Altered methionine metabolism impacts phenylpropanoid production and plant development in Arabidopsis thaliana.

Phenylpropanoids are specialized metabolites derived from phenylalanine. Glucosinolates are defense compounds derived mainly from methionine and tryptophan in Arabidopsis. It was previously shown that the phenylpropanoid pathway and glucosinolate production are metabolically linked. The accumulation of indole-3-acetaldoxime (IAOx), the precursor of tryptophan-derived glucosinolates, represses phenylpropanoid biosynthesis through accelerated degradation of phenylalanine ammonia lyase (PAL). As PAL functions at the entry point of the phenylpropanoid pathway, which produces indispensable specialized metabolites such as lignin, aldoxime-mediated phenylpropanoid repression is detrimental to plant survival. Although methionine-derived glucosinolates in Arabidopsis are abundant, any impact of aliphatic aldoximes (AAOx) derived from aliphatic amino acids such as methionine on phenylpropanoid production remains unclear. Here, we investigate the impact of AAOx accumulation on phenylpropanoid production using Arabidopsis aldoxime mutants, ref2 and ref5. REF2 and REF5 metabolize aldoximes to respective nitrile oxides redundantly, but with different substrate specificities. ref2 and ref5 mutants have decreased phenylpropanoid contents due to the accumulation of aldoximes. As REF2 and REF5 have high substrate specificity toward AAOx and IAOx, respectively, it was assumed that ref2 accumulates AAOx, not IAOx. Our study indicates that ref2 accumulates both AAOx and IAOx. Removing IAOx partially restored phenylpropanoid content in ref2, but not to the wild-type level. However, when AAOx biosynthesis was silenced, phenylpropanoid production and PAL activity in ref2 were completely restored, suggesting an inhibitory effect of AAOx on phenylpropanoid production. Further feeding studies revealed that the abnormal growth phenotype commonly observed in Arabidopsis mutants lacking AAOx production is a consequence of methionine accumulation.

ProBDNF contributed to patrolling monocyte infiltration and renal damage in systemic lupus erythematosus.

Monocyte aberrations have been increasingly recognized as contributors to renal damage in systemic lupus erythematosus (SLE), however, recognition of the underlying mechanisms and modulating strategies is at an early stage. Our studies have demonstrated that brain-derived neurotrophic factor precursor (proBDNF) drives the progress of SLE by perturbing antibody-secreting B cells, and proBDNF facilitates pro-inflammatory responses in monocytes. By utilizing peripheral blood from patients with SLE, GEO database and spontaneous MRL/lpr lupus mice, we demonstrated in the present study that CX3CR1+ patrolling monocytes (PMo) numbers were decreased in SLE. ProBDNF was specifically expressed in CX3CR1+ PMo and was closely correlated with disease activity and the degree of renal injury in SLE patients. In MRL/lpr mice, elevated proBDNF was found in circulating PMo and the kidney, and blockade of proBDNF restored the balance of circulating and kidney-infiltrating PMo. This blockade also led to the reversal of pro-inflammatory responses in monocytes and a noticeable improvement in renal damage in lupus mice. Overall, the results indicate that the upregulation of proBDNF in PMo plays a crucial role in their infiltration into the kidney, thereby contributing to nephritis in SLE. Targeting of proBDNF offers a potential therapeutic role in modulating monocyte-driven renal damage in SLE.

P75NTR+CD64+ neutrophils promote sepsis-induced acute lung injury.

Patients suffering from sepsis-induced acute lung injury (ALI) exhibit a high mortality rate, and their prognosis is closely associated with infiltration of neutrophils into the lungs. In this study, we found a significant elevation of CD64+ neutrophils, which highly expressed p75 neurotrophin receptor (p75NTR) in peripheral blood of mice and patients with sepsis-induced ALI. p75NTR+CD64+ neutrophils were also abundantly expressed in the lung of ALI mice induced by lipopolysaccharide. Conditional knock-out of the myeloid lineage's p75NTR gene improved the survival rates, attenuated lung tissue inflammation, reduced neutrophil infiltration and enhanced the phagocytic functions of CD64+ neutrophils. In vitro, p75NTR+CD64+ neutrophils exhibited an upregulation and compromised phagocytic activity in blood samples of ALI patients. Blocking p75NTR activity by soluble p75NTR extracellular domain peptide (p75ECD-Fc) boosted CD64+ neutrophils phagocytic activity and reduced inflammatory cytokine production via regulation of the NF-κB activity. The findings strongly indicate that p75NTR+CD64+ neutrophils are a novel pathogenic neutrophil subpopulation promoting sepsis-induced ALI.

Catalyst-free reactions of anilines with ß-chloroenones: synthesis of α-chloroenaminones and 1,4-benzodiazepines.

The Michael addition of anilines to ß-chloroenones gives enaminones by the elimination of hydrochloric acid (HCl). These enaminones are transformed into α-chloroenaminones via in situ sp2 C-H functionalization. Anilines that are attached to an electron-donating group react more readily with ß-chloroenone to give the corresponding products in excellent yields. A highly atom-economical method has been developed using dimethyl sulfoxide (DMSO) as a green oxidant and solvent. The desired α-functionalized enaminones are formed in good yields with excellent Z-selectivity. We have established the generality of this reaction with many substrates, and scaled-up reactions have been performed to showcase the practical applications. A catalyst-free double annulation of ß-chloroenones with o-phenylenediamine has also been demonstrated for the synthesis of 1,4-benzodiazepine derivatives in moderate yields under mild reaction conditions.

Association of osteoporotic fractures of femoral neck and femoral neck geometric parameters in native Chinese women.

BACKGROUND: Although it is generally believed that the femoral neck fracture is related to the femoral neck geometric parameters (FNGPs), the association between the risk of osteoporotic fracture of the femoral neck and FNGPs in native Chinese women is still unclear. METHODS: A total of 374 female patients (mean age 70.2 ± 9.32 years) with osteoporotic fracture of the femoral neck, and 374 non-fracture control groups were completely matched with the case group according to the age ratio of 1:1. Using DXA bone densitometer to measured eight FNGPs: the outer diameter (OD), cross-sectional area (CSA), cortical thickness (CT), endocortical diameter (ED), buckling ratio (BR), section modulus (SM), cross-sectional moment of inertia (CSMI), and compressive strength index (CSI) at the narrowest point of the femoral neck. RESULTS: Compared with the control group, the average values of OD (2.9%), ED (4.5%), and BR (26.1%) in the patient group significantly increased (p = 0.015 to < 0.001), while CSA (‒15.3%), CT (‒18.2%), SM (‒10.3%), CSMI (‒6.4%), and CSI (‒10.8%) significantly decreased (all p < 0.001). The prevalence of osteoporosis in the lumbar spine, femoral neck, and total hip was, respectively, 82%, 81%, and 65% in fracture patients. Cox proportional hazard model analysis showed that in the age adjusted model, the fracture hazard ratio (HR) of CSA, CT, BR, SM, and CSI significantly increased (HRs = 1.60‒8.33; 95% CI = 1.08‒16.6; all p < 0.001). In the model adjusted for age and femoral neck BMD, HRs of CT (HRs = 3.90‒8.03; 95% CI = 2.45‒15.1; all p < 0.001) and BR (HRs = 1.62‒2.60; 95% CI = 1.20‒5.44; all p < 0.001) were still significantly increased. CONCLUSION: These results suggest that the majority of osteoporotic fractures of the femoral neck of native Chinese women occur in patients with osteoporosis. CT thinning or BR increase of FNGPs may be independent predictors of fragility fracture of femoral neck in native Chinese women unrelated to BMD.

Effectiveness and safety of the ablative fractional 2940-nm Er: YAG laser for the treatment of androgenetic alopecia.

Laser sources have established their potential effect in inducing hair regrowth. No large cohort study has evaluated the effect of ablative fractional 2940-nm erbium yttrium aluminum garnet (Er: YAG) laser in the treatment of androgenetic alopecia (AGA). To investigate the efficacy and safety of the ablative fractional 2940-nm Er: YAG laser in combination with medication therapy for the treatment of AGA. We performed a retrospective study between first July 2021 to 30th December 2021. All included patients received oral finasteride and topical minoxidil, or combined with six sessions of Er: YAG laser at 2-week intervals. Patients were divided into medication or combined therapy groups. The efficacy of the two therapies was evaluated by the investigator's Global Assessment (IGA) scores and the patient's Likert satisfaction scale at week 12 and week 24. Changes in total, terminal and villous hair count, total and terminal hair diameter, and AGA grade were also recorded. Adverse events were evaluated at each follow-up. A total of 192 male patients with AGA were included, including 67 receiving combination treatment, and 125 receiving medication treatment. At week 24, the combination treatment afforded superior outcomes in the IGA score, patient's global assessment, total and terminal hair counts, and diameters (all P<0.05). No severe adverse events were reported in both groups. The combined therapy of ablative fractional Er: YAG laser and medication was superior in treating male AGA than single medication therapy without serious adverse effects.

Laser acupuncture and photobiomodulation therapy in Bell's palsy with a duration of greater than 8 weeks: a randomized controlled trial.

To investigate the efficacy of laser acupuncture and photobiomodulation therapy in alleviating symptoms among patients diagnosed with Bell's palsy with duration of greater than 8 weeks. The randomized controlled trial has been performed from May 2021 to April 2023. Patients were eligible who had Bell's palsy with duration of greater than 8 weeks on out-patient Department of Otorhinolaryngology in Beijing Tongren Hospital. The laser acupuncture group received class IV laser treatment for 3 times per weeks, a total of 72 times. The control group received the same treatment procedure except the laser parameter. The primary outcome measures comprised House-Brackmann facial nerve grading system and electroneurography. Secondary outcome measures comprised Sunnybrook facial grading system, electromyography, and the blink reflex. A total of 84 participants were included (42 control group, 42 laser acupuncture group). After treatment, House-Brackmann facial nerve grading system (OR, 0.11; 95% CI, 0.04-0.30; P < 0.001), and the pathologic numbers of electroneuronography were statistically different between the laser acupuncture group and control group, including orbicularis oculi (OR,0.08; 95% CI, 0.02-0.21; P < 0.001), Frontalis muscle (OR,0.14; 95% CI, 0.05-0.39; P < 0.001), Orbicularis oris (OR,0.13; 95% CI, 0.04-0.36; P < 0.001), Ala nasi muscle (OR,0.06; 95% CI, 0.02-0.18; P < 0.001). In secondary outcomes, Sunnybrook facial grading system, has significant difference between the two groups (20.26; 95% CI, 14.69 to 25.83; P < 0.01). Latency by ENoG, include orbicularis oculi (-0.61; 95% CI, -0.43 to -0.09; P < 0.001), frontalis muscle (-0.12; 95% CI, -0.21 to -0.03; P < 0.01), orbicularis oris (-0.28; 95% CI, -0.41 to -0.16; P < 0.001), and ala nasi muscle (-0.26; 95% CI, -0.38 to -0.16; P < 0.001). All amplitudes of MUAPs and durations by electromyography (EMG) showed statistically significant differences compared with the control group after treatment. For the frontalis muscle, the amplitude of MUAPs was -64.23 (95% CI, -80.89 to -47.56; P < 0.001) and duration was -1.18 (95% CI, -1.49 to -0.87; P < 0.001). For orbicularis oris, amplitude of MUAPs was -29.82 (95% CI, -55.03 to -4.62; P = 0.02) and duration was -0.57 (95% CI, -0.94 to -0.20; P < 0.001). For depressor angulli oris, amplitude of MUAPs was -47.06 (95% CI, -62.15 to -31.97; P < 0.001) and duration was -2.21 (95% CI, -2.69 to -1.72; P < 0.001). Blink reflex, including R1 (OR, 0.03; 95% CI, 0.01-0.16; P < .001), R2 (OR, 0.04; 95% CI, 0.004-0.29; P < .001), and R2 latency differences (OR, 0.15; 95% CI, 0.05-0.51; P < .001), have significant difference between the two groups, respectively. The findings suggest that laser acupuncture relieve symptoms for patients with Bell's palsy with a duration of greater than 8 weeks.Trial registration: ClinicalTrials.gov Identifier: NCT05846217.

Metabolic link between auxin production and specialized metabolites in Sorghum bicolor.

Aldoximes are amino acid derivatives that serve as intermediates for numerous specialized metabolites including cyanogenic glycosides, glucosinolates, and auxins. Aldoxime formation is mainly catalyzed by cytochrome P450 monooxygenases of the 79 family (CYP79s) that can have broad or narrow substrate specificity. Except for SbCYP79A1, aldoxime biosynthetic enzymes in the cereal sorghum (Sorghum bicolor) have not been characterized. This study identified nine CYP79-encoding genes in the genome of sorghum. A phylogenetic analysis of CYP79 showed that SbCYP79A61 formed a subclade with maize ZmCYP79A61, previously characterized to be involved in aldoxime biosynthesis. Functional characterization of this sorghum enzyme using transient expression in Nicotiana benthamiana and stable overexpression in Arabidopsis thaliana revealed that SbCYP79A61 catalyzes the production of phenylacetaldoxime (PAOx) from phenylalanine but, unlike the maize enzyme, displays no detectable activity against tryptophan. Additionally, targeted metabolite analysis after stable isotope feeding assays revealed that PAOx can serve as a precursor of phenylacetic acid (PAA) in sorghum and identified benzyl cyanide as an intermediate of PAOx-derived PAA biosynthesis in both sorghum and maize. Taken together, our results demonstrate that SbCYP79A61 produces PAOx in sorghum and may serve in the biosynthesis of other nitrogen-containing phenylalanine-derived metabolites involved in mediating biotic and abiotic stresses.

Iodine-Catalyzed Regioselective Synthesis of Diphenyl-Substituted Carbazoles via [4 + 2] Annulation of ß-Formyl Ketones with Indoles.

The [4 + 2] annulation of ß-formyl ketones with an indole has been developed for the regioselective synthesis of diphenyl-substituted carbazoles in the presence of a catalytic amount of iodine. The 1,4-dicarbonyl compound containing a phenyl group at the α-position of an aldehyde group reacts more readily with indoles to form carbazole derivatives. Using this method, a variety of carbazole derivatives can be readily accessed under mild reaction conditions.

A phase III randomized, double-blind, placebo-controlled trial of the denosumab biosimilar QL1206 in postmenopausal Chinese women with osteoporosis and high fracture risk.

The current study evaluated the efficacy and safety of a denosumab biosimilar, QL1206 (60 mg), compared to placebo in postmenopausal Chinese women with osteoporosis and high fracture risk. At 31 study centers in China, a total of 455 postmenopausal women with osteoporosis and high fracture risk were randomly assigned to receive QL1206 (60 mg subcutaneously every 6 months) or placebo. From baseline to the 12-month follow-up, the participants who received QL1206 showed significantly increased bone mineral density (BMD) values (mean difference and 95% CI) in the lumbar spine: 4.780% (3.880%, 5.681%), total hip :3.930% (3.136%, 4.725%), femoral neck 2.733% (1.877%, 3.589%) and trochanter: 4.058% (2.791%, 5.325%) compared with the participants who received the placebo. In addition, QL1206 injection significantly decreased the serum levels of C-terminal crosslinked telopeptides of type 1 collagen (CTX): -77.352% (-87.080%, -66.844%), and N-terminal procollagen of type l collagen (P1NP): -50.867% (-57.184%, -45.217%) compared with the placebo over the period from baseline to 12 months. No new or unexpected adverse events were observed. We concluded that compared with placebo, QL1206 effectively increased the BMD of the lumbar spine, total hip, femoral neck and trochanter in postmenopausal Chinese women with osteoporosis and rapidly decreased bone turnover markers. This study demonstrated that QL1206 has beneficial effects on postmenopausal Chinese women with osteoporosis and high fracture risk.