraniol linked via a disulfide bond linker (HA-SS-Geraniol) in prostate cancer. Materials and Methods: The cytotoxicity of HA-SS-Geraniol was evaluated on human PC-3 prostate cancer cells. Flow cytometry was used to assess its effects on mitochondrial membrane potential, apoptosis, and cell cycle arrest. Additionally, proteomic analysis was conducted to explore the underlying mechanism of action induced by HA-SS-Geraniol treatment. A subcutaneous xenograft tumor model was established in nude mice to evaluate the toxicity and efficacy of HA-SS-Geraniol in vivo. Results: The results demonstrated that HA-SS-Geraniol exhibited potent cytotoxicity against PC-3 prostate cancer cells by inducing mitochondrial membrane potential loss and apoptosis in vitro. The proteomic analysis further supported the hypothesis that HA-SS-Geraniol induces cell death through mitochondria-mediated apoptosis, as evidenced by differential protein expression. The in vivo mouse model confirmed the safety of HA-SS-Geraniol and its ability to inhibit tumor growth. Conclusion: HA-SS-Geraniol holds promise as a biologically safe and potentially effective therapeutic agent for prostate cancer treatment. Its targeted delivery system utilizing HA as a carrier shows potential for improving the efficacy of geraniol in cancer therapy.

USP29 activation mediated by FUBP1 promotes AURKB stability and oncogenic functions in gastric cancer.

BACKGROUND: Gastric cancer is a highly prevalent cancer type and the underlying molecular mechanisms are not fully understood. Ubiquitin-specific peptidase (USP) 29 has been suggested to regulate cell fate in several types of cancer, but its potential role in gastric carcinogenesis remains unclear. METHODS: The expression of USP29 in normal and gastric cancer tissues was analyzed by bioinformatics analysis, immunohistochemistry and immunoblot. Gene overexpression, CRISPR-Cas9 technology, RNAi, and Usp29 knockout mice were used to investigate the roles of USP29 in cell culture, xenograft, and benzo[a]pyrene (BaP)-induced gastric carcinogenesis models. We then delineated the underlying mechanisms using mass spectrometry, co-immunoprecipitation (Co-IP), immunoblot, ubiquitination assay, chromatin immunoprecipitation (ChIP), quantitative real-time PCR (qRT-PCR), and luciferase assays. RESULTS: In this study, we found that USP29 expression was significantly upregulated in gastric cancers and associated with poor patient survival. Ectopic expression of USP29 promoted, while depletion suppressed the tumor growth in vitro and in vivo mouse model. Mechanistically, transcription factor far upstream element binding protein 1 (FUBP1) directly activates USP29 gene transcription, which then interacts with and stabilizes aurora kinase B (AURKB) by suppressing K48-linked polyubiquitination, constituting a FUBP1-USP29-AURKB regulatory axis that medicates the oncogenic role of USP29. Importantly, systemic knockout of Usp29 in mice not only significantly decreased the BaP-induced carcinogenesis but also suppressed the Aurkb level in forestomach tissues. CONCLUSIONS: These findings uncovered a novel FUBP1-USP29-AURKB regulatory axis that may play important roles in gastric carcinogenesis and tumor progression, and suggested that USP29 may become a promising drug target for cancer therapy.

Gastric cancer patient-derived organoids model for the therapeutic drug screening.

BACKGROUND: Gastric cancer (GC) is a highly heterogeneous disease featuring many various histological and molecular subtypes. Therefore, it is imperative to have well-characterized in vitro models for personalized treatment development. Gastric cancer patient-derived organoids (PDOs), re-capitulating in vivo conditions, exhibit high clinical efficacy in predicting drug sensitivity to facilitate the development of cancer precision medicine. METHODS: PDOs were established from surgically resected GC tumor tissues. Histological and molecular characterization of PDOs and primary tissues were performed via IHC and sequencing analysis. We also conducted drug sensitivity tests using PDO cultures with five chemotherapeutic drugs and twenty-two targeted drugs. RESULTS: We have successfully constructed a PDOs biobank that included EBV+, intestinal/CIN, diffuse/GS, mixed and Her2+ GC subtypes, and these PDOs captured the pathological and genetic characteristics of corresponding tumors and exhibited different sensitivities to the tested agents. In a clinical case study, we performed an additional drug sensitivity test for a patient who reached an advanced progressive stage after surgery. We discovered that the combination of napabucasin and COTI-2 exhibited a stronger synergistic effect than either drug alone. CONCLUSION: PDOs maintained the histological and genetic characteristics of original cancer tissues. PDOs biobank opens up new perspectives for studying cancer cell biology and personalized medicine as a preclinical study platform.