The systemic treatments for drug reaction with eosinophilia and systemic symptoms (DRESS) beyond corticosteroids.

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DiHS), is a severe type of cutaneous adverse reaction. The gold standard therapy for DRESS involves the discontinuation of the culprit drug, supportive therapies, and administration of corticosteroids. However, in cases of primary treatment failure or suboptimal response, there arises an urgent need for alternative interventions. This review focuses on exploring alternative systemic therapies for patients with steroid-resistant DRESS, steroid-dependent DRESS, or refractory DRESS, encompassing immunosuppressive agents, intravenous immunoglobulin, plasmapheresis, biologics, and small molecule drugs, with an emphasis on their clinical efficacy and the underlying mechanisms in the treatment of DRESS. Furthermore, this review provides a summary of potential management strategies and laboratory workup during the treatment of DRESS.

Tumor necrosis factor inhibitors enhance corticosteroid therapy for Stevens-Johnson syndrome and toxic epidermal necrolysis linked to immune checkpoint inhibitors: a prospective study.

Introduction: Immune-related epidermal necrolysis (irEN), including Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), represents a potentially lethal reaction to immune checkpoint inhibitors. An optimal treatment strategy remains undefined. This study evaluates the effectiveness and safety of combination therapy with corticosteroids and tumor necrosis factor inhibitors (TNFi) in treating irEN patients. Methods: In this single-center, prospective, observational study, patients with irEN received either corticosteroid monotherapy or a combination therapy of corticosteroids and TNFi (etanercept for SJS, infliximab for TEN). The primary endpoint was re-epithelization time, with secondary endpoints including corticosteroid exposure, major adverse event incidence, acute mortality rates, and biomarkers indicating disease activity and prognosis. The study was registered at the Chinese Clinical Trial Registry (ChiCTR2100051052). Results: Thirty-two patients were enrolled (21 SJS, 11 TEN); 14 received combination therapy and 18 received corticosteroid monotherapy. IrEN typically occurred after 1 cycle of ICI administration, with a median latency of 16 days. Despite higher SCORTEN scores in the combination group (3 vs. 2, p = 0.008), these patients experienced faster re-epithelization (14 vs. 21 days; p < 0.001), shorter corticosteroid treatment duration (22 vs. 32 days; p = 0.005), and lower prednisone cumulative dose (1177 mg vs. 1594 mg; p = 0.073). Major adverse event rates were similar between groups. Three deaths occurred due to lung infection or disseminated intravascular coagulation, with mortality rates for both groups lower than predicted. Potential risk factors for increased mortality included continuous reduction in lymphocyte subset counts (CD4+ T cells, CD8+ T cells, natural killer cells) and consistent rises in inflammatory markers (serum ferritin, interleukin-6, TNF-α). Re-epithelization time negatively correlated with body mass index and positively correlated with epidermal detachment area and serum levels of interleukin-6 and TNF-α. Conclusions: Corticosteroids combined with TNFi markedly promote re-epithelization, reduce corticosteroid use, and decrease acute mortality in irEN patients without increasing major adverse events, offering a superior alternative to corticosteroid monotherapy. Inflammatory markers and lymphocyte subsets are valuable for assessing disease activity and prognosis.

Stevens-Johnson syndrome and toxic epidermal necrolysis associated with immune checkpoint inhibitors: a systematic review.

Introduction: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare yet life-threatening adverse events associated with immune checkpoint inhibitors (ICIs). This systematic review synthesizes the current literature to elucidate the clinical characteristics and outcomes of patients with ICI-related SJS/TEN. Methods: We conducted a thorough search across databases including Embase, Web of Science, Cochrane, MEDLINE, Scopus, and PubMed. Selection criteria focused on reports of SJS/TEN among cancer patients treated with ICIs, analyzing clinical manifestations, therapeutic interventions, and outcomes. Results: Our analysis included 47 articles involving 50 patients with ICI-related SJS/TEN. The cohort had a mean age of 63 years, with a slight male predominance (54%). Most patients had melanoma or non-small cell lung cancer. SJS/TEN typically occurred early, with a median onset of 23 days post-ICI initiation. Treatment primarily involved systemic corticosteroids and intravenous immunoglobulins. The overall mortality rate was 20%, higher for TEN at 32%, with infections and tumor progression as leading causes. Median time from onset to death was 28 days. Survivors experienced a median re-epithelization time of 30 days, positively correlated with the extent of epidermal detachment (rs = 0.639, p = 0.009). Deceased patients exhibited a significantly higher proportion of TEN (90% vs. 48%, p = 0.029) and a larger epidermal detachment area (90% vs. 30% of the body surface area [BSA], p = 0.005) compared to survivors. The combination therapy group showed a higher proportion of TEN compared to corticosteroid monotherapy or non-corticosteroid therapy groups (72% vs. 29% and 50%, p = 0.01), with no significant differences in mortality or re-epithelization time. Dual ICI therapy resulted in a higher TEN rate than single therapy (100% vs. 50%, p = 0.028). Among single ICI therapies, the sintilimab-treated group trended towards a higher TEN rate (75% vs. 40-50%, p = 0.417), a larger detachment area (90% vs. 30-48% of BSA, p = 0.172), and a longer re-epithelization time (44 vs. 14-28 days, p = 0.036) compared to other ICI groups, while mortality rates remained similar. Conclusion: ICI-related SJS/TEN substantially impacts patient outcomes. Prospective clinical trials are critically needed to further clarify the pathogenesis and optimize therapeutic regimens.

Pharmacological Research Progress of Novel Antihypertensive Drugs.

Cardiovascular disease stands as the leading cause of death globally, with hypertension emerging as an independent risk factor for its development. The worldwide prevalence of hypertension hovers around 30%, encompassing a staggering 1.2 billion patients, and continues to escalate annually. Medication plays a pivotal role in managing hypertension, not only effectively regulating blood pressure (BP) but also substantially mitigating the occurrence of cardiovascular and cerebrovascular diseases. This review comprehensively outlines the categories, mechanisms, clinical applications, and drawbacks of conventional antihypertensive drugs. It delves into the five primary pharmacological classifications, namely ß-receptor blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and diuretics. The emphasis is placed on elucidating the mechanisms, advantages, and research progress of novel antihypertensive drugs targeting emerging areas. These include mineralocorticoid receptor antagonists (MRAs), atrial natriuretic peptides (ANPs), neutral endopeptidase inhibitors (NEPIs), sodium-dependent glucose transporter 2 inhibitors (SGLT-2Is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) agonists, brain aminopeptidase A inhibitors (APAIs), and small interfering ribonucleic acids (siRNAs) targeting hepatic angiotensinogen. Compared to conventional antihypertensive drugs, these novel alternatives exhibit favorable antihypertensive effects with minimal adverse reactions. This review serves as a valuable reference for future research and the clinical application of antihypertensive drugs.

Gender differences in geriatric depressive symptoms in urban China: the role of ADL and sensory and communication abilities.

Objectives: ADL and Sensory and Communication Abilities are important indicators of the quality of life of the elderly which are significant determinants of health, particularly in developing countries. The present cross-sectional study investigated effect of ADL and Sensory and Communication Abilities on depressive symptoms, as well as the the role of gender in these effects. Design: This is a cross-sectional study. Setting: A nationally representative cross-sectional survey among the Chinese population aged 60 years and over. Participants: A total of 163296 females and 148724 males aged 65 and over in 2019 in urban China. Outcome measures: Prevalence, risk factors and gender differences in geriatric depressive symptoms among urban elderly. Results: Approximately 95.69% of the participants had depressive symptoms according to the CESD-10, with no statistically significant gender difference of 52.15% in females and 47.85% in males. Logistic regression findings suggest that geriatric depressive symptoms are significantly associated with the lack of eldercare (OR=2.427, female; OR=1.426, male), living alone(OR= 1.430, female; OR= 1.179, male), ADL dysfunction (OR=1.528, female; OR=1.246, male), and impaired sensory and communication ability (OR=1.338, female; OR=1.185, male) among both female and male participants. Remarkably, geriatric depressive symptoms are only significantly associated with age (≥75, OR = 1.327), marital status (unmarried, OR=1.598), the number of children (no children, OR=2.271), and the living arrangement (living alone, OR= 1.430) among female participants. Conclusion: Significant gender differences in these associations were found for living alone, ADL dysfunction and impaired sensory and communication ability. Moreover, the study emphasized that the gender difference exists in terms of geriatric depression in urban China. Females are more likely to experience depressive than males with the same circumstances.

Interleukin-17A Inhibitors in Patients with Psoriasis and Tuberculosis Infection: A 2-Year Prospective Study on Safety Without Preventive Treatment.

INTRODUCTION: The necessity for tuberculosis preventive treatment (TPT) and routine T-SPOT.TB monitoring in patients with psoriasis and tuberculosis infection (TBI) undergoing interleukin (IL)-17A inhibitor therapy remains uncertain. This study aims to evaluate the long-term safety of IL-17A inhibitors administered without TPT and analyze changes in T-SPOT.TB among these patients. It also identifies risk factors for TBI in patients with psoriasis. METHODS: This single-center prospective study enrolled adult patients with plaque psoriasis and TBI receiving IL-17A inhibitors. TBI was defined as positive T-SPOT.TB results (≥ 6 spots) without symptoms or evidence of active tuberculosis (ATB). TPT administration was based on contraindications, tuberculosis risk factors, and patient preferences. The primary endpoint was the incidence of ATB over 2 years. Secondary outcomes included T-SPOT.TB changes and TBI risk factors. RESULTS: Of the 129 patients with psoriasis and TBI enrolled in the study, 97 (75.2%) did not receive TPT, while 32 (24.8%) did. Among them, 109 patients (84.5%) completed the 2-year follow-up. During the 235 person-years of observation, no ATB cases were identified. Median T-SPOT.TB values showed no significant changes from baseline to year 2 in both the non-TPT (20 vs. 17 spots, p = 0.975) and TPT groups (55 vs. 58 spots, p = 0.830). T-SPOT.TB reversed in 14 patients (12.8%), mostly in the non-TPT group. Moreover, for TBI risk factor analysis, a cohort of 212 patients with psoriasis with negative baseline T-SPOT.TB was evaluated, revealing a TBI prevalence of 37.8%. Logistic regression analysis highlighted age ≥ 45 years (odds ratio [OR] 2.44, 95% confidence interval [CI] 1.50-3.99, p < 0.001) and body mass index (BMI) < 24.0 kg/m2 (OR 2.12, 95% CI 1.27-3.54, p = 0.004) as independent risk factors for TBI. CONCLUSION: IL-17A inhibitors do not appear to reactivate tuberculosis in patients with psoriasis and TBI, potentially reducing the need for routine TBI screening and preventive treatment. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100045823.

Chronic intermittent hypoxia-induced oxidative stress activates TRB3 and phosphorylated JNK to mediate insulin resistance and cell apoptosis in the pancreas.

This study explores the potential mechanisms of obstructive sleep apnoea (OSA) complicates type 2 diabetes mellitus (T2DM) by which chronic intermittent hypoxia (CIH) induces insulin resistance and cell apoptosis in the pancreas through oxidative stress. Four- and eight-week CIH rat models were established, and Tempol (100 mg/kg/d), was used as an oxidative stress inhibitor. This study included five groups: 4-week CIH, 4-week CIH-Tempol, 8-week CIH, 8-week CIH-Tempol and normal control (NC) groups. Fasting blood glucose and insulin levels were measured in the serum. The expression levels of 8-hidroxy-2-deoxyguanosine (8-OHdG), tribbles homologue 3 (TRB3), c-Jun N-terminal kinase (JNK), phosphorylated JNK (p-JNK), insulin receptor substrate-1 (IRS-1), phosphorylated IRS-1 (Ser307) (p-IRS-1ser307 ), protein kinase B (AKT), phosphorylated AKT (Ser473) (p-AKTser473 ), B cell lymphoma protein-2 (Bcl-2), cleaved-caspase-3 (Cl-caspase-3), and the islet cell apoptosis were detected in the pancreas. CIH induced oxidative stress in the pancreas. Compared with that in the NC group and CIH-Tempol groups individually, the homeostasis model assessment of insulin resistance (HOMA-IR) and apoptosis of islet cells was increased in the CIH groups. CIH-induced oxidative stress increased the expression of p-IRS-1Ser307 and decreased the expression of p-AKTSer473 . The expression levels of TRB3 and p-JNK were higher in the CIH groups than in both the CIH-Tempol and NC groups. Meanwhile, the expressions of Cl-caspase-3 and Bcl-2 were upregulated and downregulated, respectively, in the CIH groups. Hence, the present study demonstrated that CIH-induced oxidative stress might not only induce insulin resistance but also islet cell apoptosis in the pancreas through TRB3 and p-JNK.

Light-Emitting Diodes Modify Medicinal Quality of Mown Rabdosia rubescens, with Changes in Growth, Physiology, and Antioxidant Activity, under Drought Stress.

Medicinal plants accommodated by understory habitats can easily suffer over-exploitation in the heavy harvest of natural products. It is necessary to develop a sustainable cultural protocol to provide high-quality stocks for efficient regeneration. Drought places stress on medicinal plants during their culture by limiting new sprout growth and reducing the quality of medicinal extracts. Artificial mediating approaches should be considered in a sustainable regime of medicinal plant culture to test the potential tradeoff between resistance to drought and production ability. In this study, Rabdosia rubescens seedlings were raised in three light-emitting diode (LED) spectra from red (71.7% red, 14.6% green, 13.7% blue), green (26.2% red, 17.4% green, 56.4% blue), and blue (17.8% red, 33.7% green, 48.5% blue) lights. Mown seedlings were subjected to a simulated drought event. Drought stressed the seedlings by reducing the growth, dry mass, nitrogen (N) uptake, and oridonin content. Mowing increased the oridonin content but decreased total C and N accumulation and the δ13C level. The red light benefitted starch accumulation only under the well-watered condition, and the green light induced an upregulation of δ13C but decreased antioxidant activity. Oridonin content was negatively associated with combined δ13C and catalase activity. Overall, either mowing or blue light can be recommended for the culture of R. rubescens to increase oridonin content, alleviating some of the negative consequences of drought.

Hedgehog pathway is negatively regulated during the development of Drosophila melanogaster PheRS-m (Drosophila homologs gene of human FARS2) mutants.

Hereditary spastic paraplegia (HSP) is a neurodegeneration disease, one of the reasons is caused by autosomal recessive missense mutation of the karyogene that encodes phenylalanyl-tRNA synthetase 2, mitochondrial (FARS2). However, the molecular mechanism underlying FARS2-mediated HSP progression is unknown. Mitochondrial phenylalanyl-tRNA synthetase gene (PheRS-m) is the Drosophila melanogaster homolog gene of human FARS2. This study constructed a Drosophila HSP missense mutation model and a PheRS-m knockout model. Some of the mutant fly phenotypes included developmental delay, shortened lifespan, wing-structure abnormalities and decreased mobility. RNA-sequencing results revealed a relationship between abnormal phenotypes and the hedgehog (Hh) pathway. A qRT-PCR assay was used to determine the key genes (ptc, hib, and slmb) of the Hh pathway that exhibited increased expression during different developmental stages. We demonstrated that Hh signaling transduction is negatively regulated during the developmental stages of PheRS-m mutants but positively regulated during adulthood. By inducing the agonist and inhibitor of Hh pathway in PheRS-m larvae, the developmental delay in mutants can be partly salvaged or postponed. Collectively, our findings indicate that Hh signaling negatively regulates the development of PheRS-m mutants, subsequently leading to developmental delay.

Forage quality and physiological performance of mowed alfalfa (Medicago sativa L.) subjected to combined light quality and drought.

Alfalfa (Medicago sativa) can dwell in water-deficient habitats, where it is difficult to predict dry mass (DM) production and forage quality due to understory transmittance. Mowing is a recommended practice for alfalfa populations under drought, but its effect on forested land receives less attention. In a controlled indoor experiment, we found that drought better reduces shoot DM weight and crude fiber content (CFi) in blue light (33.7% red, 48.5% green, and 17.8% blue lights) than red light (71.7% red, 13.7% green, and 14.6% blue lights). Mowing decreases carbon (C) isotope signature (δ13C), CFi, and total C content in shoots but increases their accumulations in DM, nonstructural carbohydrates, and crude fat content (CFa). The results also demonstrated that mown alfalfa has higher starch content when exposed to green light (26.2% red, 56.4% green, and 17.4% blue lights) compared to the other two spectra. Multiple factorial regression indicated that higher soluble sugar content accounted for the increase of CFa and DM weight for CFi. Overall, mowing in blue-light-enriched understory stands is recommended and produces high-forage-quality alfalfa, which can be used as a lowered crude fiber component.

Drought effects on tree growth, water use efficiency, vulnerability and canopy health of Quercus variabilis-Robinia pseudoacacia mixed plantation.

Drought-induced forest canopy die-back and tree mortality have been commonly recorded in the lithoid mountainous regions of northern China. However, the capacity of trees to regulate their carbon and water balance in response to drought remains inadequately understood. We measured tree growth, intrinsic water use efficiency (iWUE), vulnerability, and canopy health during drought events using dendrochronology, C isotope measurements, and a tree canopy health survey in a mixed plantation of Quercus variabilis and Robinia pseudoacacia. Resistance (Rt), recovery (Rc), resilience (Rs), and increased amplitude in iWUE compared to the indices 3 years before drought (iWUEr) were calculated for each species across the dominant tree (D), co-dominant tree (CD), and suppressed tree (S). Our results revealed that D and CD showed lower Rt, higher Rc, and higher iWUEr than S. After exposure to multiple sequential drought events, Q. variabilis showed an increasing trend in Rt, and R. pseudoacacia showed a decreasing trend in Rc. R. pseudoacacia exhibited a more conservative strategy towards drought, resulting in a negative SRt-iWUEr (slope of the linear model fitted to capture the trend between Rt and iWUEr) during drought events than Q. variabilis. For individual trees, lower Rc or positive SRt-iWUEr Q. variabilis and negative SRt-iWUEr R. pseudoacacia were more susceptible to canopy die-back. In conclusion, our study offers a new perspective for improved management practices in the design of silvicultural actions for forestry plantations in lithoid mountainous areas with increasing drought risk.

Thromboxane-induced contractile response of mesenteric arterioles is diminished in the older rats and the older hypertensive rats.

Nearly all physiological processes are controlled at some level by G-protein-coupled receptor (GPCR) signaling activity. The thromboxane A2 (TXA2) receptor (TP) is a member of the GPCR family. The ultimate effect of TP receptor activation depends on the availability of specific G proteins, which in turn depend on the cell type, tissue, and disease state. However, the roles of the TXA2-TP signaling pathway executed under disease states are poorly defined. In this study, 16-week-spontaneously hypertensive rats (SHR), the 18-month-SHR (OldSHR), and the age-matched Wistar-Kyoto (WKY) rats were used to study the vasoconstriction of mesenteric resistance artery induced by TP-specific agonist, U-46619. Vasoconstriction induced by U-46619 was significantly attenuated in OldWKY and OldSHR rats, and mesenteric arteries with impaired response to U-46619 responded strongly to the adrenergic receptor agonist, phenylephrine. Similar vascular responses to U-46619 were obtained in endothelium-denuded mesenteric arteries. Accordingly, the expression of TP membrane proteins in mesenteric vessels was decreased, and the endogenous TP competitor, 8, 9-EET, in serum was increased, which was partly responsible for the decreased vascular reactivity of U-46619. Decreased TP membrane expression was associated with TP endocytosis, which involved actin cytoskeletal remodeling, including increased ratio of F-actin/G-actin in OldWKY and OldSHR rats. Hence, we studied the effects of TXA2 and its receptors on blood vessels and found that the TXA2-TP prostaglandin signaling pathway was impaired in older adults, which would facilitate the creation of "precision therapeutics" that possess selective efficacy in diseases.

[Analysis of clinical feature and genetic variants in two Chinese pedigrees affected with Bainbridge-Ropers syndrome].

OBJECTIVE: To analyze the clinical features and genetic variants in two unrelated patients with psychomotor retardation and facial abnormalities, and to explore their genotype-phenotype correlation. METHODS: Clinical data and family history of the two pedigrees were collected. Whole exome sequencing (WES) and Sanger sequencing were carried out to detect the potential variants. RESULTS: Both patients had presented with mental and language retardation, along with growth delay and facial anomalies. They were both found to harbor de novo loss-of-function variants in exon 12 of the ASXL3 gene, namely c.3096dup (p.Pro1033Thrfs*2) and c.3253G>T (p.Gly1085*). Neither variant was reported previously. Combined with their clinical features and genetic finding, both patients were diagnosed with Bainbridge-Ropes syndrome due to pathogenic variants of the ASXL3 gene. CONCLUSION: Diagnosis of Bainbridge Ropes syndrome in the two pedigrees has enriched the genotypic and phenotypic spectrum of this disorder and enabled genetic counseling for them.

Prevalence and factors associated with comorbid depressive symptoms among people with low back pain in China: A cross-sectional study.

Background: Low back pain is a common medical condition among the general population that is associated with many adverse health effects when comorbid with depressive symptoms. However, little is known about depressive symptoms in the population with low back pain in China. Our study evaluated the prevalence of depressive symptoms and analyzed the factors associated with this condition in the Chinese population with low back pain. Methods: We conducted a cross-sectional analysis of data from the 2018 China Health and Retirement Longitudinal Study. We collected low back pain information for each participant and identified depressive symptoms using the brief version of the Center for Epidemiologic Studies Depression Scale. A wide range of sociodemographic and health-related characteristics of the subjects were extracted. We measured the prevalence of depressive symptoms comorbid with low back pain and analyzed the associated factors by multiple logistic regression. Results: A total of 5,779 respondents aged 45 and over with low back pain formed the sample, 41.8% of whom reported depressive symptoms. Multiple logistic regression analysis indicated greater vulnerability to depressive symptoms among females (OR = 1.41, 95% CI, 1.16-1.73), relatively younger persons (60-74 years: OR = 0.72, 95% CI, 0.63-0.83; ≥ 75 years: OR = 0.62, 95% CI, 0.49-0.79, reference: 45-59 years), those from the central and western regions (central: OR = 1.39, 95% CI, 1.18-1.64; western: OR = 1.56, 95% CI, 1.33-1.83), participants with extremely short sleep duration (OR = 2.74, 95% CI, 2.33-3.23), those with poor self-perceived health status (OR = 2.91, 95% CI, 2.34-3.63,), multisite pain (OR = 1.54, 95% CI, 1.20-1.98) and disability in activities of daily living (Basic: OR = 1.70, 95% CI, 1.47-1.98; Instrumental: OR = 1.95, 95% CI, 1.70-2.24). Conclusion: Depressive symptoms were highly prevalent in the Chinese population ≥ 45 years with low back pain. More attention should be paid to the individuals at high-risk confirmed by this study to facilitate early identification and intervention against depressive symptoms.

New paeonol derivative C302 reduces hypertension in spontaneously hypertensive rats through endothelium-dependent and endothelium-independent vasodilation.

Hypertension is a major risk factor for cardiovascular disease and Chinese herb monomers could provide new structural skeletons for anti-hypertension new drug development. Paeonol is a Chinese herbal monomer extracted from Cortex moutan, exhibited some anti-hypertensive activity. The study focused on the structural optimization of paeonol to provide promising lead compounds for anti-hypertension new drug development. Herein, twelve new paeonol derivatives (PD) were designed and synthesized and their vasodilation activity was evaluated by in vitro vasodilation drug screening platform based on Myograph. Its anti-hypertension activity, PD-C302 (2-hydroxy-4-methoxyvalerophenone) as a representative with the optimal vasodilation activity, was determined by its response to blood pressure in spontaneously hypertensive rats (SHR) in vivo. Moreover, its molecular mechanism was probed by the vasodilation activity of rat superior mesenteric artery rings with or without endothelium pre-contracted by potassium chloride (KCl) or phenylephrine hydrochloride (PE). It was indicated that PD-C302 significantly reduced the blood pressure in SHR, which would involve in PD-C302-induced vasodilation. Furthermore, endothelium-dependent pathways and endothelium-independent pathways both contributed importantly to PD-C302-induced vasodilation at low concentration of PD-C302. Endothelium-independent pathways (vascular smooth muscle cell-mediated vasodilation), were mainly responsible for the PD-C302-induced vasodilation at high concentration of PD-C302, which involved in opening multiple K+ channels to restrain Ca2+ channels, and then triggered vasodilation to reduce blood pressure. PD-C302 has a simple structure and favorable anti-hypertensive activity in vivo, which could be a promising lead compound for anti-hypertension new drug development.

Complex Crystal Structure Determination of Hsp90N-NVP-AUY922 and In Vitro Anti-NSCLC Activity of NVP-AUY922.

New targeted chemotherapy agents greatly improved five-year survival in NSCLC patients, but which were susceptible to drug resistance. NVP-AUY922, terminated in phase II clinical trials, exhibited promising anti-NSCLC (non-small-cell lung cancer) activity targeting to Hsp90N (heat shock protein), which demonstrated advantages in overcoming drug resistance as a broad-spectrum anti-cancer target. It was expected to develop novel anti-NSCLC drugs to overcome drug resistance by the structural optimization of NVP-AUY922. However, the absence of high-resolution complex crystal structure of Hsp90N-NVP-AUY922 blocked the way. Herein, 1.59 Å-resolution complex crystal structure of Hsp90N-NVP-AUY922 (PDB ID 6LTI) was successfully determined by X-ray diffraction. Meanwhile, there was a strong binding capability between NVP-AUY922 and its target Hsp90N verified by TSA (ΔTm, -15.56 ± 1.78°C) and ITC (K d, 5.10 ± 2.10 nM). Results by the complex crystal structure, TSA and ITC verified that NVP-AUY922 well accommodated in the ATP-binding pocket of Hsp90N to disable the molecular chaperone activity of Hsp90. Therefore, NVP-AUY922 exhibited approving inhibitory activity on NSCLC cell line H1299 (IC50, 2.85 ± 0.06 µM) by inhibiting cell proliferation, inducing cell cycle arrest and promoting cell apoptosis. At the basis of the complex crystal structure and molecular interaction analysis, thirty-two new NVP-AUY922 derivatives were further designed, and among which twenty-eight new ones display enhanced binding force with Hsp90N by molecular docking evaluation. The results would promote anti-NSCLC new drug development to overcome drug resistance based on the lead compound NVP-AUY922.

Effects of Macroautophagy and Mitophagy on the Pathogenicity of Fusarium graminearum.

Fusarium graminearum is the main pathogen of Fusarium head blight (FHB), which causes huge economic losses every year. In this study, an attempt was made to control FHB from the point of view of the physiological behavior of the pathogen itself. Autophagic inhibitors and activators were used, and the pathogenicity-related indices of F. graminearum were measured. The results showed that under nitrogen-rich conditions, macroautophagy inhibition and activation greatly reduced the mycelium weight to 0.28 and 0.25 g/ml at 24 h, which were 17.82 and 24.77% lower than that of the control treatment, respectively. Mitophagy inhibition also significantly decreased the mycelium weight (P < 0.05). Conidial yield was found to be affected by factors related to autophagy occurrence. It was found that both autophagy inhibition and activation could reduce the conidiation of F. graminearum. The toxin contents in wheat medium of macroautophagy activation treatments were 0.678, 0.190, 0.402, and 0.195 µg/g when cultured for 8 and 24 h under 0% N and 100% N conditions, respectively, which were significantly higher than those of the control treatments (P < 0.05). The infection length was measured to characterize the infectivity of F. graminearum, and we found that the length was short under macroautophagy activation conditions. However, mitophagy did not seem to affect the infectivity of F. graminearum. In summary, the above results indicate that macroautophagy and mitophagy inhibition could reduce the pathogenicity of F. graminearum, which may provide a new perspective for management of plant fungal diseases.

Atheroprotective Effects and Molecular Mechanism of Berberine.

Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. Atherosclerosis is the main pathological basis of cardiovascular diseases and it is closely associated with hyperlipidemia, endothelial injury, macrophage-derived foam cells formation, proliferation and migration of vascular smooth muscle cells (VSMCs), platelet aggregation, and altered gut microbiota. Various symptomatic treatments, that are currently used to inhibit atherosclerosis, need to be administered in long term and their adverse effects cannot be ignored. Berberine (BBR) has beneficial effects on atherosclerosis through regulating multiple aspects of its progression. This review highlights the recent advances in understanding the anti-atherosclerosis mechanism of BBR. BBR alleviated atherosclerosis by attenuation of dyslipidemia, correction of endothelial dysfunction, inhibition of macrophage inflammation and foam cell formation, activation of macrophage autophagy, regulation of the proliferation and migration of VSMCs, attenuation of platelet aggregation, and modulation of gut microbiota. This review would provide a modern scientific perspective to further understanding the molecular mechanism of BBR attenuating atherosclerosis and supply new ideas for atherosclerosis management.

[Clinical features and genetic testing of a Chinese pedigree affected with Smith-Lemli-Opitz syndrome].

OBJECTIVE: To analyze the clinical features and genetic variants of two patients from a pedigree affected with Smith-Lemli-Opitz syndrome and explore their genotype-phenotype correlation. METHODS: Clinical data and family history of the pedigree were collected. Whole exome sequencing was carried out to identify the potential variants. Suspected variants were verified by Sanger sequencing of the family members. RESULTS: The proband and her sister both presented with feeding difficulty, facial dysmorphism, seizures, and mental and speech retardation. The third child of this family presented with feeding difficulty, poor weight gain and severe malnutrition after birth. He had died of unknown cause at 6 months without genetic testing. The fourth child was a healthy boy. Genetic testing showed that both the proband and her sister have carried c.127G>T (p.Val43Phe) and c.820_825del (p.Asn274_Val275del) compound heterozygous variants of the DHCR7 gene (NM_001360.2), but the fourth child carried neither of the variants. The two variants were unreported in the literature and disease-related databases, and were not included in the 1000G and gnomAD databases. The c.820_825del variant may affect the sterol-sensitive region of the DHCR7 protein, which can lead to deletion of two amino acids at positions 247 and 275, causing truncation of the DHCR7 protein. It is speculated that this may affect the stability of protein's spatial conformation, thereby decrease the activity of the enzyme. The c.127G>T variant may affect the first transmembrane region of the protein, which is involved in the transmembrane transport of proteins. Multiple software predicted it to be harmful. Conservation analysis suggested that the three amino acids all locate in a highly conserved region of the protein. In consideration of the clinical phenotype, family history and result of genetic testing, we speculated that both patients had Smith-Lemli-Opitz syndrome due to variants of the DHCR7 gene. CONCLUSION: This pedigree has enriched the phenotypic and genotypic data of Smith-Lemli-Opitz syndrome, which clarified the genetic etiology of the patients and provided a basis for genetic counseling of this pedigree.

Role of Long Non-coding RNAs on Bladder Cancer.

Bladder cancer (BC) is the most common malignant tumor in the urinary system, and its early diagnosis is conducive to improving clinical prognosis and prolonging overall survival time. However, few biomarkers with high sensitivity and specificity are used as diagnostic markers for BC. Multiple long non-coding RNAs (lncRNAs) are abnormally expressed in BC, and play key roles in tumorigenesis, progression and prognosis of BC. In this review, we summarize the expression, function, molecular mechanisms and the clinical significance of lncRNAs on bladder cancer. There are more than 100 dysregulated lncRNAs in BC, which are involved in the regulation of proliferation, cell cycle, apoptosis, migration, invasion, metabolism and drug resistance of BC. Meanwhile, the molecular mechanisms of lncRNAs in BC was explored, including lncRNAs interacting with DNA, RNA and proteins. Additionally, the abnormal expression of thirty-six lncRNAs is closely associated with multiple clinical characteristics of BC, including tumor size, metastasis, invasion, and drug sensitivity or resistance of BC. Furthermore, we summarize some potential diagnostic and prognostic biomarkers of lncRNA for BC. This review provides promising novel biomarkers in early diagnosis, prognosis and monitoring of BC based on lncRNAs.