Serine protease inhibitor Kazal-type (SPINK) is a skin keratinizing protease inhibitor, which was initially found in animal serum and is widely present in plants, animals, bacteria, and viruses, and they act as key regulators of skin keratinizing proteases and are involved in the regulation of keratinocyte proliferation and inflammation, primarily through the inhibition of deregulated tissue kinin-releasing enzymes (KLKs) in skin response. This process plays a crucial role in alleviating various skin problems caused by hyperkeratinization and inflammation, and can greatly improve the overall condition of the skin. Specifically, the different members of the SPINK family, such as SPINK5, SPINK6, SPINK7, and SPINK9, each have unique biological functions and mechanisms of action. The existence of these members demonstrates the diversity and complexity of skin health and disease. First, SPINK5 mutations are closely associated with the development of various skin diseases, such as Netherton’s syndrome and atopic dermatitis, and SPINK5 is able to inhibit the activation of the STAT3 signaling pathway, thereby effectively preventing the metastasis of melanoma cells, which is important in preventing the invasion and migration of malignant tumors. Secondly, SPINK6 is mainly distributed in the epidermis and contains lysine and glutamate residues, which can act as a substrate for epidermal transglutaminase to maintain the normal structure and function of the skin. In addition, SPINK6 can activate the intracellular ERK1/2 and AKT signaling pathways through the activation of epidermal growth factor receptor and protease receptor-2 (EphA2), which can promote the migration of melanoma cells, and SPINK6 further deepens its role in stimulating the migration of malignant tumor cells by inhibiting the activation of STAT3 signaling pathway. This process further deepens its potential impact in stimulating tumor invasive migration. Furthermore, SPINK7 plays a role in the pathology of some inflammatory skin diseases, and is likely to be an important factor contributing to the exacerbation of skin diseases by promoting aberrant proliferation of keratinocytes and local inflammatory responses. Finally, SPINK9 can induce cell migration and promote skin wound healing by activating purinergic receptor 2 (P2R) to induce phosphorylation of epidermal growth factor and further activating the downstream ERK1/2 signaling pathway. In addition, SPINK9 also plays an antimicrobial role, preventing the interference of some pathogenic microorganisms. Taken as a whole, some members of the SPINK family may be potential targets for the treatment of dermatological disorders by regulating multiple biological processes such as keratinization metabolism and immuno-inflammatory processes in the skin. The development of drugs such as small molecule inhibitors and monoclonal antibodies has great potential for the treatment of dermatologic diseases, and future research on SPINK will help to gain a deeper understanding of the physiopathologic processes of the skin. Through its functions and regulatory mechanisms, the formation and maintenance of the skin barrier and the occurrence and development of inflammatory responses can be better understood, which will provide novel ideas and methods for the prevention and treatment of skin diseases.

BACKGROUND: Temozolomide (TMZ) resistance is a significant challenge in treating glioblastoma (GBM). Collagen remodeling has been shown to be a critical factor for therapy resistance in other cancers. This study aimed to investigate the mechanism of TMZ chemoresistance by GBM cells reprogramming collagens. METHODS: Key extracellular matrix components, including collagens, were examined in paired primary and recurrent GBM samples as well as in TMZ-treated spontaneous and grafted GBM murine models. Human GBM cell lines (U251, TS667) and mouse primary GBM cells were used for in vitro studies. RNA-sequencing analysis, chromatin immunoprecipitation, immunoprecipitation-mass spectrometry, and co-immunoprecipitation assays were conducted to explore the mechanisms involved in collagen accumulation. A series of in vitro and in vivo experiments were designed to assess the role of the collagen regulators prolyl 4-hydroxylase subunit alpha 1 (P4HA1) and yes-associated protein (YAP) in sensitizing GBM cells to TMZ. RESULTS: This study revealed that TMZ exposure significantly elevated collagen type I (COL I) expression in both GBM patients and murine models. Collagen accumulation sustained GBM cell survival under TMZ-induced stress, contributing to enhanced TMZ resistance. Mechanistically, P4HA1 directly binded to and hydroxylated YAP, preventing ubiquitination-mediated YAP degradation. Stabilized YAP robustly drove collagen type I alpha 1 ( COL1A1) transcription, leading to increased collagen deposition. Disruption of the P4HA1-YAP axis effectively reduced COL I deposition, sensitized GBM cells to TMZ, and significantly improved mouse survival. CONCLUSION P4HA1 maintained YAP-mediated COL1A1 transcription, leading to collagen accumulation and promoting chemoresistance in GBM.
Temozolomide ; Humans ; Glioblastoma/drug therapy* ; Animals ; Mice ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; YAP-Signaling Proteins ; Hydroxylation ; Dacarbazine/pharmacology* ; Adaptor Proteins, Signal Transducing/metabolism* ; Transcription Factors/metabolism* ; Collagen/biosynthesis* ; Collagen Type I/metabolism* ; Prolyl Hydroxylases/metabolism* ; Antineoplastic Agents, Alkylating/therapeutic use*

Cistanches Herba(CH) is a famous tonic traditional Chinese medicine, with the effects of tonifying kidney Yang, nourishing kidney Yin, replenishing essence and blood, and moistening the intestines to relieve constipation. Modern pharmacological studies have shown that CH has anti-aging, anti-fatigue, immunomodulatory, neuroprotective, and anti-aging activities, serving as an ideal raw material for the development of pharmaceuticals and health products. In 2023, CH was added in the catalog of medicinal and food substances, which provided policy support for its application in conventional food products and expanding pathways for industrial diversification. To comprehensively understand current development status of CH products, this review systematically investigated professional databases including Yaozhi(https://db.yaozh.com), Chinese Pharmacopoeia, Compendium of National Standards for Chinese Patent Medicines, and Kezhuang and collected market survey data to thoroughly review the applications of CH as a primary ingredient in domestic and international Chinese patent medicines, health foods, cosmetics, and common food products. Furthermore, this review points out challenges in the current industrial development and future potential market prospects, aiming to provide guidance for the development and industrialization of CH-based pharmaceuticals and health products, thereby promoting the vigorous growth of the CH industry.
Drugs, Chinese Herbal/pharmacology* ; Humans ; Cistanche/chemistry* ; Animals ; Medicine, Chinese Traditional

OBJECTIVE: To compare the short-term clinical efficacy and safety of closed reduction with Kirschner wire fixation versus open reduction with plate fixation for treating osteoporotic Colles' fractures in middle-aged and elderly patients. METHODS: Between January 2018 and January 2023, 119 patients with Colles fractures were retrospectively analyzed, including 39 males and 80 females, aged from 48 to 74 years old with an average of(60.58±6.71) years old. The time from injury to operation ranged 1 to 13 days with an average of (5.29±2.52) days. According to the surgical method, they were divided into Kirschner wire fixation group (Kirschner wire group) and plate internal fixation group (plate group). In Kirschner wire group, there were a total of 68 patients, comprising 21 males and 47 females. The average age was (61.15±6.24) years old, ranged from 49 to 74 years old. Among them, 41 cases involved the left side while 27 cases involved the right side. In the plate group, there were a total of 51 patients, including 18 males and 33 females. The average age was (59.78±5.71) years old ranged from 48 to 72 years old. Among them, there were 31 cases on the left side and 20 cases on the right side. The following parameters were recorded before and after the operation:operation time, intraoperative blood loss, hospitalization days, hospitalization expenses, postoperative complications, and radiographic parameters of distal radius (distal radius height, ulnar deviation angle, palmar tilt angle). The clinical efficacy was evaluated at 3 and 12 months after the operation using Gartland-Werley and disabilites of the arm shoulder and hand (DASH) scores. RESULTS: The patients in both groups were followed up for a duration from 12 to 19 months with an average of(13.32±2.02) months. The Kirschner wire group exhibited significantly shorter operation time compared to the plate group 27.91(13.00, 42.00) min vs 67.52(29.72, 105.32) min, Z=-8.74, P=0.00. Intraoperative blood loss was also significantly lower in the Kirschner wire group than in the plate group 3.24(1.08, 5.40) ml vs 21.91(17.38, 26.44) ml, Z=-9.31, P=0.00. Furthermore, patients in the Kirschner wire group had a shorter length of hospital stay compared to those in the plate group (8.38±2.63) days vs (11.40±2.78) days, t=-3.12, P=0.00. Additionally, hospitalization cost was significantly lower in the Kirschner wire group than in the plate group 10 111.29(6 738.98, 13 483.60) yuan vs 15 871.11(11 690.40, 20 051.82) yuan, Z=-5.62, P=0.00. The incidence of complications was 2 cases in the Kirschner wire group and 1 case in the plate group, with no statistically significant difference(P>0.05). At 3 months postoprative, the radial height of the Kirschner wire group was found to be significantly smaller than that of the plate group, with measurements of (11.45±1.69) mm and (12.11±1.78) mm respectively (t=-2.06, P=0.04). However, there were no statistically significant differences observed in ulnar deviation angle and palmar tilt angle between the two groups (P>0.05). The DASH score and Gartland-Werley score in the Kirschner group were significantly higher than those in the plate group at 3 months post-operation (19.10±9.89) vs (13.47±3.51), t=4.34, P=0.00;(11.15±3.61) vs (6.41±2.75), t=8.13, P=0.00). However, there was no significant difference between the two groups at 12 months post-operation (P>0.05). CONCLUSION Compared to plate internal fixation, closed reduction with Kirschner wire support fixation yields a slightly inferior recovery of radial height;however, there is no significant disparity in the functional score of the affected limb at 12 months post-operation. Nonetheless, this technique offers advantages such as shorter operation time, reduced intraoperative blood loss, decreased hospitalization duration, and lower cost.
Humans ; Female ; Male ; Middle Aged ; Aged ; Fracture Fixation, Internal/instrumentation* ; Bone Wires ; Bone Plates ; Retrospective Studies ; Colles' Fracture/surgery* ; Minimally Invasive Surgical Procedures/methods* ; Open Fracture Reduction/methods* ; Osteoporotic Fractures/surgery*

Testicular histology based on testicular biopsy is an important factor for determining appropriate testicular sperm extraction surgery and predicting sperm retrieval outcomes in patients with azoospermia. Therefore, we developed a deep learning (DL) model to establish the associations between testicular grayscale ultrasound images and testicular histology. We retrospectively included two-dimensional testicular grayscale ultrasound from patients with azoospermia (353 men with 4357 images between July 2017 and December 2021 in The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China) to develop a DL model. We obtained testicular histology during conventional testicular sperm extraction. Our DL model was trained based on ultrasound images or fusion data (ultrasound images fused with the corresponding testicular volume) to distinguish spermatozoa presence in pathology (SPP) and spermatozoa absence in pathology (SAP) and to classify maturation arrest (MA) and Sertoli cell-only syndrome (SCOS) in patients with SAP. Areas under the receiver operating characteristic curve (AUCs), accuracy, sensitivity, and specificity were used to analyze model performance. DL based on images achieved an AUC of 0.922 (95% confidence interval [CI]: 0.908-0.935), a sensitivity of 80.9%, a specificity of 84.6%, and an accuracy of 83.5% in predicting SPP (including normal spermatogenesis and hypospermatogenesis) and SAP (including MA and SCOS). In the identification of SCOS and MA, DL on fusion data yielded better diagnostic performance with an AUC of 0.979 (95% CI: 0.969-0.989), a sensitivity of 89.7%, a specificity of 97.1%, and an accuracy of 92.1%. Our study provides a noninvasive method to predict testicular histology for patients with azoospermia, which would avoid unnecessary testicular biopsy.
Humans ; Male ; Azoospermia/diagnostic imaging* ; Deep Learning ; Testis/pathology* ; Retrospective Studies ; Adult ; Ultrasonography/methods* ; Sperm Retrieval ; Sertoli Cell-Only Syndrome/diagnostic imaging*

OBJECTIVE: To retrospectively analyze the clinical data of newly diagnosed acute myeloid leukemia (AML) patients treated with venetoclax combined with azacitidine (Ven/Aza) or standard "3+7" regimen and similar regimens, collect real-world study data, compare the treatment response and adverse events between the two regimens, as well as perform survival analysis. METHODS: To retrospectively analyze the efficacy, survival, and adverse reactions of newly diagnosed AML patients treated with Ven/Aza (24 cases) and "3+7" regimens (117 cases ) in our hospital from September 2009 to March 2023, as well as factors influencing outcomes. A propensity score matching (PSM) was performed on age and Eastern Cooperative Oncology Group performance status (ECOG PS) to obtain a 1:1 matched cohort of 20 pairs, and the efficacy and survival before and after the matching were compared. RESULTS: The median age of patients in the Ven/Aza group was 69 years, while that in the "3+7" group was 56 years (P <0.001). Objective remission rate (ORR) was 62.5% in Ven/Aza group and 74.8% in "3+7" group (P >0.05). The median overall survival (OS) in the Ven/Aza group was 522 days, while that in the "3+7" group was 1 002 days (P >0.05). After controlling the two variables of age and ECOG PS, a PSM cohort of 20 pairs was obtained, in which the ORR was 65% in Ven/Aza group and 60% in "3+7" group (P >0.05). The median OS was 522 days and 629 days, and median progression-free survival (PFS) was 531 days and 198 days between the two groups, respectively. There were no statistically significant differences in OS and PFS between the two groups (both P >0.05). Additionally, the incidence of adverse events in the Ven/Aza group was significantly reduced. CONCLUSION The overall cohort shows that the "3+7" regimen has advantages in efficacy and survival, but Ven/Aza regimen is relatively safer. After performing PSM on age and ECOG PS, the Ven/Aza group showed improved efficacy, and a longer median PFS compared to "3+7" group.
Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Retrospective Studies ; Sulfonamides/administration & dosage* ; Azacitidine/administration & dosage* ; Bridged Bicyclo Compounds, Heterocyclic/administration & dosage* ; Aged ; Middle Aged ; Male ; Female ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Treatment Outcome

[This corrects the article DOI: 10.11909/j.issn.1671-5411.2017.08.005.].

OBJECTIVE: To evaluate the efficacy and safety of Shexiang Tongxin Dropping Pill (STDP) in treating stable angina patients with phlegm-heat and blood-stasis syndrome by exercise duration and metabolic equivalents. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled stable angina patients with phlegm-heat and blood-stasis syndrome from 22 hospitals. They were randomized 1:1 to STDP (35 mg/pill, 6 pills per day) or placebo for 56 days. The primary outcome was the exercise duration and metabolic equivalents (METs) assessed by the standard Bruce exercise treadmill test after 56 days of treatment. The secondary outcomes included the total angina symptom score, Chinese medicine (CM) symptom scores, Seattle Angina Questionnaire (SAQ) scores, changes in ST-T on electrocardiogram and adverse events (AEs). RESULTS: This trial enrolled 309 patients, including 155 and 154 in the STDP and placebo groups, respectively. STDP significantly prolonged exercise duration with an increase of 51.0 s, compared to a decrease of 12.0 s with placebo (change rate: -11.1% vs. 3.2%, P<0.01). The increase in METs was significantly greater in the STDP group than in the placebo group (change: -0.4 vs. 0.0, change rate: -5.0% vs. 0.0%, P<0.01). The improvement of total angina symptom scores (25.0% vs. 0.0%), CM symptom scores (38.7% vs. 11.8%), reduction of nitroglycerin consumption (100.0% vs. 11.3%), and all domains of SAQ, were significantly greater with STDP than placebo (all P<0.01). The changes in Q-T intervals at 28 and 56 days from baseline were similar between the two groups (both P>0.05). Twenty-five participants (16.3%) with STDP and 16 (10.5%) with placebo experienced AEs (P=0.131), with no serious AEs observed. CONCLUSION STDP could improve exercise tolerance in patients with stable angina and phlegm-heat and blood stasis syndrome, with a favorable safety profile. (Registration No. ChiCTR-IPR-15006020).
Humans ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Angina, Stable/physiopathology* ; Aged ; Syndrome ; Treatment Outcome ; Placebos ; Tablets

Neuropathic pain, a debilitating condition caused by dysfunction of the somatosensory nervous system, remains difficult to treat due to limited understanding of its molecular mechanisms. Bioinformatics analysis identified cerebellin 2 (CBLN2) as highly enriched in human and murine proprioceptive and nociceptive neurons. We found that CBLN2 expression is persistently upregulated in dorsal root ganglia (DRG) following spinal nerve ligation (SNL) in mice. In addition, transcription factor SOX11 binds to 12 cis-regulatory elements within the Cbln2 promoter to enhance its transcription. SNL also induced SOX11 upregulation, with SOX11 and CBLN2 co-localized in nociceptive neurons. The siRNA-mediated knockdown of Sox11 or Cbln2 attenuated SNL-induced mechanical allodynia and thermal hyperalgesia. High-throughput sequencing of DRG following intrathecal injection of CBLN2 revealed widespread gene expression changes, including upregulation of numerous NF-κB downstream targets. Consistently, CBLN2 activated NF-κB signaling, and inhibition with pyrrolidine dithiocarbamate reduced CBLN2-induced pain hypersensitivity, proinflammatory cytokines and chemokines production, and neuronal hyperexcitability. Together, these findings identified the SOX11/CBLN2/NF-κB axis as a critical mediator of neuropathic pain and a promising target for therapeutic intervention.
Animals ; Neuralgia/metabolism* ; Ganglia, Spinal/metabolism* ; Up-Regulation ; Mice ; NF-kappa B/metabolism* ; SOXC Transcription Factors/genetics* ; Male ; Neuroinflammatory Diseases/metabolism* ; Mice, Inbred C57BL ; Nerve Tissue Proteins/genetics* ; Hyperalgesia/metabolism* ; Signal Transduction ; Spinal Nerves

Aim To investigate the regulatory mecha-nism of butin on the proliferation,migration,cycle blockage and pyroptosis related inflammatory factors in human fibroblast-like synoviocytes of rheumatoid arthri-tis(HFLS-RA).Methods Cell proliferation,migra-tion and invasion were studied using cell migration and invasion assays.Cell cycle was detected by flow cytom-etry,and the expression of the pyroptosis-associated in-flammatory factors IL-1β,IL-18,caspase-1 and caspase-3 was detected by ELISA,RT-qPCR and West-ern blot.Results Migration and invasion experiments showed that the cell proliferation rate of the butin group was lower than that of the blank control group(P＜0.05).Cell cycle analysis demonstrated that in the G0/G1 phase,the DNA expression was elevated in the medium and high-dose groups of butin(P＜0.05),while in the G2 and S phases,the DNA expression was reduced in the medium and high-dose groups of butin(P＜0.05).The results of ELISA,RT-qPCR and Western blot assay revealed that the expression of IL-1β,IL-1 8,caspase-1,and caspase-3 decreased in the butin group compared with the IL-1β+caspase-3 in-hibitor group(P＜0.05).Conclusions Butin inhib-its HFLS-RA proliferation by inhibiting the synthesis of inflammatory vesicles by caspase-1 in the pyroptosis pathway,thereby reducing the production and release of inflammatory factors such as IL-1β and IL-18 down-stream of the pathway,and also inhibits HFLS-RA pro-liferation by exerting a significant blocking effect in the G1 phase,which may be one of the potential mecha-nisms of butin in the treatment of RA.