CRISPR metabolic screen identifies ATM and KEAP1 as targetable genetic vulnerabilities in solid tumors.

Cancer treatments targeting DNA repair deficiencies often encounter drug resistance, possibly due to alternative metabolic pathways that counteract the most damaging effects. To identify such alternative pathways, we screened for metabolic pathways exhibiting synthetic lethality with inhibition of the DNA damage response kinase Ataxia-telangiectasia-mutated (ATM) using a metabolism-centered Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 library. Our data revealed Kelch-like ECH-associated protein 1 (KEAP1) as a key factor involved in desensitizing cancer cells to ATM inhibition both in vitro and in vivo. Cells depleted of KEAP1 exhibited an aberrant overexpression of the cystine transporter SLC7A11, robustly accumulated cystine inducing disulfide stress, and became hypersensitive to ATM inhibition. These hallmarks were reversed in a reducing cellular environment indicating that disulfide stress was a crucial factor. In The Cancer Genome Atlas (TCGA) pan-cancer datasets, we found that ATM levels negatively correlated with KEAP1 levels across multiple solid malignancies. Together, our results unveil ATM and KEAP1 as new targetable vulnerabilities in solid tumors.

Dalbergia odorifera undergoes massive molecular shifts in response to waterlogging combined with salinity.

Field and greenhouse studies attempting to describe the molecular responses of plant species under waterlogging (WL) combined with salinity (ST) are almost nonexistent. We integrated transcriptional, metabolic, and physiological responses involving several crucial transcripts and common differentially expressed genes and metabolites in fragrant rosewood (Dalbergia odorifera) leaflets to dissect plant-specific molecular responses and patterns under WL combined with ST (SWL). We discovered that the synergistic pattern of the transcriptional response of fragrant rosewood under SWL was exclusively characterized by the number of regulated transcripts. The response patterns under SWL based on transcriptome and metabolome regulation statuses revealed different patterns (additive, dominant, neutral, minor, unilateral, and antagonistic) of transcripts or metabolites that were commonly regulated or expressed uniquely under SWL. Under SWL, the synergistic transcriptional response of several functional gene subsets was positively associated with several metabolomic and physiological responses related to the shutdown of the photosynthetic apparatus and the extensive degradation of starch into saccharides through α-amylase, ß-amylase, and α-glucosidase or plastoglobuli accumulation. The dissimilarity between the regulation status and number of transcripts in plants under combined stresses led to nonsynergistic responses in several physiological and phytohormonal traits. As inferred from the impressive synergistic transcriptional response to morpho-physiological changes, combined stresses exhibited a gradually decreasing effect on the changes observed at the molecular level compared to those in the morphological one. Here, by characterizing the molecular responses and patterns of plant species under SWL, our study considerably improves our understanding of the molecular mechanisms underlying combined stress.

Physio-biochemical and metabolomic responses of the woody plant Dalbergia odorifera to salinity and waterlogging.

BACKGROUND: Trees have developed a broad spectrum of molecular mechanisms to counteract oxidative stress. Secondary metabolites via phenolic compounds emblematized the hidden bridge among plant kingdom, human health, and oxidative stress. Although studies have demonstrated that abiotic stresses can increase the production of medicinal compounds in plants, research comparing the efficiency of these stresses still needs to be explored. Thus, the present research paper provided an exhaustive comparative metabolomic study in Dalbergia odorifera under salinity (ST) and waterlogging (WL). RESULTS: High ST reduced D. odorifera's fresh biomass compared to WL. While WL only slightly affected leaf and vein size, ST had a significant negative impact. ST also caused more significant damage to water status and leaflet anatomy than WL. As a result, WL-treated seedlings exhibited better photosynthesis and an up-regulation of nonenzymatic pathways involved in scavenging reactive oxygen species. The metabolomic and physiological responses of D. odorifera under WL and salinity ST stress revealed an accumulation of secondary metabolites by the less aggressive stress (WL) to counterbalance the oxidative stress. Under WL, more metabolites were more regulated compared to ST. ST significantly altered the metabolite profile in D. odorifera leaflets, indicating its sensitivity to salinity. WL synthesized more metabolites involved in phenylpropanoid, flavone, flavonol, flavonoid, and isoflavonoid pathways than ST. Moreover, the down-regulation of L-phenylalanine correlated with increased p-coumarate, caffeate, and ferulate associated with better cell homeostasis and leaf anatomical indexes under WL. CONCLUSIONS: From a pharmacological and medicinal perspective, WL improved larger phenolics with therapeutic values compared to ST. Therefore, the data showed evidence of the crucial role of medical tree species' adaptability on ROS detoxification under environmental stresses that led to a significant accumulation of secondary metabolites with therapeutic value.

Systematic optimization of host-directed therapeutic targets and preclinical validation of repositioned antiviral drugs.

Inhibition of host protein functions using established drugs produces a promising antiviral effect with excellent safety profiles, decreased incidence of resistant variants and favorable balance of costs and risks. Genomic methods have produced a large number of robust host factors, providing candidates for identification of antiviral drug targets. However, there is a lack of global perspectives and systematic prioritization of known virus-targeted host proteins (VTHPs) and drug targets. There is also a need for host-directed repositioned antivirals. Here, we integrated 6140 VTHPs and grouped viral infection modes from a new perspective of enriched pathways of VTHPs. Clarifying the superiority of nonessential membrane and hub VTHPs as potential ideal targets for repositioned antivirals, we proposed 543 candidate VTHPs. We then presented a large-scale drug-virus network (DVN) based on matching these VTHPs and drug targets. We predicted possible indications for 703 approved drugs against 35 viruses and explored their potential as broad-spectrum antivirals. In vitro and in vivo tests validated the efficacy of bosutinib, maraviroc and dextromethorphan against human herpesvirus 1 (HHV-1), hepatitis B virus (HBV) and influenza A virus (IAV). Their drug synergy with clinically used antivirals was evaluated and confirmed. The results proved that low-dose dextromethorphan is better than high-dose in both single and combined treatments. This study provides a comprehensive landscape and optimization strategy for druggable VTHPs, constructing an innovative and potent pipeline to discover novel antiviral host proteins and repositioned drugs, which may facilitate their delivery to clinical application in translational medicine to combat fatal and spreading viral infections.

Genomic Characteristics of Emerging Intraerythrocytic Anaplasma capra and High Prevalence in Goats, China.

Anaplasma capra is an emerging tickborne human pathogen initially recognized in China in 2015; it has been reported in ticks and in a wide range of domestic and wild animals worldwide. We describe whole-genome sequences of 2 A. capra strains from metagenomic sequencing of purified erythrocytes from infected goats in China. The genome of A. capra was the smallest among members of the genus Anaplasma. The genomes of the 2 A. capra strains contained comparable G+C content and numbers of pseudogenes with intraerythrocytic Anaplasma species. The 2 A. capra strains had 54 unique genes. The prevalence of A. capra was high among goats in the 2 endemic areas. Phylogenetic analyses revealed that the A. capra strains detected in this study were basically classified into 2 subclusters with those previously detected in Asia. Our findings clarify details of the genomic characteristics of A. capra and shed light on its genetic diversity.

Manipulating the Interfacial Band Bending For Enhancing the Thermoelectric Properties of 1T'-MoTe2 /Bi2 Te3 Superlattice Films.

Interfacial charge effects, such as band bending, modulation doping, and energy filtering, are critical for improving electronic transport properties of superlattice films. However, effectively manipulating interfacial band bending has proven challenging in previous studies. In this study, (1T'-MoTe2 )x (Bi2 Te3 )y superlattice films with symmetry-mismatch were successfully fabricated via the molecular beam epitaxy. This enables to manipulate the interfacial band bending, thereby optimizing the corresponding thermoelectric performance. These results demonstrate that the increase of Te/Bi flux ratio (R) effectively tailored interfacial band bending, resulting in a reduction of the interfacial electric potential from ≈127 meV at R = 16 to ≈73 meV at R = 8. It is further verified that a smaller interfacial electric potential is more beneficial for optimizing the electronic transport properties of (1T'-MoTe2 )x (Bi2 Te3 )y . Especially, the (1T'-MoTe2 )1 (Bi2 Te3 )12 superlattice film displays the highest thermoelectric power factor of 2.72 mW m-1 K-2 among all films, due to the synergy of modulation doping, energy filtering, and the manipulation of band bending. Moreover, the lattice thermal conductivity of the superlattice films is significantly reduced. This work provides valuable guidance to manipulate the interfacial band bending and further enhance the thermoelectric performances of superlattice films.

The fungal quorum-sensing molecule, farnesol, regulates the immune response of vaginal epithelial cells against Candida albicans.

BACKGROUND: Farnesol is a Candida-secreted quorum-sensing molecule of great interest as a potential antifungal agent for serious and hardly curable infections-candidiasis, especially vulvovaginal candidiasis (VVC). METHODS: The effect of farnesol on cellular morphology and viability and evaluated the production of Th1 (IL-2), Th2 (IL-4), proinflammatory (IL-6), chemotactic (IL-8), and Th17 (IL-17) cytokines in the culture supernatants of vaginal epithelial cell line (VK2) were evaluated. Moreover, we tested the inhibitory effect of farnesol on C. albicans adhesion. Scanning electron microscopy was conducted to observe any VK2 cell ultrastructural changes. RESULTS: Only low concentrations (≤ 50 µmol/L) of farnesol did not affect the morphology and viability of the VK2 cells (P > 0.05). Farnesol reduced the adhesion of C. albicans to the VK2 cells. When treated with farnesol, statistical elevated levels of both IL-4 and IL-17 secreted by the infected VK2 cells were present in the culture supernatants (P < 0.05). CONCLUSIONS: Farnesol acts as a stimulator to up-regulate the Th17-type innate immune response, as well as Th2-type humoral immunity following C. albicans infection. Further research is required to select the optimal therapeutic dose to develop efficacious and safe mucosal immune adjuvant for treating VVCs.

Major Vault Protein Prevents Atherosclerotic Plaque Destabilization by Suppressing Macrophage ASK1-JNK Signaling.

BACKGROUND: Macrophages are implicated in atherosclerotic plaque instability by inflammation and degradation of extracellular matrix. However, the regulatory mechanisms driving these macrophage-associated processes are not well understood. Here, we aimed to identify the plaque destabilization-associated cytokines and signaling pathways in macrophages. METHODS: The atherosclerotic models of myeloid-specific MVP (major vault protein) knockout mice and control mice were generated. Atherosclerotic instability, macrophage inflammatory signaling, and active cytokines released by macrophages were examined in vivo and in vitro by using cellular and molecular biological approaches. RESULTS: MVP deficiency in myeloid cells exacerbated murine plaque instability by increasing production of both MMP (matrix metallopeptidase)-9 and proinflammatory cytokines in artery wall. Mechanistically, expression of MMP-9 was mediated via ASK1 (apoptosis signal-regulating kinase 1)-MKK-4 (mitogen-activated protein kinase kinase 4)-JNK (c-Jun N-terminal kinase) signaling in macrophages. MVP and its α-helical domain could bind with ASK1 and inhibit its dimerization and phosphorylation. A 62 amino acid peptide (MVP-[686-747]) in the α-helical domain of MVP showed a crucial role in preventing macrophage MMP-9 production and plaque instability. CONCLUSIONS: MVP may act as an inhibitor for ASK1-JNK signaling-mediated MMP-9 production in macrophages and, thereby, attenuate unstable plaque formation. Our findings suggest that suppression of macrophage ASK1-JNK signaling may be a useful strategy antagonizing atherosclerotic diseases.

Selective COX-2 inhibitors do not increase gastrointestinal reactions after colorectal cancer surgery: a systematic review and meta-analysis.

BACKGROUND: The effectiveness of selective COX-2 inhibitors in preventing colorectal cancer recurrence has been demonstrated, however it is unknown how safe and successful they will be over the long term. As a result, we looked at the efficacy, safety, and consequences of adding COX-2 inhibitors to the treatment plan afterward. METHODS: In patients with advanced colorectal cancer, we compared the efficacy of celecoxib at two different doses (200 mg twice day and 400 mg twice daily) with placebo. To evaluate the impacts of post-treatment, several datasets from inception to June 2022 were searched. Response rate, illness control rate, and 3-year survival were the main results. And evaluated several safety outcomes, particularly those that were susceptible to adverse events. RESULTS: The study comprised a total of 9 randomized controlled trials (3206 participants). Celecoxib and rofecoxib doidn't significantly improved the 1-3 year remission rate (OR, 1.57 [95% CI: 0.95-2.57]) and disease control rate (OR, 1.08 [95% CI: 0.99-1.17]). Subgroup analysis of different doses showed that 400 mg of celecoxib significantly improved the response rate (OR, 2.82 [95%CI: 1.20-6.61]). 200 mg celecoxib was not significant (OR, 1.28 [95% CI: 0.66-2.49]). Rofecoxib also did not fully improve disease response rates. Celecoxib at any dose improved 3-year survival (OR, 1.21 [95% CI: 1.02-1.45]). It is important to note that COX-2 inhibitors did not significantly enhance the likelihood of adverse events including gastrointestinal or cardiovascular side effects at any dose. CONCLUSIONS: For patients with advanced colorectal cancer, a reasonable chemoprevention regimen can include celecoxib 400 mg twice daily.

A propensity score matching analysis of gasless endoscopic transaxillary thyroidectomy with five-settlement technique versus conventional open thyroidectomy in patients with papillary thyroid microcarcinoma.

BACKGROUND: In a previous study, we proposed a novel anatomy-based five-settlement method for transaxillary endoscopic thyroidectomy (fs-TAT) for patients with papillary thyroid carcinoma. The safety of this new method has been reported in a retrospective study of a single cohort. The safety and short-term oncological outcome of this method was confirmed by comparing it with conventional open surgery (COT) in patients with papillary thyroid microcarcinoma. METHODS: The medical records of patients who underwent fs-TAT or COT by a single surgeon from February 2019 to December 2021 were reviewed retrospectively. All patients were diagnosed with papillary thyroid microcarcinoma and underwent lobectomy and ipsilateral central compartment neck dissection. Propensity score matching was used to compare the technical safety and short-term oncologic outcomes of fs-TAT and COT for the purpose of reducing potential selection bias. Reporting was consistent with the STROCSS 2021 guidelines. RESULT: After propensity score matching, 460 (fs-TAT: 230; COT: 230) patients remained in the study population. There were no significant differences in sex, age, tumor size, Hashimoto's thyroiditis, or tumor multifocality between the groups. The operative time was longer [104.5 (90.3, 120.0) vs. 62.0 (52.0, 76.0), P < 0.001] and the total postoperative drainage volume [135(90, 210) vs. 75 (55, 115), P < 0.001] was greater in the fs-TAT group than in the COT group. However, intraoperative bleeding [3.0 (2.0, 5.0) vs. 5.0 (5.0, 7.5), P < 0.001] was greater, and the median number of lymph nodes yielded [5.0 (2.3, 8.0) vs. 7.0 (5.0, 11.0), P < 0.001] was greater in the COT group than in the fs-TAT group. The groups exhibited no significant difference in the rate of complications (fs-TAT: 2.2% vs. COT: 2.6%, P = 0.856), rate of positive lymph nodes (fs-TAT: 32.2% vs. COT: 36.5%, P = 0.377), length of postoperative hospital stay (3 days vs. 3 days, P = 0.305) or total medical costs (26,936 vs. 26,549, P = 0.144). CONCLUSION: Compared to conventional open surgery, fs-TAT offered excellent safety and acceptable short-term oncological outcomes in a selected cohort of patients with papillary thyroid microcarcinoma.

The anterior hip capsule is thinner in dysplastic hips: a study comparing different young adult hip patients.

PURPOSE: To investigate the thickness and intra-substance change of anterior capsule of the hip joint, and compare the difference of the capsular features in patients with different statuses of hip stability. METHODS: A retrospective study was performed to review a hip preservation database. Using the lateral center edge angle(LCEA), patients with borderline dysplasia of the hip (BDH) of 20° ≤ LCEA ≤ 25°, femoracetabular impingement(FAI) with LCEA > 30° and dysplasia of the hip (DH) of LCEA < 20° were enrolled and stratified into different treatment groups. The patients' imaging was reviewed by two experienced musculoskeletal radiologists who were blinded to clinical outcomes. Thickness and intra-substance change of the anterior hip capsule was measured on the sagittal oblique sequences of MRI. A surgeon measured the thickness of the anterior hip capsule during arthroscopy. The capsular thickness and intra-substance change were compared among different groups. RESULTS: Thirty patients (17 women and 13 men) enrolled in each group (FAI, BDH, and DH) matched by sex and ages were evaluated. There were no significant differences in terms of age, sex, BMI, Alpha angle, and Tönnis grade among all three groups. The mean thickness of the anterior capsule in the DH group was 3.2 ± 0.5 mm, which was significantly thinner than that in the BDH and FAI groups (4.5 ± 0.8 mm and 4.7 ± 0.6 mm), and there was no significant difference in capsular thickness between the BDH and FAI groups. The Median of anterior capsule thickness via arthroscopic measuring was 6 mm and 7 mm in the BDH and FAI groups respectively, which has no statistical difference. The intra-substance change of the anterior capsule shows a significant difference among the three groups, and a higher incidence of delamination of the capsule was found in DH groups (p < 0.001). CONCLUSIONS: Patients with hip dysplasia have a significantly reduced capsular thickness on MRI and delaminated anterior joint capsule, which could be a sequence of instability. The clinical relevance of this study is that capsular thickness and intra-substance changes of the anterior capsule vary which could alter capsular management strategies. LEVEL OF EVIDENCE: Level III of evidence, DIAGNOSTIC STUDIES, No consistently applied reference standard.

Imidazole-octyl mixed-mode stationary phase based on macroporous silica for the purification of ovomucoid and ovotransferrin.

A process-simplified hard template approach was established to synthesize the monodisperse macroporous silica microspheres with homogeneous structures by twice alkali-thermal treatment and calcination routes. Porous vinyl-functionalized polysesquioxane microspheres (V-PMSQ) were synthesized through a hydrolyzation-polycondensation method and used as templates. The template particles with large aperture and high pore volume were obtained by adjusting the pH value and reaction time of the twice alkali-thermal reaction. After calcination, monodisperse silica microspheres with an average pore size of 30 nm, homogeneous pore structures, and narrow particle size distribution were fabricated, which can be directly used as chromatographic matrices without classification. After that, a new reversed-phase/strong anion-exchange (RP/SAX) mixed-mode stationary phase Sil-S-VOIM was prepared by bonding the 1-vinyl-3-octyl-imidazole ligands to the above silica microspheres through a "thiol-ene" click reaction. The performance of the Sil-S-VOIM column was evaluated by one acidic protein (transferrin) and two basic proteins (lysozyme, α-chymotrypsin) and compared to a single imidazole-modified Sil-S-VIM column and an octyl-modified Sil-C8 column, respectively. Due to the synergistic effect of electrostatic repulsion and hydrophobic interactions, baseline separations of the above proteins were observed only on the Sil-S-VOIM column, with resolutions of 2.55 and 2.01 between lysozyme and transferrin, and between transferrin and α-chymotrypsin, respectively, indicating good selectivity and separation ability compared with single-mode stationary phases. It was applied to the isolation of egg white samples with peaks identified by SDS-PAGE and MALDI-TOF-MS. The results showed that the selective retention and isolation of ovomucoid and ovotransferrin were successfully achieved, with yields of 78.8% and 67.2%, respectively. The protocol described in this work is simpler, faster, and has higher protein recovery. Overall, this new mixed-mode stationary phase provided a promising potential for the separation and determination of intact proteins.

Electrically Tunable Antiferroelectric to Paraelectric Switching in a Semiconductor.

The monoclinic α-Cu2Se phase is the first multipolar antiferroelectric semiconductor identified recently by electron microscopy. As a semiconductor, although there are no delocalized electrons to form a static macroscopic polarization, a spontaneous and localized antiferroelectric polarization was found along multiple directions. In conventional ferroelectrics, the polarity can be switched by an applied electric field, and a ferroelectric to paraelectric transition can be modulated by temperature. Here, we show that a reversible and robust antiferroelectric to paraelectric switching in a Cu2Se semiconductor can be tuned electrically by low-voltage and high-frequency electric pulses, and the structural transformations are imaged directly by transmission electron microscopy (TEM). The atomic mechanism of the transformation was assigned to an electrically triggered cation rearrangement with a low-energy barrier. Due to differences of the antiferroelectric and paraelectric phases regarding their electrical, mechanical, and optical properties, such an electrically tunable transformation has a great potential in various applications in microelectronics.

Cold exposure induces browning of bovine subcutaneous white fat in vivo and in vitro.

White adipocytes can be transformed into beige adipocytes through the process of browning under cold exposure. To investigate the effects and underlying mechanisms of cold exposure on subcutaneous white fat in cattle, in vitro and in vivo studies were performed. Eight bulls of Jinjiang cattle breed (Bos taurus) aged 18 months were allocated to the control group (n = 4, autumn) or the cold group (n = 4, winter) by different slaughter seasons. Biochemical and histomorphological parameters were detected in blood and backfat samples. Subcutaneous adipocytes from Simental cattle (Bos taurus) were then isolated and cultured at a normal body temperature (37 °C) and at a cold temperature (31 °C) in vitro. In the in vivo study, cold exposure stimulated subcutaneous white adipose tissue (sWAT) browning by reducing adipocyte sizes and up-regulating the expression levels of browning-specific makers (UCP1, PRDM16, and PGC-1α) in cattle. In addition, cold-exposed cattle displayed lower lipogenesis transcriptional regulator levels (PPARγ and CEBPα) and higher lipolysis regulator levels (HSL) in sWAT. In the in vitro study, cold temperature inhibited subcutaneous white adipocytes (sWA) adipogenic differentiation by reducing lipid contents and decreasing the expression of adipogenic marker genes and proteins. Furthermore, cold temperature led to sWA browning which was characterized by increased browning-related genes, mitochondrial contents, and mitochondrial biogenesis-specific markers. In addition, p38 MAPK signaling pathway activity was stimulated by the incubation in cold temperature for 6 h in sWA. We concluded that the cold-induced browning of the subcutaneous white fat was beneficial to the production of heat and the maintenance of body temperature regulation in cattle.

A Soybean Sucrose Non-Fermenting Protein Kinase 1 Gene, GmSNF1, Positively Regulates Plant Response to Salt and Salt-Alkali Stress in Transgenic Plants.

Soybean is one of the most widely grown oilseed crops worldwide. Several unfavorable factors, including salt and salt-alkali stress caused by soil salinization, affect soybean yield and quality. Therefore, exploring the molecular basis of salt tolerance in plants and developing genetic resources for genetic breeding is important. Sucrose non-fermentable protein kinase 1 (SnRK1) belongs to a class of Ser/Thr protein kinases that are evolutionarily highly conserved direct homologs of yeast SNF1 and animal AMPKs and are involved in various abiotic stresses in plants. The GmPKS4 gene was experimentally shown to be involved with salinity tolerance. First, using the yeast two-hybrid technique and bimolecular fluorescence complementation (BiFC) technique, the GmSNF1 protein was shown to interact with the GmPKS4 protein. Second, the GmSNF1 gene responded positively to salt and salt-alkali stress according to qRT-PCR analysis, and the GmSNF1 protein was localized in the nucleus and cytoplasm using subcellular localization assay. The GmSNF1 gene was then heterologously expressed in yeast, and the GmSNF1 gene was tentatively identified as having salt and salt-alkali tolerance function. Finally, the salt-alkali tolerance function of the GmSNF1 gene was demonstrated by transgenic Arabidopsis thaliana, soybean hairy root complex plants overexpressing GmSNF1 and GmSNF1 gene-silenced soybean using VIGS. These results indicated that GmSNF1 might be useful in genetic engineering to improve plant salt and salt-alkali tolerance.

[Clinical observational study on the treatment of oligozoospermia with Shizi Sanhua decoction combined with Nuoyu].

OBJECTIVE: To study the clinical therapeutic effect as well as drug effectiveness and safety of Shizi Sanhua decoction combined with Nuoyu in the treatment of oligozoospermia in men. METHODS: 102 patients with oligozoospermia diagnosed at Longhua Hospital of Shanghai University of Traditional Chinese Medicine from February 2022 to March 2023 were selected and randomly divided into 3 groups. The treatment group was treated with Shizi Sanhua Decoction + Nuoyu; the traditional Chinese medicine group was treated with Shizi Sanhua Decoction; and the Nuoyu nutrient group was treated with Nuoyu nutrient. A review assessment and record were made after one course of treatment (3 months). RESULTS: A total of 102 patients completed the trial due to the treatment process. There were 34 cases in each of the traditional Chinese medicine group, the Nuoyu nutrient group, and the treatment group. Clinical efficacy: total effective rate of 52.94% in the traditional Chinese medicine group; 58.82% in the Nuoyu nutrient group; 82.35% in the treatment group. The clinical efficacy of the treatment group was better than that of the traditional Chinese medicine group and the Nuoyu nutrient group (P<0.05), which was statistically significant. Semen routine: the treatment group was better than the traditional Chinese medicine group and Nuoyu nutrient group in improving the total number of sperm and sperm concentration. CONCLUSION: The semen concentration and forward sperm count of patients with oligozoospermia treated with Shizi Sanhua Decoction combined with Nuoyu improved more significantly, and the clinical efficacy was remarkable. And the clinical efficacy is not affected by age and disease duration. It can be popularized and applied as a treatment for oligozoospermia.

Activation of adenosine A3 receptor attenuates progression of osteoarthritis through inhibiting the NLRP3/caspase-1/GSDMD induced signalling.

The specific adenosine A3 receptor (A3AR) agonist (CF101) has potential for inflammation and pain in various disease, such as arthritis, cancer and neuropathic pain, while the role of A3AR in post-traumatic OA and the underlying mechanism is largely unknown. CF101 was orally administrated in OA rats induced by anterior cruciate ligament transection (ACLT) surgery, and the rat primary chondrocytes were stimulated by hydrogen peroxide (H2 O2 , 300 µM). Histologic grading system was performed for detecting cartilage degeneration and immunohistochemistry for determining pyroptosis. The moleculars associated with cartilage homeostasis and inflammatory cytokines were analysed; moreover, the activation of NLRP3 inflammasome was determined. CF101 treatment significantly attenuated OA cartilage damage, OA-related pain and cartilage pyroptosis. Chondrocytes stimulated by H2 O2 evoked ROS release, thereby promoting the activation of NLRP3 inflammasome and facilitating the cleavage of GSDMD, which ultimately resulted in the mass release of pro-inflammatory cytokines including IL-1ß and IL-18, and production of matrix hydrolase. The pre-treatment with CF101 powerfully inhibited the above process both in vivo and in vitro. Our findings demonstrated that activation of A3AR attenuates OA progression and relieves pain perception through suppression of cartilage degradation and inhibition of ROS/NLRP3/GSDMD signalling, indicating pyroptosis is a potential candidate for OA treatment.

A study on the processing technology for Rhizoma Coptidis.

BACKGROUND: The present study intends to optimize the processing technology for the wine-processing of Rhizoma Coptidis, using alkaloids as indicators. METHOD: In the present study, the Box-Behnken design method was adopted to optimize the processing technology for Rhizoma Coptidis, using the alkaloid component quantities as the index. 100 g of Rhizoma Coptidis slices and 12.5 g of Rhizoma Coptidis wine were used. After full mixing, box-Behnken design method was used to optimize the processing time, processing temperature and processing time of coptis chinensis by taking alkaloid content as index. After mixing well, these components were fried in a container at 125 °C for 6 min and exhibited good parallelism. RESULTS: The content of alkaloids in coptis chinensis was the highest after roasting at 125 °C for 6 min. The characteristic components were berberine hydrochloride, and the relative content was about 15.96%. And showed good parallelism. The effective components of Rhizoma Coptidis were primarily alkaloids. CONCLUSION: The optimized processing technology for Rhizoma Coptidis is good.

Interactions between hydrogen sulphide and rhizobia modulate the physiological and metabolism process during water deficiency-induced oxidative defense in soybean.

Hydrogen sulphide (H2 S), a new gas signal molecule, participates in the regulation of various abiotic stresses in plants. However, how the tandem working of H2 S and rhizobia affects the adaptation of soybean to water deficiency is still unclear. In this study, we investigated the adaptation mechanism of H2 S and rhizobia in soybean to water deficiency. Our results revealed that H2 S and rhizobia jointly enhanced the leaf chlorophyll content and relative water content in plants, and caused an increase in the biomass of soybean seedlings under water deficiency. Besides, in the absence of water, H2 S enhanced the biomass by affecting the number of nodules and nitrogenase activity during vegetative growth. The expression of nodulation marker genes including early nodulin 40 (GmENOD40), ERF required for nodulation (GmERN) and nodulation inception genes (GmNIN1a, GmNIN2a and GmNIN2b) were upregulated by H2 S and rhizobia in the nodules. Moreover, the combined effect of H2 S and rhizobia was proved to affect the enzyme activities and gene expression level of antioxidants, as well as osmotic protective substance content and related gene expression levels under water deficiency in soybean seedlings. In addition, the metabolomic results suggested that the combined effect of H2 S and rhizobia remarkably promoted the contents of lipids and lipid-like molecules. Our results indicated that H2 S and rhizobia synergistically reduced the oxidative damage caused by water deficiency through increasing the accumulation of metabolites and strengthening the plant antioxidant capacity.

Proteomics and bioinformatics reveal insights into neuroinflammation in the acute to subacute phases in rat models of spinal cord contusion injury.

Neuroinflammation is recognized as a hallmark of spinal cord injury (SCI). Although neuroinflammation is an important pathogenic factor that leads to secondary injuries after SCI, neuroprotective anti-inflammatory treatments remain ineffective in the management of SCI. Moreover, the molecular signatures involved in the pathophysiological changes that occur during the course of SCI remain ambiguous. The current study investigated the proteins and pathways involved in C5 spinal cord hemi-contusion injury using a rat model by means of 4-D label-free proteomic analysis. Furthermore, two Gene Expression Omnibus (GEO) transcriptomic datasets, Western blot assays, and immunofluorescent staining were used to validate the expression levels and localization of dysregulated proteins. The present study observed that the rat models of SCI were associated with the enrichment of proteins related to the complement and coagulation cascades, cholesterol metabolism, and lysosome pathway throughout the acute and subacute phases of injury. Intriguingly, the current study also observed that 75 genes were significantly altered in both the GEO datasets, including ANXA1, C1QC, CTSZ, GM2A, GPNMB, and PYCARD. Further temporal clustering analysis revealed that the continuously upregulated protein cluster was associated with immune response, lipid regulation, lysosome pathway, and myeloid cells. Additionally, five proteins were further validated by means of Western blot assays and the immunofluorescent staining showed that these proteins coexisted with the F4/80+ reactive microglia and infiltrating macrophages. In conclusion, the proteomic data pertaining to the current study indicate the notable proteins and pathways that may be novel therapeutic targets for the treatment of SCI.