Protein kinases are intimately involved in the pathogenesis of many diseases such as cancer, inflammation, and autoimmune and neurological diseases. Therefore, kinases have been widely studied as drug targets over the past three decades. As of April, 2020, the FDA had approved 59 small molecule kinase inhibitors (SMKIs) in the emerging field of targeted drug therapy. This paper focuses on the biochemistry and pharmacology of these 59 SMKIs and 121 SMKIs for which structures can be retrieved and that are now in phase Ⅱ and Ⅲ clinical trials. In addition, this paper also conducts a simple analysis of several popular targets and their inhibitors.

Background Whether ocular anterior and posterior chamber exist a blood-aqueous barrier is in controversy.Conventional method can not offer a good evidence because it is unable to detect the aqueous component in the posterior chamber.Objective This study was to investigate the distribution of Gadolinium-diethylene triamine pentaacetic acids(Gd-DTPA)after peripheral iridectomy with magnetic resonance imaging(MRI)in rabbit.Methods Monocular peripheral iridectomy was performed on the right eyes in 8 clean New Zealand white rabbits and the fellow eyes were as controls.0.2 ml/kg(0.5 mol/L)Gd-DTPA,a tracer of MRI,was injected into ear vein in vivo to scan the eyes with MRI for the observation of the permeability and distribution.The signal enhanced ratio of interest region associated with time were analyzed.Results The signal in ciliary body of both eyes showed an immediately sharp enhancement within 10 minutes following the injection of Gd-DTPA with a peak intensity at 30-40 minutes,and then the intensity was gradually weaken over time.The signal was stronger in the operative eyes than that in the fellow eyes.The signal in the posterior chamber was gradually increased after operation,however,that in posterior chamber of the control eyes was lower.The interest regions of Gd-DTPA were ciliary,anterior chamber and posterior chamber,and the enhanced signal intensities were consisted in the posterior chamber after operation.However,the increase of the signal was not seen in the posterior chamber in the control eyes.Conclusions The pathway of plasma protein entering into the anterior chamber is very different from that of aqueous secretion.There exists a barrier between the anterior and posterior chamber which might be an integral part of the blood-ocular barrier.

Objective To establish a rat model of coal-burning-borne fluorosis,and to observe the expression changes of bone morphogenetic protein-2 (BMP-2) and bone morphogenetic protein-3 (BMP-3) in the serum of rat treated with different dose of fluoride and different treatment duration.Methods A total of 120 clean grade SD rats(body mass between 80 to 120 g) weaned for 4 weeks were randomly assigned into four groups,which were control,low-dose fluorid,medium-dose fluorid and high-dose fluorid groups,respectively,and 30 rats in each group (female 15,male 15).All of the rats were fed with coal drying corn from fluorosis area.Ten rats were killed by femoral artery bleeding 30 d,90 d and 180 d after exposed to fluoride,respectively.Serum BMP-2 and BMP-3 level was tested by enzyme-linked immunosorbent assay (ELISA).Results ①Results of BMP-2:after exposed to fluoride for 90 d and 180 d,the differences of serum BMP-2 level between groups were statistically significant(F=385.08,173.98,all P ＜ 0.01).In low-dose fluorid,medium-dose fluorid and high-dose fluorid groups,the expression of serum BMP-2 at 90 d[(18.80 ± 0.43),(22.22 ± 0.85),(25.14 ± 0.69)μg/L] and 180 d[(7.98 ± 0.68),(8.97 ± 0.78),(15.04 ± 0.89)μg/L] was higher than that of control group[(12.54 ± 1.29),(7.53 ± 0.97)μg/L,all P ＜ 0.05],and the level of BMP-2 increased with increasing dose of fluoride (all P ＜ 0.05).Within each group,the difference of serum BMP-2 was statistically significant(F =55.42,511.58,686.35,671.64,all P ＜ 0.01).The expression of BMP-2 in each group at 90 d [(12.54 ± 1.29),(18.80 ± 0.43),(22.22 ± 0.85),(25.14 ± 0.69)μg/L] was higher than that at 30 d[(11.75 ± 1.15),(11.42 ± 1.07),(11.38 ± 0.92),(11.15 ±1.03)μg/L,all P ＜ 0.05].The expression of BMP-2 in each group at 180 d[(7.53 ± 0.97),(7.98 ± 0.68),(8.97 ± 0.78),(15.04 ± 0.89) μg/L] was lower than that at 90 d.②Results of BMP-3:the difference between groups was not statistically significant at every experimental stage(F =0.7215,1.2951,0.0964,all P ＞ 0.05).Conclusions Longer excessive fluoride intake stimulates the expression of BMP-2 in rats,but with prolonged fluoride intake,the stimulation becomes weak.The effect of fluoride on BMP-3 is not as sensitive as that on BMP-2.

Objective To study the sources and the relationship between the management and the outcome of hemorrhage after cephalic pancreatoduodenectomy.Methods The clinical data of 370 patients who underwent pancreatic resection at the Lihuili Hospital and the Second Affiliated Hospital of Zhejiang University were retrospectively analyzed.Results Postoperative bleeding occurred in 35 patients with 11 deaths.Among those intraabominal bleeding occurred in 14 cases and gastrointestinal hemorrhage occurred in 22,with one case suffering from both.Bleediug developing within 72 hours after operation in 12 cases (early-stage group),which was caused by improper intraoperative homeostasis.In other 23 cases,bleeding 72 hours after operation(later stage group)was caused by the erosion following pancreatic and/or bile leakage.Relaparotomy was performed in 13 cases and endoscopic homeostasis was performed in 3. Relaparotomy or endoscopic homeostasis was superior to that of conservative therapy in the early-stage group (P0.05).Pancreatic or bile leakage was identified as the significant risk factors for the postoperative bleeding.Conclusions In order to prevent the postoperative hemorrhage and to reduce the mortality of pancreatic resection,skillful techniques,expeditious homeostasis,proper management of stump pancreas and the prevention of pancreatic and bile leakage are essential.

Retaining or improving periodontal ligament (PDL) function is crucial for restoring periodontal defects. The aim of this study was to evaluate the physiological effects of low-power laser irradiation (LPLI) on the proliferation and osteogenic differentiation of human PDL (hPDL) cells. Cultured hPDL cells were irradiated (660 nm) daily with doses of 0, 1, 2 or 4 J⋅cm(-2). Cell proliferation was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, and the effect of LPLI on osteogenic differentiation was assessed by Alizarin Red S staining and alkaline phosphatase (ALP) activity. Additionally, osteogenic marker gene expression was confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR). Our data showed that LPLI at a dose of 2 J⋅cm(-2) significantly promoted hPDL cell proliferation at days 3 and 5. In addition, LPLI at energy doses of 2 and 4 J⋅cm(-2) showed potential osteogenic capacity, as it stimulated ALP activity, calcium deposition, and osteogenic gene expression. We also showed that cyclic adenosine monophosphate (cAMP) is a critical regulator of the LPLI-mediated effects on hPDL cells. This study shows that LPLI can promote the proliferation and osteogenic differentiation of hPDL cells. These results suggest the potential use of LPLI in clinical applications for periodontal tissue regeneration.
Adenine ; analogs & derivatives ; pharmacology ; Adenylyl Cyclase Inhibitors ; Alkaline Phosphatase ; analysis ; genetics ; radiation effects ; Anthraquinones ; Bone Morphogenetic Protein 2 ; genetics ; Calcium ; metabolism ; radiation effects ; Cell Culture Techniques ; Cell Differentiation ; radiation effects ; Cell Line ; Cell Proliferation ; radiation effects ; Coloring Agents ; Core Binding Factor Alpha 1 Subunit ; genetics ; Cyclic AMP ; antagonists & inhibitors ; radiation effects ; Gene Expression ; radiation effects ; Humans ; L-Lactate Dehydrogenase ; analysis ; Lasers, Semiconductor ; Low-Level Light Therapy ; instrumentation ; Osteocalcin ; genetics ; Osteogenesis ; genetics ; radiation effects ; Periodontal Ligament ; cytology ; radiation effects ; Radiation Dosage ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Tetrazolium Salts ; Thiazoles

Purpose: The purpose of this study was to retrospectively compare the clinical characteristics and imaging features on (CEUS) of combined hepatocellular cholangiocarcinoma (CHC) with those of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Methods: The clinical information and CEUS features of 45 patients with CHC from 2015 to 2019 and 1-to-1-matched control subjects with HCC and CC (45 each) were compared. Results: Simultaneous elevation of α-fetoprotein (AFP) and cancer antigen (CA) 19-9 was more common in CHC than in HCC and CC. In the arterial phase, hyperenhancement (homogeneous and heterogeneous) was more common in CHC (73.3%) and HCC (100%), while peripheral rimlike enhancement was more common in CC (55.6%). In the portal phase, marked washout was significantly more frequent in CHC and CC than in HCC (42.2% and 53.3% vs. 6.7%). In the delayed phase, marked washout was more common in CHC (82.2%) and CC (93.3%) than in HCC (40.0%). The washout time (WT) was much shorter in CHC and CC than in HCC (33.8±13.1 seconds and 30.1±11.6 seconds vs. 58.4±23.5 seconds). Using the combination of simultaneous elevation of AFP and CA 19-9 with marked washout in the delayed phase and a WT <38 seconds or arterial hyperenhancement to differentiate CHC from HCC or CC, the accuracy, sensitivity, and specificity were 74.4%, 93.3%, and 55.6% and 71.1%, 80.0%, and 62.2%, respectively. Conclusion Although some CEUS imaging features of CHC, HCC, and CC overlap, the combination of tumor markers and CEUS features can be helpful in differentiating CHC from HCC and CC.

OBJECTIVETo establish of acute respiratory distress syndrome (ARDS) model in canine after inhalation of perfluoroisobutylene (PFIB), and to observe the progressing of lung injury, and to study the mechanisms of injury.

METHODSA device of inhalation of PFIB for canine was made. The concentration of PFIB was 0.30 - 0.32 mg/L. Serum IL-6 and IL-8 were dynamically measured. Clinical manifestations, pathology of organs in canine were observed.

RESULTS(1) During inhalation, the concentration of PFIB remained stable; (2) After inhalation, blood arterial oxygen partial pressure fell gradually, and eventually met the criteria for diagnosing ARDS; (3) The level of IL-8 in serum rises significantly after inhalation (P < 0.05), whereas that of IL-6 was not obviously altered (P > 0.05); (4) Within 6 hours after inhalation, no abnormality in canine was observed, but afterwards symptoms gradually appeared, and typical breath of ARDS, such as high frequency and lower level could be seen in later phase; (5) Pathological examination showed severe congestion, edema and atelectasis in most part of both lungs, and signs of anoxia in other organs.

CONCLUSIONS(1) The device designed is capable of ensuring control of inhalation of PFIB; (2) Exposure to PFIB for 30 mins, canines all met the criteria for diagnosing ARDS 22 hours after inhalation, therefore the modeling is successful; (3) PFIB specifically damages the lung by causing excessive inflammation.

Administration, Inhalation ; Animals ; Disease Models, Animal ; Dogs ; Female ; Fluorocarbons ; toxicity ; Interleukin-6 ; blood ; Interleukin-8 ; blood ; Lung ; drug effects ; pathology ; Male ; Random Allocation ; Respiratory Distress Syndrome, Adult ; blood ; chemically induced

OBJECTIVEAlthough chondroprotective activities have been documented for polysaccharides, the potential target of different polysaccharide may differ. The study was aimed to explore the effect of glucan HBP-A in chondrocyte monolayer culture and chondrocytes-alginate hydrogel constructs in vivo, especially on the expression of type II collagen.

METHODSChondrocytes isolated from rabbit articular cartilage were cultured and verified by immunocytochemical staining of type II collagen. Chondrocyte viability was assessed after being treated with HBP-A in different concentrations. Morphological status of chondrocytes-alginate hydrogel constructs in vitro was observed by scanning electron microscope (SEM). The constructs were treated with HBP-A and then injected to nude mice subcutaneously. Six weeks after transplantation, the specimens were observed through transmission electron microscopy (TEM). The mRNA expressions of disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTs-5), aggrecan and type II collagen in both monolayer culture and constructs were determined by real time polymerase chain reaction (PCR). The expression of type II collagen and matrix metalloproteinases-3 (MMP-3) in chondrocyte monolayer culture was also tested through Western blot and enzyme linked immunosorbent assay (ELISA), respectively.

RESULTSMMP-3 secretion and ADAMTs-5 mRNA expression in vitro were inhibited by HBP-A at 0.3 mg/mL concentration. In morphological study, there were significant appearance of collagen in those constructs treated by HBP-A. Accordingly, in both chondrocyte monolayer culture and chondrocytes-alginate hydrogel constructs, the expression of type II collagen was increased significantly in HBP-A group when compared with control group (P<0.001).

CONCLUSIONSThe study documented that the potential pharmacological target of glucan HBP-A in chondrocytes monolayer culture and tissue engineered cartilage in vivo may be concerned with the inhibition of catabolic enzymes MMP-3, ADAMTs-5, and increasing of type II collagen expression.

ADAM Proteins ; genetics ; metabolism ; Aggrecans ; genetics ; metabolism ; Alginates ; pharmacology ; Animals ; Cartilage, Articular ; drug effects ; physiology ; Cell Proliferation ; drug effects ; Cell Shape ; drug effects ; Cell Survival ; drug effects ; Chondrocytes ; cytology ; drug effects ; metabolism ; ultrastructure ; Collagen Type II ; genetics ; metabolism ; Female ; Glucans ; pharmacology ; Glucuronic Acid ; pharmacology ; Hexuronic Acids ; pharmacology ; Hydrogel, Polyethylene Glycol Dimethacrylate ; pharmacology ; Immunohistochemistry ; Matrix Metalloproteinase 3 ; metabolism ; Mice, Nude ; RNA, Messenger ; genetics ; metabolism ; Rabbits ; Tissue Engineering ; methods

BACKGROUND:It has been found that mitochondrial function is abnormal in patients with chronic fatigue syndrome,and the administration of coenzymes can improve the symptoms.Warm acupuncture is one of the most important treatments for this disease,but its mechanism of action is unclear. OBJECTIVE:To investigate the effects of warm acupuncture on the phosphatase and tensin inducible kinase 1(PINK1)/Parkin pathway in the skeletal muscle of rats with chronic fatigue syndrome. METHODS:After 3 days of adaptive feeding,32 male Sprague-Dawley rats were randomly divided into normal control,model,warm acupuncture,and coenzyme Q groups with 8 rats in each group.The chronic fatigue syndrome model was established by multiple factors,including swimming exhaustion,chronic immobilization and fasting.After successful modeling,the normal group and the model group were treated with the same fixation and gavage procedures,and the warm acupuncture group was treated with acupuncture at Guanyuan,Zhongwan and Zusanli(bilateral)points,once a day.After the needling was inserted,the moxa pillar was put on the needle handle and ignited,three sessions once.The coenzyme Q group was given 1 mL/kg coenzyme by gavage,once a day for 14 days.The body mass,exhaustive swimming time and food utilization rate during the treatment were recorded.After the treatment,the bilateral gastrocnemius muscles of rats in each group were collected.The pathological morphology of the gastrocnemius muscle was observed by hematoxylin-eosin staining,the mitochondrial morphology and autophagosome of the gastrocnemius muscle were observed by transmission electron microscope.The expression level of microtubule-associated protein light chain 3(LC3)Ⅱ protein in the skeletal muscle was detected by immunohistochemistry.Western blot was used to detect the expression of PINK1,Parkin,LC3 Ⅰ,and LC3 Ⅱ in the skeletal muscle. RESULTS AND CONCLUSION:Compared with the normal group,the gastrocnemius muscle nuclei of the model group were pyknotic,condensed,the number of cells was increased,the cells were arranged disorderly,and the fibers in the gastrocnemius muscle were tightly arranged in the model group.Compared with the model group,the intercellular space became smaller,the nuclei were reduced,and the cell arrangement was orderly in the warm acupuncture group and coenzyme Q group.Compared with the normal group,the skeletal muscle mitochondria in the model group were swollen,fused,and vacuolated seriously,the membrane was partially broken,the matrix was more dissolved,the cristae was broken and disappeared,and autophagy appeared.Compared with the model group,the number of mitochondria increased,the arrangement was relatively neat,mitochondrial vacuolization and rupture of cristae in the gastrocnemius muscle were improved,the membrane structure was relatively intact,and autophagy occurred.Compared with the normal group,the expression of PINK1 protein in the skeletal muscle of the model group was significantly increased(P<0.05),while the expression of Parkin,LC3 Ⅱ and LC3 Ⅱ/Ⅰ protein was slightly upregulated(P>0.05).Compared with the model group,the protein expressions of PINK1,Parkin,LC3 Ⅱ and LC3 Ⅱ/Ⅰ were significantly upregulated in the warm acupuncture and coenzyme Q groups(P<0.05),and the up-regulation was more significant in the warm acupuncture group.To conclude,warm acupuncture can play a role in the treatment of chronic fatigue syndrome by activating the PINK1/Parkin pathway,upregulating LC3 Ⅱ expression,forming mitochondrial autophagosomes,promoting the degradation of damaged mitochondria,and improving mitochondrial quality.

Objective To investigate the performance of brands and types of high-flow nasal cnnula oxygen therapy(HFNC)devices at different altitudes.Methods Four different models of HFNC devices,including R-80S bi-level non-invasive ventilator integrated with HFNC device,HF-60A HFNC device,HFT-300 HFNC device and H-80A HFNC device,were connected with the gas flow meter,simularted head and QuickLung and then put into a low-pressure chamber.The flow rates of the HFNC devices were set to 10,15,20,25,30,35,40,45,50,55 and 60 L/min,and the simulated altitudes of the low-pressure chamber were set to 6 000,5 000,4 000,3 000,2 000,1 000 and 0 m.The actual output airway flow rates,airway pressure changes and trends of the four HFNC devices were recorded at different setting altitudes and flow rates.SPSS 25.0 software was used for statistical analysis.Results The actual output airway flow rates of the four HFNC devices showed an increasing trend as the altitude rose with the simulated altitude of 6 000 m and the setting flow rate kept constant,which increased slowly and even went to decrease when the altitude and flow rate exceeded some limits.The degree of changes in the flow rate with the increasing altitude varied,and there was no uniform pattern.With the rising of altitude,the actual output airway pressure of the four HFNC devices with the flow rate raning from 10 to 35 L/min also increased gradually,which showed a decreasing trend(turning point)after going up to some certain value when the flow rate exceeded 35 L/min,and the altitude where the turning point appeared was lowered as the flow rate increased.Conclusion The actual output airway flow rates and airway pressure during HFNC rise at a high-altitude environment,and generally considerations have to be taken on required airway pressure,patient comfort and the altitude of the patient's usual place of residence when setting the flow rates of the HFNC device.[Chinese Medical Equipment Journal,2024,45(6):49-58]