Pancreatic cancer is a highly malignant solid tumor of the digestive system with extremely poor treatment prognosis. Although its incidence rate is low， its mortality rate is extremely high. In recent years， the number of diagnosed cases worldwide has continued to rise， making pancreatic cancer the sixth leading cause of cancer-related deaths globally. Currently， clinical treatment primarily relies on operation and chemotherapy to suppress tumors. However， these approaches face challenges such as suboptimal efficacy， high postoperative recurrence rates， and severe adverse reactions. Therefore， identifying safe and effective treatment modalities remains a pressing challenge for the medical community. In recent years， research on traditional Chinese medicine （TCM） interventions for pancreatic cancer has increased significantly. Multiple studies have shown that single-herb TCM， TCM formulas， and their derived single compounds can regulate the levels of tumor cell signaling pathways through multiple action targets. They inhibit the development and progression of pancreatic cancer by inhibiting cancer cell proliferation， promoting cell apoptosis， inhibiting tumor angiogenesis， reducing cancer cell invasion and migration capabilities， regulating the cell cycle， and modulating the tumor microenvironment. Additionally， TCM has the advantages of significantly enhancing the anticancer efficacy of chemotherapy drugs and causing fewer adverse reactions. However， the specific action mechanisms by which TCM intervenes in pancreatic cancer remain unclear. Further extensive research is still needed to validate the role of regulating classical signaling pathways such as phosphoinositide 3-kinase （PI3K）/protein kinase B （Akt）/mammalian target of rapamycin （mTOR）， Wnt/β-catenin， nuclear transcription factor-κB （NF-κB）， notch， and hedgehog in the treatment of pancreatic cancer. Therefore， this paper reviewed Chinese and international studies on TCM intervention in pancreatic cancer through relevant signaling pathways in recent years， summarized the potential action mechanisms of TCM in the treatment of pancreatic cancer， and provided references for related research in the future.

Obesity， a global chronic disease， is associated with adipose tissue dysfunction， which is one of the contributing factors to obesity. The cyclic adenosine monophosphate （cAMP） signaling pathway， a key regulator of lipid metabolism， plays a pivotal role in obesity development. Various of traditional Chinese medicine monomers， such as flavonoids， lignans， phenols， and terpenoids， as well as traditional Chinese medicine compound formulas like Xiaoyao powder， Shengmai powder， and Zexie decoction， can maintain energy homeostasis， balance adipose tissue function， regulate glucose metabolism， improve insulin resistance， and suppress inflammatory responses through cAMP signaling pathway regulation， thereby intervening in lipid metabolism for obesity treatment. Although a substantial amount of basic research has preliminarily elucidated the potential mechanisms by which traditional Chinese medicine intervenes in obesity through the cAMP signaling pathway， clinical translational research remains inadequate. There is an urgent need for large-sample， high-quality randomized controlled trials to validate these findings.

Objective To investigate the role and possible mechanism of celastrol(Cel)in sodium oxalate(NaOx)-induced acute kidney injury(AKI)and crystal deposition in the kidney tissues in mice.Methods Male C57BL/6 mice(aged 8～12 weeks,weighing 22～24 g)were randomly divided into 3 groups.Saline group(control group,intraperitoneal injection with normal saline and drinking water freely),NaOx group(injured group,intraperitoneal injection of 75 mg/kg NaOx,and drinking water containing 50 μmol/L NaOx),and NaOx+Cel group(treatment group,intraperitoneal injection of 1 mg/kg Cel firstly and then 75 mg/kg NaOx in 24 h later,drinking water containing 50 μmol/L NaOx).All specimens were collected in 24 h after NaOx injection.HK-2 cells were randomly divided into 4 groups:Medium group(no treatment),NaOx group(500 μmol/L NaOx),NaOx+Cel group(400 nmol/L Cel pre-treatment for 2 h followed by 500 μmol/L NaOx treatment),and NaOx+Cel+BA group[8 μmol/L betulinic acid(BA,NF-κB agonist)after the interventions as the NaOx+Cel group].Cells of each group were collected in 24 h after corresponding treatments.Von Koosa and cell adhesion assays were used to observe crystal deposition.HE staining was employed to observe renal histopathology and score the damage.CCK-8 assay was utilized to detect cell viability to obtain the optimal concentrations of NaOx and Cel.Serum urea and creatinine levels were detected.Immunohisotochemical assay was conducted to detect the expression of OPN,CD44,KIM-1,NGAL,p65,IL-1β,BAX,and Caspase-3,and Western blotting was performed for protein levels of OPN,CD44,KIM-1,p65,P-p65 and IL-1β.Results The mice in the NaOx+Cel group showed reduced crystal deposition(P<0.0001),attenuated renal tubular damage(P<0.01),decreased serum urea and creatinine levels(P<0.05),and declined expression levels of the renal adhesion molecules OPN and CD44,the kidney injury molecules KIM-1 and NGAL,the inflammation-associated molecules p65 and IL-1β,and the apoptosis related molecules BAX and Caspase-3 when compared with the NaOx group(P<0.05).In in vitro study,the NaOx+Cel group showed reduced crystal adhesion(P<0.0001),decreased expression of the adhesion molecules OPN and CD44(P<0.05),down-regulation of the inflammatory molecule IL-1β and P-p65/p65 ratio(P<0.05),and down-regulation of the renal injury molecule KIM-1(P<0.05)when compared with the NaOx group.In the NaOx+Cel+BA group,crystal adhesion was significantly increased(P<0.0001),the inflammatory molecule IL-1β and the ratio of P-p65/p65 were increased(P<0.05),and the kidney injury molecule KIM-1 was increased when compared with the NaOx+Cel group(P<0.05).Conclusion Cel may reduce NaOx-induced crystal deposition and AKI by inhibiting NF-κB activation.

This study was designed to investigate the effects of TNFSF14 on mitochondrial function in ischemia/reperfusion-induced acute kidney injury(I/R-AKI)and its mechanism.TNFSF14-/-and TNFSF14+/+mice underwent renal ischemia-reperfusion operation to establish I/R-AKI models,and their histopathology changes were compared by using Periodic Acid-Schiff stain,transmission electron microscopy.Immunohistochemistry(IHC)was used to detect levels of TNFSF14,HVEM,LT[3R,mitochondrial activity related proteins(Dpr1 and Mfn2)and inflammatory cells infiltration in kidney tissues of mice and relevant patients.In vitro cell experiments,immunofluorescence and immunoblotting were used to observe the effects of exogenous recombinant TNFSF14 factor on the damage and mitochondrial activity of renal tubular epithelial cell line HK-2 cells.Data showed that the expression of TNFSF14 and its receptors were significantly increased in kidney tissues of I/R-AKI mice and clinical human renal tissues of acute tubular injury.Compared with the sham group,I/R mice showed significantly higher levels of renal tubular injury score,inflammatory cells infiltration,cell apoptosis,mitochondrial damage,and Drp1 expression,while knocking out the TNFSF14 gene,the above indicators were significantly reduced.In vitro,exogenous TNFSF14 stimulation could aggravate the hypoxia-induced apoptosis and the decrease of mitochondrial membrane potential in HK-2 cells,while increasing phosphorylation of Drp1 at Se616 to promote its transfer from cytoplasm to mitochondria,leading to an abnormal increase in mitochondrial fission.In conclusions,TNFSF14 may mediate the pathological process of I/R-AKI by promoting mitochondrial damage.

Objective To investigate how substrate stiffness regulates the morphology of primary cilia in chondrocytes and to illustrate how Piezo1 mediates the morphology regulation of primary cilia by substrate stiffness.Methods Polydimethylsiloxane(PDMS)curing agent and the main agent(Dow Corning,Beijing,China)were mixed at the ratio of 1∶10(stiff),1∶50(medium stiffness),and 1∶70(soft),respectively,to prepare substrate films with the thickness of 1 mm at different levels of stiffness,including stiff substrate of(2.21±0.12)MPa,medium-stiffness substrate of(54.47±6.06)kPa,and soft substrate of(2.13±0.10)kPa.Chondrocytes were cultured with the substrates of three different levels of stiffness.Then,the cells were treated with Tubastatin A(Tub A)to inhibit histone deacetylase 6(HDAC6),Piezo1 activator Yoda1,and inhibitor GsMTx4,respectively.The effects of HDAC6,Yoda1,and GsMTx4 on chondrocyte morphology and the length of primary cilia were analyzed through immunofluorescence staining.Results The stiff substrate increased the spread area of the chondrocytes.Immunofluorescence assays showed that the cytoskeleton and the nuclear area of the cells on the stiff substrate were significantly increased(P<0.05)and the primary cilia were significantly extended(P<0.05)compared with those on the medium-stiffness and soft substrates.However,the presence rate of primary cilia was not affected.The HDAC6 activity of chondrocytes increased with the decrease in substrate stiffness.When the activity of HDAC6 was inhibited,the cytoskeletal area,the nuclei area,and the primary cilium length were increased more significantly on the stiff substrate(P<0.05).Further testing showed that Piezo1 activator and inhibitor could regulate the activity of HDAC6 in chondrocytes,and that the length of primary cilia was significantly increased after treatment with the activator Yoda1(P<0.05).On the other hand,the length of primary cilia was significantly shortened on the stiff substrate after treatment with the inhibitor GsMTx4(P<0.05).Conclusion Both substrate stiffness and Piezo1 may affect the morphology of chondrocyte primary cilia by regulating HDAC6 activity.

Mechanical signal transduction are crucial for chondrocyte in response to mechanical cues during the growth, development and osteoarthritis (OA) of articular cartilage. Extracellular matrix (ECM) turnover regulates the matrix mechanical microenvironment of chondrocytes. Thus, understanding the mechanotransduction mechanisms during chondrocyte sensing the matrix mechanical microenvironment can develop effective targeted therapy for OA. In recent decades, growing evidences are rapidly advancing our understanding of the mechanical force-dependent cartilage remodeling and injury responses mediated by TRPV4 and PIEZOs. In this review, we highlighted the mechanosensing mechanism mediated by TRPV4 and PIEZOs during chondrocytes sensing mechanical microenvironment of the ECM. Additionally, the latest progress in the regulation of OA by inflammatory signals mediated by TRPV4 and PIEZOs was also introduced. These recent insights provide the potential mechanotheraputic strategies to target these channels and prevent cartilage degeneration associated with OA. This review will shed light on the pathogenesis of articular cartilage, searching clinical targeted therapies, and designing cell-induced biomaterials.
Chondrocytes ; TRPV Cation Channels ; Mechanotransduction, Cellular ; Biocompatible Materials ; Cartilage, Articular

Extracellular matrix (ECM) has been implicated in tumor progress and chemosensitivity. Ovarian cancer brings a great threat to the health of women with a significant feature of high mortality and poor prognosis. However, the potential significance of matrix stiffness in the pattern of long non-coding RNAs (lncRNAs) expression and ovarian cancer drug sensitivity is still largely unkown. Here, based on RNA-seq data of ovarian cancer cell cultured on substrates with different stiffness, we found that a great amount of lncRNAs were upregulated in stiff group, whereas SNHG8 was significantly downregulated, which was further verified in ovarian cancer cells cultured on polydimethylsiloxane (PDMS) hydrogel. Knockdown of SNHG8 led to an impaired efficiency of homologous repair, and decreased cellular sensitivity to both etoposide and cisplatin. Meanwhile, the results of the GEPIA analysis indicated that the expression of SNHG8 was significantly decreased in ovarian cancer tissues, which was negatively correlated with the overall survival of patients with ovarian cancer. In conclusion, matrix stiffening related lncRNA SNHG8 is closely related to chemosensitivity and prognosis of ovarian cancer, which might be a novel molecular marker for chemotherapy drug instruction and prognosis prediction.
Female ; Humans ; Cisplatin/pharmacology* ; Elasticity/physiology* ; Etoposide ; Extracellular Matrix/physiology* ; Ovarian Neoplasms/metabolism* ; RNA, Long Noncoding/metabolism*

Objective To fabricate a foldable microplate for single cell culture and establish finite element model of the folding microplate, so as to calculate traction force of single cells during contraction in three-dimensional (3D) state.Methods The folding angle of the microplate casued by cell traction force was calculated. Then the relation between bending moment and folding angle as well as the relation between traction force and bending moment were derived by using finite element simulation, so as to realize the characterization of traction force for singel cell in 3D state.Results The folding angles of the microplate with HSF and MC3T3-E1 cells in 3D state were 73°-173° and 49°-138°, respectively. The single cell traction forces of HSF and MC3T3-E1 cells were 55-210 nN and 52-161 nN, respectively.Conclusions The proposed method for measuring traction force of single cells in 3D state by fabricating the foldable microplate for single cell culture will provide some references for further development of calculating traction forces in 3D cell adhesion, spreading and migration.

Generally, extracellular matrix (ECM) has the characteristics of viscoelasticity. In osteoarthritis (OA), catabolic processes alter the viscoelastic properties of functional pericellular matrix (PCM) of chondrocytes. Chondrocytes sense and respond to their mechanical microenvironment via an array of mechanosensitive receptors and channels that activate a complex network of downstream signaling pathways to regulate several cell processes central to OA pathology. Advances in understanding the specific mechanosignalling mechanisms in articular cartilage will promote the development of cell microenvironment construction in cartilage tissue engineering and the targeted precision therapeutics for OA. In this review, the work on the mechanism of matrix viscoelasticity regulating chondrocytes mechanotransduction by Agarwal et al. was briefly commented, and the recent advances related with their work was also discussed.

Objective:To observe the clinical effect of ablative fractional CO 2 laser in the treatment of hypertrophic scar in children after burn. Methods:The clinical data of patients with post-burn hypertrophic scar in children who met the inclusion and exclusion criteria in the Cosmetic Clinic and Burn Clinic of the Third People’s Hospital of Bengbu City Affiliated to Bengbu Medical College from January 2019 to March 2021 were collected, and a retrospective study was conducted. All patients were divided into laser group and control group, and laser group was further divided into 1-2 times subgroups and 3-4 times subgroups. The laser group received ablative fractional CO 2 laser treatment 1-4 times on the basis of conventional anti-scar treatment (pressure therapy and topical silicone drugs), and the treatment interval was 1-3 months; the control group only received conventional anti-scar treatment. The color, blood vessel distribution, thickness and softness of scar were scored by Vancouver Scar Scale (VSS), before treatment and 2 months after treatment In the laser group, and at 3 and 6 months in the control group, respectively. The degree of pruritus of the scar was scored with Visual Analogue Scale (VAS). The patient’s satisfaction evaluation is graded as four levels: very satisfied, relatively satisfied, generally satisfied, and dissatisfied. All data were analyzed by SPSS 19.0 software with paired t-test, Wilcoxon rank-sum test or chi-square test according to the type and nature of the data. Results:A total of 103 patients with hypertrophic scars were included, with a total of 134 scars, including 58 males and 45 females; the age was (3.9±3.0) years, range 0-11 years old; the scar area accounted for 4.2%±3.1% of the body surface area; the course of scar was (3.6±2.2) months. There were 72 patients (94 scars) in the laser group, including 29 patients (37 scars) in the 1-2 times subgroup and 43 (57 scars) in the 3-4 times subgroup; 31 patients in the control group(40 scars). (1) Vascular distribution, softness and overall score assessed by VSS in 1-2 times subgroup after treatments were significantly lower than those before treatment ( P<0.05). The thickness, blood vessel distribution, softness and overall score assessed by VSS in 3-4 times subgroup after treatments were significantly lower than those before treatment ( P<0.05). The improvement degree of scar after treatment in each group was different. Compared with the control group, the improvement degree in the 1-2 times subgroup and the 3-4 times subgroup was more obvious ( P<0.05). The improvement degree in the 3-4 times subgroup was better than that in the 1-2 times subgroups ( P<0.05). (2) Compared with before treatment, the VSS scores of scars after laser treatment in different parts were significantly different except for the thickness scores of face and neck, trunk, and upper limbs group ( P<0.05). (3) The degree of pruritus was assessed by VAS method. The pruritus score of the 1-2 times subgroups and 3-4 times subgroups before treatment was (4.86±1.35) points, (4.97±0.93) points, and the pruritus score 2 months after treatment was (1.93±0.99) points, (1.90±0.83) points, the pruritus score improved significantly after treatment, and the difference was statistically significant ( P<0.01). The pruritus scores of the control group at 3 months and 6 months were (4.83±0.82) points and (4.22±0.66) points, and the scores at 6 months were slightly improved compared with those at 3 months, and the difference was statistically significant ( P<0.01). (4) In the laser group, 5 patients (6.9%) had pigmentation after the first treatment, and then gradually subsided; 7 patients (9.7%) had blisters after the second treatment, which healed after dressing change. In the control group, 3 cases (9.7%) had erosions, and the erosions improved after adjusting the pressure appropriately. (5) The overall satisfaction of patients in the laser group was higher than that in the control group [100% (72/72) vs. 80.6% (25/31), P<0.05]. Conclusions:Fractional CO 2 laser has a good effect on the treatment of hypertrophic scars in early childhood burns. It can effectively inhibit scar hyperplasia and improve the degree of itching in patients. The satisfaction of both doctors and patients is high.