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ObjectiveAddressing the rising prevalence of pain disorders and limitations of current analgesics, our study explores repurposing antihypertensive drugs for pain management, inspired by the link between hypertension and pain. We leverage a drug-target Mendelian Randomization (MR) approach to explore their dual benefits and establish causal connections.MethodsA comprehensive compilation of antihypertensive drug classes was undertaken through British National Formulary, with their target genes identified using the DrugBank database. Relevant single nucleotide polymorphisms (SNPs) associated with these targets were selected from published genomic studies on systolic blood pressure (SBP) as genetic instruments. These SNPs were validated through MR against acute coronary artery disease (CAD) to ensure genes not linked to CAD were excluded from acting as proxies for antihypertensive drugs. An MR analysis of 29 pain-related outcomes was conducted using the FinnGen R10 database employing the selected and validated genetic instruments. We utilized the Inverse Variance Weighted (IVW) method for primary analysis, applying Bonferroni correction to control type I error. IVW’s multiplicative random effects (MRE) addressed heterogeneity, and MR-PRESSO managed pleiotropy, ensuring accurate causal inference.ResultsOur analysis differentiates strong and suggestive evidence in linking antihypertensive drugs to pain disorder risks. Strong evidence was found for adrenergic neuron blockers increasing migraine without aura risk, loop diuretics reducing panniculitis, and vasodilator antihypertensives lowering limb pain risk. Suggestive evidence suggests alpha-adrenoceptor blockers might increase migraine risk, while beta-adrenoceptor blockers could lower radiculopathy risk. Adrenergic neuron blockers also show a potential protective effect against coxarthrosis (hip osteoarthritis) and increased femgenpain risk (pain and other conditions related to female genital organs and menstrual cycle). Additionally, suggestive links were found between vasodilator antihypertensives and reduced radiculopathy risk, and both alpha-adrenoceptor blockers and renin inhibitors possibly decreasing dorsalgianas risk (unspecified dorsalgia). These findings highlight the intricate effects of antihypertensive drugs on pain disorders, underlining the need for further research.ConclusionThe findings indicate that antihypertensive medications may exert varied effects on pain management, suggesting a repurposing potential for treating specific pain disorders. The results advocate for further research to confirm these associations and to explore underlying mechanisms, to optimize pain management practices.

ObjectiveThis study aimed to explore the potential causal link between three specific types of occupational exposure on rheumatoid arthritis (RA) and ankylosing spondylitis (AS).MethodA Two-sample Mendelian randomization (TSMR) analysis, comprising univariate MR (UVMR) and multivariate MR (MVMR) analyses, was performed to investigate the potential causal association between three types of occupational exposures, jobs involving mainly walking or standing (JWS), jobs involving heavy manual or physical work (JMP), and jobs involving shift work(JSW) on RA and AS. Genetic variants for genome-wide association studies (GWAS) of occupational exposure and AS were obtained from the UK Biobank. GWAS summary data for RA were obtained from FinnGen Biobank analysis. For UVMR, six methods of Inverse Variance Weighted (IVW), MR-Egger, Weighted Mode, Weighted Median, Simple Mode, MR pleiotropy residual sum, and outlier (MR-PRESSO) were used for the analysis. The MVMR was analyzed using the IVW model as well as the MR-Egger model.ResultsThe UVMR suggested no causal relationship between the three occupational exposure and RA [IVW: P=0.59,0.21,0.63] or AS [IVW: P=0.43,0.57,0.04], as did the bidirectional MR [IVW: P=0.73,0.70,0.16], [IVW: P=0.65,0.68,0.74]. Although unadjusted MVMR suggested a causal relationship between JMP and AS [IVW: OR = 1.01, 95% CI = 1.00- 1.02, p = 0.02], the adjusted MVMR denied this relationship and concluded that there was no causal relationship between the other occupational exposure and either RA or AS.ConclusionOur MR analysis did not establish a direct causal relationship between certain occupational exposures and either RA or AS.

Biosynthesis of the flavonoid naringenin in plants and bacteria is commonly catalysed by a type III polyketide synthase (PKS) using one p-coumaroyl-CoA and three malonyl-CoA molecules as substrates. Here, the authors report a fungal non-ribosomal peptide synthetase PKS hybrid FnsA catalysing the formation of naringenin.

Abstract Background Knee osteoarthritis (KOA) is one of the most common musculoskeletal disorders. Acupotomy may be effective for KOA, but the evidence is limited. This trial aims to determine the effectiveness and safety of acupotomy for KOA. Methods/design This is a parallel-group, assessor-blinded randomized controlled trial. Two hundred patients with KOA will be recruited and randomly assigned to two groups (group A or group D) in a 1:1 ratio. Patients in group A will receive acupotomy and topical diclofenac diethylamine for 4 weeks, while patients in group D will receive topical diclofenac diethylamine alone for 4 weeks. The primary outcome will be the response rate—the proportion of patients who achieve the minimal clinically important improvement in pain and function at week 4 compared with baseline. Secondary outcomes will include pain, function, quality of life, the use of rescue medicine (loxoprofen sodium), and adverse events at weeks 4, 8, and 24 after randomization. Besides, joint fluid and serum will be collected to assess the level of inflammatory cytokines, like TNF-α, IL-1β, and MMP-3. Discussion This study will contribute to a better understanding of the effectiveness and safety of acupotomy in combination with topical nonsteroidal anti-inflammatory drugs. If the hypothesis is confirmed, acupotomy may be recommended as adjunctive therapy for patients with KOA. Results of the study will be of great importance for the guidelines of clinical therapy. Trial registration Chinese Clinical Trial Registry ChiCTR2100043005 Registered on 4 February 2021.

Oxepinamides are a class of fungal oxepins with biological activities. Here, the authors elucidate the biosynthetic pathway of oxepinamide F from Aspergillus ustus and show that it involves enyme-catalysed oxepin ring formation, hydroxylation-induced double bond migration, epimerization and methylation.

Fungi are important sources for the discovery of natural products. During the last decades, technological progress and the increasing number of sequenced genomes facilitated the exploration of new secondary metabolites. Among those, polyketides represent a structurally diverse group with manifold biological activities. In this study, we successfully used genome mining and genetic manipulation for functional proof of a polyketide biosynthetic gene cluster from the filamentous fungus Penicillium crustosum. Gene activation in the native host and heterologous expression in Aspergillus nidulans led to the identification of the xil cluster, being responsible for the formation of the 6-methyl-2-pyrone derivative xylariolide D. Feeding with 13C-labeled precursors supported the hypothesis of chain branching during the backbone formation catalyzed by a highly reducing fungal polyketide synthase. A cytochrome P450-catalyzed hydroxylation converts the PKS product to the final metabolite. This proved that just two enzymes are required for the biosynthesis of xylariolide D.

(1) Background: Extracellular vesicles (EVs) are considered to be efficient nanocarriers for improved drug delivery and can be derived from mammalian or plant cells. Cucumber-derived EVs are not yet described in the literature. Therefore, the aim of this study was to produce and characterize cucumber-derived EVs and to investigate their suitability to improve the dermal penetration efficacy of a lipophilic active ingredient (AI) surrogate. (2) Methods: The EVs were obtained by classical EVs isolation methods and by high pressure homogenization (HPH). They were characterized regarding their physico-chemical and biopharmaceutical properties. (3) Results: Utilization of classical isolation and purification methods for EVs resulted in cucumber-derived EVs. Their dermal penetration efficacy for the AI surrogate was 2-fold higher when compared to a classical formulation and enabled a pronounced transdermal penetration into the viable dermis. HPH resulted in submicron sized particles composed of a mixture of disrupted plant cells. A successful isolation of pure EVs from this mixture was not possible with classical EVs isolation methods. The presence of EVs was, therefore, proven indirectly. For this, the lipophilic drug surrogate was admixed to the cucumber juice either prior to or after HPH. Admixing of the drug surrogate to the cucumber prior to the HPH resulted in a 1.5-fold increase in the dermal penetration efficacy, whereas the addition of the AI surrogate to the cucumber after HPH was not able to improve the penetration efficacy. (4) Conclusions: Results, therefore, indicate that HPH causes the formation of EVs in which AI can be incorporated. The formation of plant EVs by HPH was also indicated by zeta potential analysis.

Background: Successful antiretroviral therapy (ART) has been demonstrated to be effective in reducing the infectivity of human immunodeficiency virus (HIV). We conducted a study to predict the potential effect of ART on the spread of HIV in Chaoyang District, Beijing, China, using the Asian Epidemic Model (AEM). Methods: The AEM baseline workbook was used to determine the current infection status and to project the future spread of HIV under current conditions. We changed the input on the ART coverage from 2014 to 2025 and also modified the treatment eligibility in the AEM intervention workbook, in order to allow for analysis of the projected downstream impact of ART. Results: By gradually increasing the ART coverage rate from 29.7% (rate of 2013) to 40.0%, 50.0%, 60.0%, 70.0%, 80.0%, and 90.0% (at CD4+ ≤350 cells/μl), and by changing the dates of coverage from 2014 to 2020, the number of new infections showed a cumulative decline of 0.60%, 1.59%, 2.94%, 5.33%, 9.32%, and 14.98%, respectively. After 2020, the projected rates of infection rebounded slightly, so with the exception of the years with very high coverage (90.0%), new infections continued to decrease. When we changed the initial threshold of therapy to CD4+ cell counts ≤500 cells/μl, new infections decreased 6.00%, 11.64%, 15.92%, 21.11%, 26.92%, 33.05%, and 38.75%, respectively, under varying ART coverages. Conclusion: Our study demonstrates that the early initiation of ART for people living with HIV/acquired immune deficiency syndrome (AIDS) has a positive effect in slowing the spread of HIV.

Background. Systemic inflammation impairs cognitive performance, yet the brain networks mediating this process remain to be elucidated. The purpose of the current study was to use resting-state functional magnetic resonance imaging (fMRI) to explore changes in the functional connectivity in a lipopolysaccharide- (LPS-) induced systemic inflammation animal model. Materials and Methods. We used the regional homogeneity (ReHo) method to examine abnormal brain regions between the control and LPS groups and then considered them as seeds of functional connectivity analysis. Results. Compared with the control group, our study showed that (1) LPS impaired mood function, as reflected by a depression-like behavior in the forced swim test; (2) LPS induced significantly increased ReHo values in the anterior cingulate cortex (ACC) and caudate putamen (CPu); (3) the ACC seed showed increased functional connectivity with the retrosplenial cortex, superior colliculus, and inferior colliculus; and (4) the right CPu seed showed increased functional connectivity with the left CPu. Linear regression analysis showed a LPS-induced depression-like behavior which was associated with increased ReHo values in the ACC and right CPu. Moreover, the LPS-induced depression-like behavior was related to increased functional connectivity between the right CPu and left CPu. Conclusion. This is the first study to show that systemic inflammation impairs mood function that is associated with an altered resting-state functional network based on ReHo analysis, providing evidence of the abnormal regional brain spontaneous activity which might be involved in inflammation-related neurobehavioral abnormalities.

Clavicipitaceous fungi producing ergot alkaloids were recently discovered to be epibiotically associated with peltate glandular trichomes of Ipomoea asarifolia and Turbina corymbosa, dicotyledonous plants of the family Convolvulaceae. Mediators of the close association between fungi and trichomes may be sesquiterpenes, main components in the volatile oil of different convolvulaceous plants. Molecular biological studies and microscopic investigations led to the observation that the trichomes do not only secrete sesquiterpenes and palmitic acid but also seem to absorb ergot alkaloids from the epibiotic fungal species of the genus Periglandula. Thus, the trichomes are likely to have a dual and key function in a metabolic dialogue between fungus and host plant.

Ergot alkaloids are nitrogen-containing natural products belonging to indole alkaloids. The best known producers are fungi of the phylum Ascomycota, e.g., Claviceps, Epichloë, Penicillium and Aspergillus species. According to their structures, ergot alkaloids can be divided into three groups: clavines, lysergic acid amides and peptides (ergopeptines). All of them share the first biosynthetic steps, which lead to the formation of the tetracyclic ergoline ring system (except the simplest, tricyclic compound: chanoclavine). Different modifications on the ergoline ring by specific enzymes result in an abundance of bioactive natural products, which are used as pharmaceutical drugs or precursors thereof. From the 1950s through to recent years, most of the biosynthetic pathways have been elucidated. Gene clusters from several ergot alkaloid producers have been identified by genome mining and the functions of many of those genes have been demonstrated by knock-out experiments or biochemical investigations of the overproduced enzymes.

Ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLCâQ-TOF/MS) was developed to identify the absorbed parent components and metabolites in rat bile, plasma and urine after oral administration of Radix Paeoniae Alba extract (RPAE). A total of 65 compounds were detected in rat bile, plasma and urine samples, including 11 parent compounds and 54 metabolites. The results indicated that glucuronidation, hydroxylation and methylation were the major metabolic pathways of the components of RPAE. Furthermore, the results of this work demonstrated that UPLCâQ-TOF/MS combined with MetaboLynx⢠software and mass defect filtering (MDF) could provide unique high throughput capabilities for drug metabolism study, with excellent MS mass accuracy and enhanced MSE data acquisition. With the MSE technique, both precursor and fragment mass spectra can be simultaneously acquired by alternating between high and low collision energy during a single chromatographic run. Keywords: Radix Paeoniae Alba, Metabolite profiling, UPLCâQ-TOF/MS, Monoterpene glycosides

Cellulose-silica composite fiber samples have been successfully synthesized using cellulose solution, tetraethoxysilane, and NH3•H2O in ethanol/water mixed solvents at room temperature for 24 h. The cellulose solution was previously prepared by the dissolution of microcrystalline cellulose in a solvent mixture of N,N-dimethylacetamide (DMAc)/lithium chloride (LiCl). The effect of the tetraethoxysilane concentration on the product was investigated. The products were characterized by X-ray powder diffraction (XRD), thermogravimetric analysis (TG), differential scanning calorimetric analysis (DSC), scanning electron microscopy (SEM), Fourier transform infrared spectrometry (FT-IR), energy-dispersive X-ray spectrum (EDS), and cross polarization magic angle spinning (CP/MAS) solid state 13C-NMR. The morphology of the cellulose-silica composite fiber was investigated by SEM, while their composition was established from EDS measurements combined with the results of FT-IR spectral analysis and XRD patterns. The XRD, FT-IR and EDS results indicated that the obtained product was cellulose-silica composite fiber. The SEM micrographs showed that the silica particles were homogeneously dispersed in the cellulose fiber. The CP/MAS solid state 13C-NMR results indicated that the silica concentration had an influence on the crystallinity of the cellulose. This method is simple for preparation of cellulose-based composites.

Abstract Background and aim China has used traditional Chinese medicine (TCM) to treat diseases for more than 2000 years. Traditionally, TCMs in medicine cabinets are arranged alphabetically or on the basis of experience, but this arrangement greatly affects dispensing efficiency. However, owing to the unique properties and qualities of TCM, very few automatic approaches or systems have specifically addressed TCM dispensing problems. Therefore, it is necessary to establish a method of optimizing the traditional Chinese medicine placement scheme (TCMPS) via computer algorithms to improve the work efficiency of pharmacists. Methods A prescription dataset from a hospital in 2022 was obtained, and the association rule algorithm (ARA) was used to calculate the frequency of use for each type of TCM and the associations between different types of TCMs. On the basis of these association and frequency data, the optimal TCMPS was calculated using the simulated annealing algorithm (SAA) and then verified using the prescription dataset from 2023. Results A total of 10,601 prescriptions were collected in 2022, involving 360 different TCMs, and each prescription contained an average of 9.485 TCMs, with Danggui (3628) being the most frequently used. When the threshold of support was set to 0.05 and the confidence was set to 0.8, 78 couplet medicines used in orthopedics clinics were found through ARA. When the threshold value of support was set to 0, the confidence was set to 0, and the rule length was 2, a total of 129,240 rules were obtained, indicating support between all pairwise TCMs. The TCMPS, calculated using SAA, had a correlation sum of 14.183 and a distance sum of 3.292. The TCMPS was verified using a prescription dataset from 2023 and theoretically improved the dispensing efficiency of pharmacists by approximately 50%. Conclusions In this study, the ARA and SAA were successfully applied to pharmacies for the first time, and the optimal TCMPS was calculated. This approach not only significantly improves the dispensing efficiency of pharmacists and reduces patient waiting time but also enhances the quality of medical services and patient satisfaction, and provides a valuable reference for the development of smart medicine.