Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune chec...Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints.Thousands of small molecule drugs or biological materials,especially antibody-based ICIs,are actively being studied and antibodies are currently widely used.Limitations,such as anti-tumor efficacy,poor membrane permeability,and unneglected tolerance issues of antibody-based ICIs,remain evident but are thought to be overcome by small molecule drugs.Recent structural studies have broadened the scope of candidate immune checkpoint molecules,as well as innovative chemical inhibitors.By way of comparison,small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features.Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions,including immune regulation,anti-angiogenesis,and cell cycle regulation.In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins,which will lay the foundation for further exploration.展开更多
AIM: To investigate the effect of a fat rich diet onnon-steroidal anti-inflammatory drug(NSAID)-induced mucosal damage in the murine small intestine.METHODS: C57BL6 mice were fed 4 types of diets with or without indom...AIM: To investigate the effect of a fat rich diet onnon-steroidal anti-inflammatory drug(NSAID)-induced mucosal damage in the murine small intestine.METHODS: C57BL6 mice were fed 4 types of diets with or without indomethacin.One group was fed standard laboratory chow.The other groups were fed a fat diet consisting of 8% w/w fat,beef tallow(rich in SFA),fish oil,(rich in omega-3 PUFA),or safflower oil(rich in omega-6 PUFA).Indomethacin(3 mg/kg) was injected intraperitoneally from day 8 to day 10.On day 11,intestines and adhesions to submucosal microvessels were examined.RESULTS: In the indomethacin-treated groups,mucosal damage was exacerbated by diets containing beef tallow and fish oil,and was accompanied by leukocyte infiltration(P < 0.05).The mucosal damage induced by indomethacin was significantly lower in mice fed the safflower oil diet than in mice fed the beef tallow or fish oil diet(P < 0.05).Indomethacin increased monocyte and platelet migration to the intestinal mucosa,whereas safflower oil significantly decreased monocyte and platelet recruitment(P < 0.05).CONCLUSION: A diet rich in SFA and omega-3 PUFA exacerbated NSAID-induced small intestinal damage via increased leukocyte infiltration.Importantly,a diet rich in omega-6-PUFA did not aggravate inflammation as monocyte migration was blocked.展开更多
Non-steroidal anti-inflammatory drug （NSAID）-induced small bowel injury is a topic that deserves attention since the advent of capsule endoscopy and balloon enteroscopy. NSAID enteropathy is common and is mostly asy...Non-steroidal anti-inflammatory drug （NSAID）-induced small bowel injury is a topic that deserves attention since the advent of capsule endoscopy and balloon enteroscopy. NSAID enteropathy is common and is mostly asymptomatic. However, massive bleeding, stricture, or perforation may occur. The pathogenesis of small intestine injury by NSAIDs is complex and different from that of the upper gastrointestinal tract. No drug has yet been developed that can completely prevent or treat NSAID enteropathy. Therefore, a long-term randomized study in chronic NSAID users is needed.展开更多
According to the physiological and anatomical characteristics of small intestine,neglecting the effect of its motility on the distribution and absorption of drug and nutrient,Y.Miyamoto et al.proposed a model of two-d...According to the physiological and anatomical characteristics of small intestine,neglecting the effect of its motility on the distribution and absorption of drug and nutrient,Y.Miyamoto et al.proposed a model of two-dimensional laminar flow in a circular porous tube with permeable wall and calculated the concentration profile of drugby numerical analysis.In this paper,we give a steady-state analytical solution of the above model including deactivationterm.The obtained results are in agreement with the results of their numerical analysis. Moreover the analytical solution presented in this paper reveals the relation among the physiological parameters of the model and describes the basic absorption rule of drug and nutrient through the intestinal wall and hence pro- vides a theoretical basis for determining the permeability and reflection coefficient through in situ experiments.展开更多
AIM:To investigate the effect of mesalazine granules on small intestinal injury induced by naproxen using capsule endoscopy (CE).METHODS:This was a single center,non-randomized,open-label,uncontrolled pilot study,usin...AIM:To investigate the effect of mesalazine granules on small intestinal injury induced by naproxen using capsule endoscopy (CE).METHODS:This was a single center,non-randomized,open-label,uncontrolled pilot study,using the PillCam SB CE system with RAPID 5 software.The Lewis Index Score (LIS) for small bowel injury was investigated to evaluate the severity of mucosal injury.Arthropathy patients with at least one month history of daily naproxen use of 1000 mg and proton pump inhibitor co-therapy were screened.Patients with a minimum LIS of 135 were eligible to enter the 4-wk treatment phase of the study.During this treatment period,3 × 1000 mg/d mesalazine granules were added to ongoing therapies of 1000 mg/d naproxen and 20 mg/d omeprazole.At the end of the 4-wk combined treatment period,a second small bowel CE was performed to re-evaluate the enteropathy according to the LIS results.The primary objective of this study was to assess the mucosal changes after 4 wk of mesalazine treatment.RESULTS:A total of 18 patients (16 females),ranging in age from 46 to 78 years (mean age 60.3 years) were screened,all had been taking 1000 mg/d naproxen for at least one month.Eight patients were excluded from the mesalazine therapeutic phase of the study for the following reasons:the screening CE showed normal small bowel mucosa or only insignificant damages (LIS < 135) in five patients,the screening esophagogastroduodenoscopy revealed gastric ulcer in one patient,capsule technical failure and incomplete CE due to poor small bowel cleanliness in two patients.Ten patients (9 female,mean age 56.2 years) whose initial LIS reached mild and moderate-to-severe enteropathy grades (between 135 and 790 and ≥ 790) entered the 4-wk therapeutic phase and a repeat CE was performed.When comparing the change in LIS from baseline to end of treatment in all patients,a marked decrease was seen (mean LIS:1236.4 ± 821.9 vs 925.2 ± 543.4,P=0.271).Moreover,a significant difference between pre-and post-treatment mean total LIS was detected in 7 patients who had moderate-tosevere enteropathy gradings at the inclusion CE (mean LIS:1615 ± 672vs 1064 ± 424,P=0.033).CONCLUSION:According to the small bowel CE evaluation mesalazine granules significantly attenuated mucosal injuries in patients with moderate-to-severe enteropathies induced by naproxen.展开更多
Intestinal bacteria play a role in the development of non-steroidal anti-inflammatory drugs （NSAID）-induced small intestinal injury. Agents such as probiotics, able to modi~ the gut ecology, might theoretically be u...Intestinal bacteria play a role in the development of non-steroidal anti-inflammatory drugs （NSAID）-induced small intestinal injury. Agents such as probiotics, able to modi~ the gut ecology, might theoretically be useful in preventing small intestinal damage induced by NSAIDs. The clinical studies available so far do suggest that some probiotic agents can be effective in this respect.展开更多
Nanomedicine has made great progress in the targeted therapy of cancer. Here, we established a novel drug-mate strategy by studying the formulation of nanodrugs at the molecular level. In the drug-mate combination, th...Nanomedicine has made great progress in the targeted therapy of cancer. Here, we established a novel drug-mate strategy by studying the formulation of nanodrugs at the molecular level. In the drug-mate combination, the drug is a hydrophobic drug that is poorly soluble in water, and the mate is an amphiphilic small molecule (SMA) that has both hydrophilic and lipophilic properties. We proposed that the hydrophobic drug could co-assemble with a suitable SMA on a nanoscale without additive agents. The proof-ofconcept methodology and results were presented to support our hypothesis. We selected five hydrophobic drugs and more than ten amphiphilic small molecules to construct a library. Through molecular dynamic simulation and quantum chemistry computation,we speculated that the formation of nanoassemblies was related to the binding energy of the drug-mate, and the drug-mate interaction must overcome drug-drug interaction.Furthermore, the obtained SF/VECOONa nanoassemblieswas selected as a model, which had an ultra-high drug loading content (46%), improved pharmacokinetics, increased bioavailability, and enhanced therapeutic efficacy. In summary, the drug-mate strategy is an essential resource to design exact SMA for many hydrophobic drugs and provides a reference for the design of a carrier-free drug delivery system.展开更多
AIM:To investigate the small bowel of seronegative spondyloarthropathy(SpA) patients in order to ascertain the presence of mucosal lesions.METHODS:Between January 2008 and June 2010,54 consecutive patients were enroll...AIM:To investigate the small bowel of seronegative spondyloarthropathy(SpA) patients in order to ascertain the presence of mucosal lesions.METHODS:Between January 2008 and June 2010,54 consecutive patients were enrolled and submitted to avideo capsule endoscopy(VCE) examination.Historyand demographic data were taken,as well as the history of non-steroidal anti-inflammatory drug(NSAID) consumption.After reading each VCE recording,a capsule endoscopy scoring index for small bowel mucosal inflammatory change(Lewis score) was calculated.Statistical analysis of the data was performed.RESULTS:The Lewis score for the whole cohort was 397.73.It was higher in the NSAID consumption subgroup(P = 0.036).The difference in Lewis score between NSAID users and non-users was reproduced for the first and second proximal tertiles of the small bowel,but not for its distal third(P values of 0.036,0.001 and 0.18,respectively).There was no statistical significant difference between the groups with regard to age or sex of the patients.CONCLUSION:The intestinal inflammatory involvement of SpA patients is more prominent in NSAID users for the proximal/mid small bowel,but not for its distal part.展开更多
Generally, proton-pump inhibitors(PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestin...Generally, proton-pump inhibitors(PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating nonsteroidal anti-inflammatory drug-induced small intestinal injury.Several meta-analyses and systematic reviews have reported that patients treated with PPIs, as well as post-gastrectomy patients, have a higher frequency of small intestinal bacterial overgrowth(SIBO) compared to patients who lack the aforementioned conditions.Furthermore, there is insufficient evidence that these conditions induce Clostridium difficile infection. At this time, PPI-induced dysbiosis is considered a type of SIBO. It now seems likely that intestinal bacterial flora influence many diseases, such as inflammatory bowel disease, diabetes mellitus, obesity, nonalcoholic fatty liver disease, and autoimmune diseases.When attempting to control intestinal bacterial flora with probiotics, prebiotics, and fecal microbiota transplantation, etc., the influence of acid suppression therapy, especially PPIs, should not be overlooked.展开更多
Most of the early prostate cancer has no obvious symptoms, but its malignancy metastasis will cause largely deaths. The treatment options for patients with prostate cancer include traditional surgery, external beam th...Most of the early prostate cancer has no obvious symptoms, but its malignancy metastasis will cause largely deaths. The treatment options for patients with prostate cancer include traditional surgery, external beam therapy, hormone therapy, small molecular drug and cryosurgery. It was considered non-traditional treatments also can be used in alternative medicines for prostate cancer therapy. There are well-known molecular mechanisms and their pathogenesis, which provide potential targets for drug screening on the prostate cancer. Currently, natural plant extracts or human tissues active ingredients are widely used for the treatment of cancer. Then isolated effective substances in the extract, and further prepared large amounts of small molecule drugs by chemical synthesis. In this review, we summarized four small molecular drugs, abiraterone, docetaxel, isochaihulactone and butylidenephthalide, and their detailed anti-tumor mechanisms. These indicate that small molecular drug is a very efficient way and can be used for prostate cancer treatment.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.82203539 and 92259102)Provincial Cooperation Project of Science and Technology Department of Sichuan Province(Grant No.2023YFSY0043)the National Key Research and Development Program of China(Grant No.2023YFC3402100).
文摘Immune checkpoint inhibitors(ICIs)are used to relieve and refuel anti-tumor immunity by blocking the interaction,transcription,and translation of co-inhibitory immune checkpoints or degrading co-inhibitory immune checkpoints.Thousands of small molecule drugs or biological materials,especially antibody-based ICIs,are actively being studied and antibodies are currently widely used.Limitations,such as anti-tumor efficacy,poor membrane permeability,and unneglected tolerance issues of antibody-based ICIs,remain evident but are thought to be overcome by small molecule drugs.Recent structural studies have broadened the scope of candidate immune checkpoint molecules,as well as innovative chemical inhibitors.By way of comparison,small molecule drug-based ICIs represent superior oral bioavailability and favorable pharmacokinetic features.Several ongoing clinical trials are exploring the synergetic effect of ICIs and other therapeutic strategies based on multiple ICI functions,including immune regulation,anti-angiogenesis,and cell cycle regulation.In this review we summarized the current progression of small molecule ICIs and the mechanism underlying immune checkpoint proteins,which will lay the foundation for further exploration.
基金Supported by National Defense Medical College,by Intractable Diseasesthe Health and Labour Sciences Research Grants fromMinistry of HealthLabour and Welfare and by Research for the similarity and difference in epidemiology,pathophysiology,diagnosis and treatment of rare intestinal refractory diseases andby a grant from the Smoking Research Foundation
文摘AIM: To investigate the effect of a fat rich diet onnon-steroidal anti-inflammatory drug(NSAID)-induced mucosal damage in the murine small intestine.METHODS: C57BL6 mice were fed 4 types of diets with or without indomethacin.One group was fed standard laboratory chow.The other groups were fed a fat diet consisting of 8% w/w fat,beef tallow(rich in SFA),fish oil,(rich in omega-3 PUFA),or safflower oil(rich in omega-6 PUFA).Indomethacin(3 mg/kg) was injected intraperitoneally from day 8 to day 10.On day 11,intestines and adhesions to submucosal microvessels were examined.RESULTS: In the indomethacin-treated groups,mucosal damage was exacerbated by diets containing beef tallow and fish oil,and was accompanied by leukocyte infiltration(P < 0.05).The mucosal damage induced by indomethacin was significantly lower in mice fed the safflower oil diet than in mice fed the beef tallow or fish oil diet(P < 0.05).Indomethacin increased monocyte and platelet migration to the intestinal mucosa,whereas safflower oil significantly decreased monocyte and platelet recruitment(P < 0.05).CONCLUSION: A diet rich in SFA and omega-3 PUFA exacerbated NSAID-induced small intestinal damage via increased leukocyte infiltration.Importantly,a diet rich in omega-6-PUFA did not aggravate inflammation as monocyte migration was blocked.
文摘Non-steroidal anti-inflammatory drug （NSAID）-induced small bowel injury is a topic that deserves attention since the advent of capsule endoscopy and balloon enteroscopy. NSAID enteropathy is common and is mostly asymptomatic. However, massive bleeding, stricture, or perforation may occur. The pathogenesis of small intestine injury by NSAIDs is complex and different from that of the upper gastrointestinal tract. No drug has yet been developed that can completely prevent or treat NSAID enteropathy. Therefore, a long-term randomized study in chronic NSAID users is needed.
基金The project supported by NSF of Shandong Province
文摘According to the physiological and anatomical characteristics of small intestine,neglecting the effect of its motility on the distribution and absorption of drug and nutrient,Y.Miyamoto et al.proposed a model of two-dimensional laminar flow in a circular porous tube with permeable wall and calculated the concentration profile of drugby numerical analysis.In this paper,we give a steady-state analytical solution of the above model including deactivationterm.The obtained results are in agreement with the results of their numerical analysis. Moreover the analytical solution presented in this paper reveals the relation among the physiological parameters of the model and describes the basic absorption rule of drug and nutrient through the intestinal wall and hence pro- vides a theoretical basis for determining the permeability and reflection coefficient through in situ experiments.
基金Supported by Dr.Falk Pharma GmbH,in part,study code:SAG-43/SBE
文摘AIM:To investigate the effect of mesalazine granules on small intestinal injury induced by naproxen using capsule endoscopy (CE).METHODS:This was a single center,non-randomized,open-label,uncontrolled pilot study,using the PillCam SB CE system with RAPID 5 software.The Lewis Index Score (LIS) for small bowel injury was investigated to evaluate the severity of mucosal injury.Arthropathy patients with at least one month history of daily naproxen use of 1000 mg and proton pump inhibitor co-therapy were screened.Patients with a minimum LIS of 135 were eligible to enter the 4-wk treatment phase of the study.During this treatment period,3 × 1000 mg/d mesalazine granules were added to ongoing therapies of 1000 mg/d naproxen and 20 mg/d omeprazole.At the end of the 4-wk combined treatment period,a second small bowel CE was performed to re-evaluate the enteropathy according to the LIS results.The primary objective of this study was to assess the mucosal changes after 4 wk of mesalazine treatment.RESULTS:A total of 18 patients (16 females),ranging in age from 46 to 78 years (mean age 60.3 years) were screened,all had been taking 1000 mg/d naproxen for at least one month.Eight patients were excluded from the mesalazine therapeutic phase of the study for the following reasons:the screening CE showed normal small bowel mucosa or only insignificant damages (LIS < 135) in five patients,the screening esophagogastroduodenoscopy revealed gastric ulcer in one patient,capsule technical failure and incomplete CE due to poor small bowel cleanliness in two patients.Ten patients (9 female,mean age 56.2 years) whose initial LIS reached mild and moderate-to-severe enteropathy grades (between 135 and 790 and ≥ 790) entered the 4-wk therapeutic phase and a repeat CE was performed.When comparing the change in LIS from baseline to end of treatment in all patients,a marked decrease was seen (mean LIS:1236.4 ± 821.9 vs 925.2 ± 543.4,P=0.271).Moreover,a significant difference between pre-and post-treatment mean total LIS was detected in 7 patients who had moderate-tosevere enteropathy gradings at the inclusion CE (mean LIS:1615 ± 672vs 1064 ± 424,P=0.033).CONCLUSION:According to the small bowel CE evaluation mesalazine granules significantly attenuated mucosal injuries in patients with moderate-to-severe enteropathies induced by naproxen.
文摘Intestinal bacteria play a role in the development of non-steroidal anti-inflammatory drugs （NSAID）-induced small intestinal injury. Agents such as probiotics, able to modi~ the gut ecology, might theoretically be useful in preventing small intestinal damage induced by NSAIDs. The clinical studies available so far do suggest that some probiotic agents can be effective in this respect.
基金supported by the National Natural Science Foundation of China (grant numbers:81974498)Natural Science Foundation of Shandong Province (grant numbers:ZR2019BH079)。
文摘Nanomedicine has made great progress in the targeted therapy of cancer. Here, we established a novel drug-mate strategy by studying the formulation of nanodrugs at the molecular level. In the drug-mate combination, the drug is a hydrophobic drug that is poorly soluble in water, and the mate is an amphiphilic small molecule (SMA) that has both hydrophilic and lipophilic properties. We proposed that the hydrophobic drug could co-assemble with a suitable SMA on a nanoscale without additive agents. The proof-ofconcept methodology and results were presented to support our hypothesis. We selected five hydrophobic drugs and more than ten amphiphilic small molecules to construct a library. Through molecular dynamic simulation and quantum chemistry computation,we speculated that the formation of nanoassemblies was related to the binding energy of the drug-mate, and the drug-mate interaction must overcome drug-drug interaction.Furthermore, the obtained SF/VECOONa nanoassemblieswas selected as a model, which had an ultra-high drug loading content (46%), improved pharmacokinetics, increased bioavailability, and enhanced therapeutic efficacy. In summary, the drug-mate strategy is an essential resource to design exact SMA for many hydrophobic drugs and provides a reference for the design of a carrier-free drug delivery system.
基金Supported by CNCSIS-UEFISCSU, Romanian Ministry of Education and Research, project number PNII-IDEI 320/2007part of a study registered on ClinicalTrials.gov with the number NCT00768950
文摘AIM:To investigate the small bowel of seronegative spondyloarthropathy(SpA) patients in order to ascertain the presence of mucosal lesions.METHODS:Between January 2008 and June 2010,54 consecutive patients were enrolled and submitted to avideo capsule endoscopy(VCE) examination.Historyand demographic data were taken,as well as the history of non-steroidal anti-inflammatory drug(NSAID) consumption.After reading each VCE recording,a capsule endoscopy scoring index for small bowel mucosal inflammatory change(Lewis score) was calculated.Statistical analysis of the data was performed.RESULTS:The Lewis score for the whole cohort was 397.73.It was higher in the NSAID consumption subgroup(P = 0.036).The difference in Lewis score between NSAID users and non-users was reproduced for the first and second proximal tertiles of the small bowel,but not for its distal third(P values of 0.036,0.001 and 0.18,respectively).There was no statistical significant difference between the groups with regard to age or sex of the patients.CONCLUSION:The intestinal inflammatory involvement of SpA patients is more prominent in NSAID users for the proximal/mid small bowel,but not for its distal part.
文摘Generally, proton-pump inhibitors(PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating nonsteroidal anti-inflammatory drug-induced small intestinal injury.Several meta-analyses and systematic reviews have reported that patients treated with PPIs, as well as post-gastrectomy patients, have a higher frequency of small intestinal bacterial overgrowth(SIBO) compared to patients who lack the aforementioned conditions.Furthermore, there is insufficient evidence that these conditions induce Clostridium difficile infection. At this time, PPI-induced dysbiosis is considered a type of SIBO. It now seems likely that intestinal bacterial flora influence many diseases, such as inflammatory bowel disease, diabetes mellitus, obesity, nonalcoholic fatty liver disease, and autoimmune diseases.When attempting to control intestinal bacterial flora with probiotics, prebiotics, and fecal microbiota transplantation, etc., the influence of acid suppression therapy, especially PPIs, should not be overlooked.
文摘Most of the early prostate cancer has no obvious symptoms, but its malignancy metastasis will cause largely deaths. The treatment options for patients with prostate cancer include traditional surgery, external beam therapy, hormone therapy, small molecular drug and cryosurgery. It was considered non-traditional treatments also can be used in alternative medicines for prostate cancer therapy. There are well-known molecular mechanisms and their pathogenesis, which provide potential targets for drug screening on the prostate cancer. Currently, natural plant extracts or human tissues active ingredients are widely used for the treatment of cancer. Then isolated effective substances in the extract, and further prepared large amounts of small molecule drugs by chemical synthesis. In this review, we summarized four small molecular drugs, abiraterone, docetaxel, isochaihulactone and butylidenephthalide, and their detailed anti-tumor mechanisms. These indicate that small molecular drug is a very efficient way and can be used for prostate cancer treatment.
