Hinokione: an abietene diterpene with pancreatic ß cells regeneration and hypoglycemic activity, and other derivatives with novel structures from the woods of Agathis dammara.

In this study, 14 abietene and pimarene diterpenoids were isolated from the woods of Agathis dammara. Among them, 4 new compounds, dammarone A-C and dammaric acid A (1-4), were firstly reported, respectively. The structure of the new compounds was determined by HR ESI-MS and 1D/2D NMR spectroscopy, and their absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. The hypoglycemic effect of all compounds was evaluated by transgenic zebrafish model, and the structure-activity relationship was discussed. Hinokione (7, HO) has low toxicity and significant hypoglycemic effects on zebrafish, the mechanism is mainly by promoting the differentiation of zebrafish pancreatic endocrine precursor cells (PEP cells) into ß cells, thereby promoting the regeneration of pancreatic ß cells.

Research Progress of Baihe Gujin Decoction in the Treatment of Lung Cancer.

Baihe Gujin decoction is one of the most commonly used decoction in traditional Chinese medicine for the treatment of lung cancer. It can nourish yin and moisten the lung as well as prevent phlegm from forming and stop coughing. On the one hand, Baihe Gujin decoction is characterized with extensive application, proven efficacy, a long history, and high safety. On the other hand, Baihe Gujin decoction can induce apoptosis of tumor cells, improve immune function and inhibit inflammation. The main anti-tumor components of this include kaempferol, quercetin, isorhamnetin, glycyrrhizin and ß-sitosterol. Clinically, Baihe Gujin decoction can improve the adverse reactions caused by radiotherapy, chemotherapy and immunotherapy for lung cancer, enhance the quality of life of patients, and prolong their survival time. At present, there are a large number of clinical and basic researches on the treatment of lung cancer with Baihe Gujin decoction. In this paper, we mainly discussed the treatment of lung cancer with Baihe Gujin decoction through analyzing basic and clinical researches at home and abroad in the past 20 years. Through the discussion, we aimed to probe deeper into Baihe Gujin decoction for the treatment of lung cancer, thereby providing a broader idea for clinical diagnosis and treatment of lung cancer.

mTORc2 in Distal-Convoluted-Tubule and Renal K+-Excretion during High Dietary K+ Intake.

BACKGROUND: Renal mTORc2 plays a role in regulating renal K+-excretion (renal-EK) and K+-homeostasis. Inhibition of renal mTORc2 caused hyperkalemia due to suppressing epithelial-Na+-channel (ENaC) and ROMK (Kir1.1) in the collecting duct. We now explore whether mTORc2 of DCT regulates basolateral Kir4.1/Kir5.1, NCC and renal-EK. METHODS: We used patch-clamp-technique to examine basolateral Kir4.1/Kir5.1 in early-DCT, immunoblotting and immunofluorescence to examine NCC expression and in vivo measurement of urinary K+-excretion to determine baseline renal-EK in the mice treated with mTORc2-inhibitor and in DCT-specific Rapamycin-Insensitive-Companion- of-mTOR knockout (DCT-RICTOR-KO) mice. RESULTS: Inhibition of mTORc2 with AZD8055 abolished high-K+-induced inhibition of Kir4.1/Kir5.1 in DCT, high-K+-induced depolarization of DCT membrane and high-K+-induced suppression of pNCC expression. AZD8055 stimulated the 40-pS-inwardly-rectifying-K+ channel (Kir4.1/Kir5.1-heterotetramer) in early-DCT in the mice on overnight-high-K+, this effect was absent in the presence of PKC-inhibitor which also stimulated Kir4.1/Kir5.1. AZD8055-treatment decreased renal-EK in animals on overnight-high-K+. Deletion of RICTOR in the DCT increased the Kir4.1/Kir5.1-mediated K+-currents, hyperpolarized DCT membrane and increased the expression of pWNK4 and pNCC. Renal-EK was lower and plasma-K+ was higher in DCT-RICTOR-KO mice than corresponding control mice. Also, overnight-high-K+ did not inhibit Kir4.1/Kir5.1 activity in the DCT and failed to inhibit the expression of pNCC in DCT-RICTOR-KO mice. Overnight-high-K+ stimulated renal-EK in control mice, but this effect was attenuated in DCT-RICTOR-KO mice. Thus, overnight-high-K+ induced hyperkalemia in DCT-RICTOR-KO mice but not in control mice. CONCLUSIONS: mTORc2 of the DCT inhibits Kir4.1/Kir5.1 activity and NCC expression, and stimulates renal-EK during high-K+-intake.

Age-dependent distribution of IgA and IgG antibody-secreting cells in the pharyngeal tonsil of the Bactrian camel.

The pharyngeal tonsil, located in the nasopharynx, can effectively defend against pathogens invading the body from the upper respiratory tract and play a crucial role in mucosal immunity of the respiratory tract. Immunoglobulin A (IgA) and Immunoglobulin G (IgG) serve as key effector molecules in mucosal immunity, exhibiting multiple immune functions. This study aimed to investigate the distribution patterns and age-related alterations of IgA and IgG antibody-secreting cells (ASCs) in the pharyngeal tonsils of Bactrian camels. Twelve Alashan Bactrian camels were categorized into four age groups: young (1-2 years, n=3), pubertal (3-5 years, n=3), middle-aged (6-16 years, n=3) and old (17-20 years, n=3). The distribution patterns of IgA and IgG ASCs in the pharyngeal tonsils of Bactrian camels of different ages were meticulously observed, analyzed and compared using immunohistochemical and statistical methods. The results revealed that IgA ASCs in the pharyngeal tonsils of all age groups were primarily clustered or diffusely distributed in the reticular epithelium and its subepithelial regions (region A) and around the glands (region C), scattered in the subepithelial regions of non-reticular epithelium (region B), and sporadically distributed in the interfollicular regions (region D). Interestingly, the distribution pattern of IgG ASCs in the pharyngeal tonsils closely mirrored that of IgA ASCs. The distribution densities of IgA and IgG ASCs in these four regions were significantly decreased in turn (P<0.05). However, IgA ASCs exhibited significantly higher densities than IgG ASCs in the same region (P<0.05). Age-related alterations indicated that the distribution densities of IgA and IgG ASCs in each region of the pharyngeal tonsils exhibited a trend of initially increasing and subsequently decreasing from young to old camels, reaching a peak in the pubertal group. As camels age, there was a significant decrease in the densities of IgA and IgG ASCs in all regions of the pharyngeal tonsils (P<0.05). The results demonstrate that the reticular epithelium and its subepithelial regions in the pharyngeal tonsils of Bactrian camels are the primary regions where IgA and IgG ASCs colonize and exert their immune functions. These regions play a pivotal role in inducing immune responses and defending against pathogen invasions in the pharyngeal tonsils. IgA ASCs may be the principal effector cells of the mucosal immune response in the pharyngeal tonsils of Bactrian camels. Aging significantly reduces the densities of IgA and IgG ASCs, while leaving their distribution patterns unaffected. These findings will provide valuable insights for further investigations into the immunomorphology, immunosenescence, and response mechanisms of the pharyngeal tonsils in Bactrian camels.

Developmental characteristics of aggregated lymphoid nodules area in the abomasum of fetal Bactrian camels (Camelus bactrianus).

BACKGROUND: Bactrian camel is one of the important economic animals in northwest China. They live in arid desert, and their gestation period is about 13 months, which is longer than other ruminants (such as cattle and sheep). The harsh living conditions have made its unique histological characteristics a research focus. Aggregated lymphoid nodules area (ALNA) in the abomasum of Bactrian camels, as one of the most important sites for the induction of the immune response, provide a comprehensive and effective protective role for the organism, and their lack of information will affect the feeding management, reproduction and epidemic prevention of Bactrian camels. In this study, the histological characteristics of the fetal ALNA in the abomasum of Bactrian camels at different developmental gestation have been described by using light microscopy and histology . RESULTS: The ALNA in the abomasum of the Chinese Alashan Bactrian camel is a special immune structure that was first discovered and reported by Wen-hui Wang. To further establish the developmental characteristics of this special structure in the embryonic stage, the abomasum ALNA of 8 fetuses of Alashan Bactrian camels with different gestational ages (5~13 months) were observed and studied by anatomy and histology. The results showed that the aggregation of reticular epithelial cells (RECs) surrounded by a very small number of lymphoid cells was detected for the first time in the abomasum of fetal camel at 5 months gestation, which was presumed to be primitive ALNA. At 7 months gestation, the reticular mucosal folds region (RMFR) appeared, but the longitudinal mucosal folds region (LMFR) was not significant, and histological observations showed that there were diffusely distributed lymphocytes around the RECs. At 10months gestation, RMFR and LMFR were clearly visible, lymphoid follicles appeared in histological observation, lymphocytes proliferated vigorously. By 13 months, the volume of lymphoid follicles increased, forming the subepithelial dome (SED), and there was a primitive interfollicular area between the lymphoid follicles, which contained high endothelial vein (HEV), but no germinal center (GC) was found. In summary, ALNA of Bactrian camels is not fully mature before birth. CONCLUSIONS: Generally, the small intestine PPs of ruminants (such as cattle and sheep) is already mature before birth, while the ALNA in the abomasum of Bactrian camels is not yet mature in the fetal period. During the development of ALNA in Bactrian camel, the development of lymphoid follicles extends from submucosa to Lamina propria. Interestingly, the deformation of FAE changes with age from simple columnar epithelium at the beginning of pregnancy to Simple cuboidal epithelium, which is opposite to the FAE deformation characteristics of PPs in the small intestine of fetal cattle and sheep. These results are the basis of further research on the specificity of ALNA in the abomasum of Bactrian camels.

TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception.

Efforts on developing transient receptor potential vanilloid 1 (TRPV1) drugs for pain management have been hampered by deleterious hypo- or hyperthermia caused by TRPV1 agonists/antagonists. Here, we compared the effects of four antagonists on TRPV1 polymodal gating and core body temperature (CBT) in Trpv1+/+, Trpv1-/-, and Trpv1T634A/T634A. Neither the effect on proton gating nor drug administration route, hair coverage, CBT rhythmic fluctuations, or inflammation had any influence on the differential actions of TRPV1 drugs on CBT. We identified the S4-S5 linker region exposed to the vanilloid pocket of TRPV1 to be critical for hyperthermia associated with certain TRPV1 antagonists. PSFL2874, a TRPV1 antagonist we discovered, is effective against inflammatory pain but devoid of binding to the S4-S5 linker and inducing CBT changes. These findings implicate that biased allosteric mechanisms exist for TRPV1 coupling to nociception and CBT regulation, opening avenues for the development of non-opioid analgesics without affecting CBT.

ROCK1 inhibition improves wound healing in diabetes via RIPK4/AMPK pathway.

Refractory wounds are a severe complication of diabetes mellitus that often leads to amputation because of the lack of effective treatments and therapeutic targets. The pathogenesis of refractory wounds is complex, involving many types of cells. Rho-associated protein kinase-1 (ROCK1) phosphorylates a series of substrates that trigger downstream signaling pathways, affecting multiple cellular processes, including cell migration, communication, and proliferation. The present study investigated the role of ROCK1 in diabetic wound healing and molecular mechanisms. Our results showed that ROCK1 expression significantly increased in wound granulation tissues in diabetic patients, streptozotocin (STZ)-induced diabetic mice, and db/db diabetic mice. Wound healing and blood perfusion were dose-dependently improved by the ROCK1 inhibitor fasudil in diabetic mice. In endothelial cells, fasudil and ROCK1 siRNA significantly elevated the phosphorylation of adenosine monophosphate-activated protein kinase at Thr172 (pThr172-AMPKα), the activity of endothelial nitric oxide synthase (eNOS), and suppressed the levels of mitochondrial reactive oxygen species (mtROS) and nitrotyrosine formation. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that ROCK1 inhibited pThr172-AMPKα by binding to receptor-interacting serine/threonine kinase 4 (RIPK4). These results suggest that fasudil accelerated wound repair and improved angiogenesis at least partially through the ROCK1/RIPK4/AMPK pathway. Fasudil may be a potential treatment for refractory wounds in diabetic patients.

Compounds from Agathis dammara exert hypoglycaemic activity by enhancing glucose uptake: lignans, terpenes and others.

In this study, two new kaurane diterpenes (16, 17), together with 12 lignans (1-12), a triterpene (15), and two other compounds (13, 14) were isolated from the woods of Agathis dammara. The structure of the new compound was determined by HR ESIMS and 1D/2D NMR spectroscopy, and its absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. Compounds 5, 11, 14 exhibit significant hypoglycaemic activity in zebrafish, and their mechanism of action is to enhance glucose uptake in zebrafish.

Moniezia benedeni infection increases IgE+ cells in sheep (Ovis aries) small intestine.

The concentration of immunoglobulin (Ig) E is the lowest among serum Igs, but it can induces type I hypersensitivity and plays an important role in anti-parasitic infection. The present study aimed to explore the residence characteristics of IgE+ cells in the sheep small intestine and the impact of Moniezia benedeni infection on them. The recombinant plasmids pET-28a-IgE were constructed and induced and expressed in Escherichia coli. BL21 (DE3). The rabbit anti-sheep IgE polyclonal antibody was prepared using the obtained recombinant protein as antigen. Finally, the levels of IgE+ cells in the small intestine of healthy (Control group) and naturally M. benedeni-infected (Infected group) sheep were detected analyzed. The results showed that the rabbit anti-sheep IgE polyclonal antibody with good immunogenicity (titer = 1: 128000) could specifically bind to the heavy chain of natural sheep IgE. In the Control group, the IgE+ cells were mainly distributed in lamina propria of the small intestine, and the densities were significantly decreased from duodenum to ileum (P<0.05), with respective values of (4.28 cells / 104 µm2, 1.80 cells / 104 µm2, and 1.44 cells / 104 µm2 in duodenum, jejunum, and ileum. In the Infected group, IgE+ cells density were 6.26 cells / 104 µm2, 3.01 cells / 104 µm2, and 2.09 cells / 104 µm2 in duodenum, jejunum and ileum respectively, which were significantly higher in all segments compared to the Control group (P<0.05), increasing by 46.26%, 67.22% and 45.14%, respectively. In addition, compared with the Control group, the IgE protein levels were significantly increased in all intestinal segments of the Infected group (P<0.01), however, there was no significant differences among the different intestinal segments within the same group (P>0.05). The results demonstrated that M. benedeni infection could significantly increase the content of IgE and the distribution density of its secreting cells in sheep small intestine. The intestinal mucosal immune system of sheep presented obvious specificity against M. benedeni infection. This lays a good foundation for further exploring molecular mechanisms of the intestinal mucosal immune system monitoring and responding to M. benedeni infection.

Feasibility and Tolerability of Anlotinib Plus PD-1 Blockades for Patients with Treatment-Refractory Metastatic Colorectal Cancer: A Retrospective Exploratory Study.

Objective: Therapeutic regimens are relatively scarce among patients with treatment-refractory metastatic colorectal cancer (CRC). This study aimed to determine the feasibility and tolerability of anlotinib plus PD-1 blockades in patients with treatment-refractory metastatic CRC retrospectively. Methods: A total of 68 patients with previously treated metastatic CRC who received anlotinib plus PD-1 blockades in clinical practice were included in this study retrospectively. Demographic and clinical characteristics of the patients, therapeutic outcomes and safety profile during administration were collected and briefly analyzed. All subjects were followed up regularly. Therapeutic outcomes, including drug response and prognosis, were presented, and a safety profile was depicted to illustrate the adverse reactions. Results: A total of 68 patients with treatment-refractory metastatic CRC who received anlotinib plus PD-1 blockades in clinical practice were included in the final analysis. Best therapeutic response during treatment indicated that partial response was observed in 11 patients, stable disease was noted in 41 patients, and progressive disease was found in 16 patients, producing an objective response rate of 16.2% (95% CI: 8.4%-27.1%) and a disease control rate of 76.5% (95% CI: 64.6%-85.9%). Prognostic analysis suggested that the median progression-free survival (PFS) of the 68 patients was 5.3 months (95% CI: 3.01-7.59), and the median overall survival (OS) was 12.5 months (95% CI: 9.40-15.60). Of the 11 patients who responded, the median duration of response was 6.7 months (95% CI: 2.89-10.53). Safety profile during treatment showed that patients experienced adverse reactions regardless of grade, and grade ≥3 adverse reactions were found in 61 patients (89.7%) and 41 patients (60.3%), respectively. Common adverse reactions were hypertension, myelosuppression (including leukopenia, neutropenia, thrombocytopenia, and anemia), fatigue, and hand-foot syndrome. Conclusion: Anlotinib plus PD-1 blockades demonstrated encouraging efficacy and acceptable safety profile in patients with treatment-refractory metastatic CRC preliminarily in clinical practice. This conclusion should be confirmed in prospective clinical trials.

Biocompatible N-carbazoleacetic acid decorated CuxO nanoparticles as self-cascading platforms for synergistic single near-infrared triggered phototherapy treating microbial infections.

In this work, positively charged N-carbazoleacetic acid decorated CuxO nanoparticles (CuxO-CAA NPs) as novel biocompatible nanozymes have been successfully prepared through a one-step hydrothermal method. CuxO-CAA can serve as a self-cascading platform through effective GSH-OXD-like and POD-like activities, and the former can induce continuous generation of H2O2 through the catalytic oxidation of overexpressed GSH in the bacterial infection microenvironment, which in turn acts as a substrate for the latter to yield ˙OH via Fenton-like reaction, without introducing exogenous H2O2. Upon NIR irradiation, CuxO-CAA NPs possess a high photothermal conversion effect, which can further improve the enzymatic activity for increasing the production rate of H2O2 and ˙OH. Besides, the photodynamic performance of CuxO-CAA NPs can produce 1O2. The generated ROS and hyperthermia have synergetic effects on bacterial mortality. More importantly, CuxO-CAA NPs are more stable and biosafe than Cu2O, and can generate electrostatic adsorption with negatively charged bacterial cell membranes and accelerate bacterial death. Antibacterial results demonstrate that CuxO-CAA NPs are lethal against methicillin-resistant Staphylococcus aureus (MRSA) and ampicillin-resistant Escherichia coli (AREC) through destroying the bacterial membrane and disrupting the bacterial biofilm formation. MRSA-infected animal wound models show that CuxO-CAA NPs can efficiently promote wound healing without causing toxicity to the organism.

Role of Angiotensin II Type 1a Receptor (AT1aR) of Renal Tubules in Regulating Inwardly Rectifying Potassium Channels 4.2 (Kir4.2), Kir4.1, and Epithelial Na+ Channel (ENaC).

BACKGROUND: Kir4.2 and Kir4.1 play a role in regulating membrane transport in the proximal tubule (PT) and in the distal-convoluted-tubule (DCT), respectively. METHODS: We generated kidney-tubule-specific-AT1aR-knockout (Ks-AT1aR-KO) mice to examine whether renal AT1aR regulates Kir4.2 and Kir4.1. RESULTS: Ks-AT1aR-KO mice had a lower systolic blood pressure than Agtr1aflox/flox (control) mice. Ks-AT1aR-KO mice had a lower expression of NHE3 (Na+/H+-exchanger 3) and Kir4.2, a major Kir-channel in PT, than Agtr1aflox/flox mice. Whole-cell recording also demonstrated that the membrane potential in PT of Ks-AT1aR-KO mice was lesser negative than Agtr1aflox/flox mice. The expression of Kir4.1 and Kir5.1, Kir4.1/Kir5.1-mediated K+ currents of DCT and DCT membrane potential in Ks-AT1aR-KO mice, were similar to Agtr1aflox/flox mice. However, angiotensin II perfusion for 7 days hyperpolarized the membrane potential in PT and DCT of the control mice but not in Ks-AT1aR-KO mice, while angiotensin II perfusion did not change the expression of Kir4.1, Kir4.2, and Kir5.1. Deletion of AT1aR did not significantly affect the expression of αENaC (epithelial Na+ channel) and ßENaC but increased cleaved γENaC expression. Patch-clamp experiments demonstrated that deletion of AT1aR increased amiloride-sensitive Na+-currents in the cortical-collecting duct but not in late-DCT. However, tertiapin-Q sensitive renal outer medullary potassium channel currents were similar in both genotypes. CONCLUSIONS: AT1aR determines the baseline membrane potential of PT by controlling Kir4.2 expression/activity but AT1aR is not required for determining the baseline membrane potential of the DCT and Kir4.1/Kir5.1 activity/expression. However, AT1aR is required for angiotensin II-induced hyperpolarization of basolateral membrane of PT and DCT. Deletion of AT1aR had no effect on baseline renal outer medullary potassium channel activity but increased ENaC activity in the CCD.

An investigation study on the interpretation of ultrasonic medical reports using OpenAI's GPT-3.5-turbo model.

OBJECTIVES: Ultrasound medical reports are an important means of diagnosing diseases and assessing treatment effectiveness. However, their professional terms and complex sentences often make it difficult for ordinary people to understand. Therefore, this study explores the clinical value of using artificial intelligence systems based on ChatGPT to interpret ultrasound medical reports. METHODS: In this study, a combination of online and offline questionnaires were used to survey both physicians and non-medical individuals. The questionnaires evaluated ChatGPT's interpretation of ultrasound reports from both professional and comprehensibility perspectives, and the results were analyzed using Excel spreadsheets. Additionally, a portion of the research content was evaluated using the Likert Scale 5-point method in the questionnaire. RESULTS: According to survey results, 67.4% of surveyed doctors believe that using ChatGPT for interpreting ultrasound medical reports can help improve work efficiency. At the same time, 69.72% of non-medical professionals believe it is necessary to enhance their understanding of medical ultrasound reports through ChatGPT interpretation, and 62.58% support the application of ChatGPT to ultrasound medical reports. The non-medical group's understanding of ultrasound medical reports significantly improved (p < 0.01) after implementing ChatGPT, However, 67.49% of the general public are concerned about ChatGPT's imperfect functionality, which may cause misleading information. This reflects that the public's trust in new technology is not high enough, and they are also worried about possible privacy leaks and security issues with ChatGPT technology. CONCLUSIONS: The higher acceptance and support of non-medical individuals for the interpretation of medical reports by ChatGPT might be due to the system's natural language processing abilities that allow them to better understand and evaluate report contents. However, the expertise and experience of physicians are still irreplaceable. This suggests that the ChatGPT-based ultrasound medical report interpretation system has certain clinical value and application prospects, but further optimization is necessary to address its shortcomings in data quality and professionalism. This study provides a reference and inspiration for promoting the application and development of ultrasound technology and artificial intelligence systems in the medical field.

Antibody preparation and age-dependent distribution of TLR8 in Bactrian camel spleens.

BACKGROUND: Toll-like receptor 8 (TLR8) can recognize specific pathogen-associated molecular patterns and exert multiple immunological functions through activation of signaling cascades. However, the precise distribution and age-related alterations of TLR8 in the spleens of Bactrian camels have not yet been investigated. This study aimed to prepare a rabbit anti-Bactrian camel TLR8 polyclonal antibody and elucidate the distribution of TLR8 in the spleens of Bactrian camels at different age groups. The methodology involved the construction of the pET-28a-TLR8 recombinant plasmid, followed by the expression of TLR8 recombinant protein via prokaryotic expression. Subsequently, rabbits were immunized with the purified protein to prepare the TLR8 polyclonal antibody. Finally, twelve Alashan Bactrian camels were categorized into four groups: young (1-2 years), pubertal (3-5 years), middle-aged (6-16 years) and old (17-20 years). These camels received intravenous sodium pentobarbital (20 mg/kg) anesthesia and were exsanguinated to collect spleen samples. Immunohistochemical techniques were employed to observe and analyze the distribution patterns and age-related changes of TLR8 in the spleen. RESULTS: The results showed that the TLR8 recombinant protein was expressed in the form of inclusion body with a molecular weight of 52 kDa, and the optimal induction condition involved 0.3 mmol/L IPTG induction for 8 h. The prepared antibody yielded a titer of 1:32 000, and the antibody demonstrated specific binding to TLR8 recombinant protein. TLR8 positive cells exhibited a consistent distribution pattern in the spleen across different age groups of Bactrian camels, primarily scattered within the periarterial lymphatic sheath of the white pulp, marginal zone, and red pulp. The predominant cell type expressing TLR8 was macrophages, with expression also observed in neutrophils and dendritic cells. Statistical analysis revealed that there were significant differences in the distribution density of TLR8 positive cells among different spleen regions at the same age, with the red pulp, marginal zone, and white pulp showing a descending order (P<0.05). Age-related changes indicated that the distribution density in the marginal zone and red pulp exhibited a similar trend of initially increasing and subsequently decreasing from young to old camels. As camels age, there was a significant decrease in the distribution density across all spleen regions (P<0.05). CONCLUSIONS: The results confirmed that this study successfully prepared a rabbit anti-Bactrian camel TLR8 polyclonal antibody with good specificity. TLR8 positive cells were predominantly located in the red pulp and marginal zone of the spleen, signifying their pivotal role in the innate immune response of the spleen. Aging was found to significantly reduce the density of TLR8 positive cells, while leaving their scattered distribution characteristics unaffected. These findings provide valuable support for further investigations into the immunomorphology and immunosenescence of the spleen in Bactrian camels.

Chronic cough relief by allosteric modulation of P2X3 without taste disturbance.

P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs were achieved by preventing allosteric changes of IP-HD in P2X3. While being therapeutically comparable to the newly licensed P2X3 RCC drug gefapixant, quercetin and PSFL2915 do not have an adverse effect on taste as gefapixant does. Thus, allosteric modulation of P2X3 via IP-HD may be a druggable strategy to alleviate RCC.

Adenosine stimulates the basolateral 50 pS K+ channel in renal proximal tubule via adenosine-A1 receptor.

Background: The basolateral potassium channels play an important role in maintaining the membrane transport in the renal proximal tubules (PT) and adenosine receptors have been shown to regulate the trans-epithelial Na+ absorption in the PT. The aim of the present study is to explore whether adenosine also regulates the basolateral K+ channel of the PT and to determine the adenosine receptor type and the signaling pathway which mediates the effect of adenosine on the K+ channel. Methods: We have used the single channel recording to examine the basolateral K+ channel activity in the proximal tubules of the mouse kidney. All experiments were performed in cell-attached patches. Results: Single channel recording has detected a 50 pS inwardly-rectifying K+ channel with high channel open probability and this 50 pS K+ channel is a predominant type K+ channel in the basolateral membrane of the mouse PT. Adding adenosine increased 50 pS K+ channel activity in cell-attached patches, defined by NPo (a product of channel Numbers and Open Probability). The adenosine-induced stimulation of the 50 pS K+ channel was absent in the PT pretreated with DPCPX, a selective inhibitor of adenosine A1 receptor. In contrast, adenosine was still able to stimulate the 50 pS K+ channel in the PT pretreated with CP-66713, a selective adenosine A2 receptor antagonist. This suggests that the stimulatory effect of adenosine on the 50 pS K+ channel of the PT was mediated by adenosine-A1 receptor. Moreover, the effect of adenosine on the 50 pS K+ channel was blocked in the PT pretreated with U-73122 or Calphostin C, suggesting that adenosine-induced stimulation of the 50 pS K+ channels of the PT was due to the activation of phospholipase C (PLC) and protein kinase C (PKC) pathway. In contrast, the inhibition of phospholipase A2 (PLA2) with AACOCF3 or inhibition of protein kinase A (PKA) with H8 failed to block the adenosine-induced stimulation of the 50 pS K+ channel of the PT. Conclusion: We conclude that adenosine activates the 50 pS K+ channels in the basolateral membrane of PT via adenosine-A1 receptor. Furthermore, the effect of adenosine on the 50 pS K+ channel is mediated by PLC-PKC signaling pathway.

Endovascular treatment for massive haemoptysis due to pulmonary pseudoaneurysm: report of 23 cases.

PURPOSE: To evaluate the safety and effectiveness of endovascular treatment for massive haemoptysis caused by pulmonary pseudoaneurysm (PAP). METHODS: The clinical data, imaging data, and endovascular treatment protocol of 23 patients with massive haemoptysis caused by continuous PAP were retrospectively analysed. The success, complications, postoperative recurrence rate, and influence of the treatment on pulmonary artery pressure were also evaluated. RESULTS: Nineteen patients with a bronchial artery-pulmonary artery (BA-PA) and/or nonbronchial systemic artery-pulmonary artery (NBSA-PA) fistula underwent bronchial artery embolization (BAE) and/or nonbronchial systemic artery embolization (NBSAE) + pulmonary artery embolization (PAE). The pulmonary artery (PA) pressures before and after embolization were 52.11 ± 2.12 (35-69 cmH2O) and 33.58 ± 1.63 (22-44 cmH2O), respectively (P = 0.001). Four patients did not have a BA-PA and/or NBSA-PA fistula. Embolization was performed in two patients with a distal PAP of the pulmonalis lobar arteria. Bare stent-assisted microcoils embolization was performed in the other two patients with a PAP of the main pulmonary lobar arteries. The PA pressures of the four patients before and after treatment were 24.50 ± 1.32 (22-28 cmH2O) and 24.75 ± 1.70 (22-29 cmH2O), respectively (P = 0.850). The technique had a 100% success rate with no serious complications and a postoperative recurrence rate of 30%. CONCLUSION: Endovascular treatment is safe and effective for massive haemoptysis caused by PAP. BAE and/or NBSAE can effectively reduce pulmonary hypertension in patients with a BA-PA and/or NBSA-PA fistula.

A meta-analysis of the incidence and risk of skin toxicity with nab-paclitaxel and paclitaxel in cancer treatment.

BACKGROUND: Skin toxicity of varying severity occurs mostly during various courses of chemotherapy. In clinical trials and practice, we have found that both nab-paclitaxel and paclitaxel cause side effects such as rash and pruritus. To further clarify the incidence of rash and pruritus in both, we conducted the present study by a systematic evaluation, the results of which can be used to guide clinical dosing choices. METHODS: An electrical search was performed on randomized controlled research trials of nab-paclitaxel and paclitaxel for the treatment of malignancies. The necessary data were extracted, integrated, and analyzed from the included studies by systematic evaluation and meta-analysis, depending on the study design. Further subgroup analyses were performed to explore the incidence of rash and pruritus in nab-paclitaxel and paclitaxel. RESULTS: Eleven studies with a total of 971 patients with malignancy were included. Four studies were application of single-agent nab-paclitaxel compared with paclitaxel, and seven studies were comparative chemotherapy drug combinations. The incidence of rash was higher in all grades of nab-paclitaxel than that in paclitaxel (OR=1.39, CI 95% [1.18-1.62]); the incidence of rash was higher in lower grades of paclitaxel than that in solvent-based paclitaxel (OR=1.31, CI 95% [1.11-1.53]); the incidence of rash was higher in all grades in the single-agent application comparison. The incidence of rash was higher in nab-paclitaxel than that in paclitaxel (OR=1.81, CI 95% [1.26-2.59]); there was no significant difference in the incidence of pruritus between nab-paclitaxel and paclitaxel (OR=1.19, CI 95% [0.88-1.61]). CONCLUSION: In comparison with paclitaxel, nab-paclitaxel significantly increased the risk of a teething rash. There was a significant risk correlation between nab-paclitaxel and teething rash. Early prevention, identification, and treatment of rash could significantly improve patient's quality of life and optimize their clinical survival.

Ocular manifestations and quality of life in patients after hematopoietic stem cell transplantation.

AIM: To explore the relationship between ocular and systemic conditions and the impact of ocular complications on the quality of life (QOL) in patients after allogeneic hematopoietic stem cell transplantation (ALLO-HSCT). METHODS: Forty-four patients with severe hematopoietic disease were enrolled after ALLO-HSCT at our center from July 2018 to October 2020. They completed two questionnaires: the Ocular Surface Disease Index (OSDI) and the quality-of-life scale for Chinese patients with visual impairment (SQOL-DV1). Ocular conditions and systemic conditions were also assessed. RESULTS: Eye damage was correlated with total bilirubin (P=0.005), and gamma-glutamyl transferase (GGT) (P=0.021). There was no significant correlation between the overall QOL score and OSDI (P=0.8226) or SQOL-DV1 (P=0.9526) scores. The OSDI and the overall QOL score were not correlated with ocular conditions, including best-corrected visual acuity (BCVA), intraocular pressure, Schirmer tear test II, sodium fluorescein staining, tear film breakup time, and tear meniscus height. SQOL-DV1 was correlated with BCVA (P=0.0007), sodium fluorescein staining (P=0.007), and tear film breakup time (P=0.0146). CONCLUSION: In some patients, early ocular symptoms are not evident after ALLO-HSCT, while ocular surface complications can be observed after a comprehensive ophthalmological examination. Especially for those with elevated total bilirubin or GGT, regular ophthalmic follow-up visits are essential to diagnose and treat ocular graft versus host disease (oGVHD), especially for patients with elevated total bilirubin or GGT.

Distribution characteristics of FcµR positive cells in small intestinal lymph nodes of Bactrian camel.

Exploring the expression characteristics of FcµR in small intestinal lymph nodes of bactrian camels can lay the foundation for further revealing the function of FcµR. The FcµR expression characteristics were systematically analysed by using prokaryotic expression, antibody preparation, immunohistochemical staining and statistical analysis. FcµR positive cells were mainly located in the lymphoid follicles and their numbers decreased in the order of duodenal lymph nodes, jejunal lymph nodes and ileal lymph nodes, and the number of positive cells was statistically significant between different intestinal segments (P<0.05). The FcµR is expressed in lymphoid follicular B cells, which not only facilitates the body's ability to regulate secretory IgM levels, but also acts as a local immune defence barrier. The small intestine has dual functions of immune tolerance and immune response, the proximal part mainly focuses on immune tolerance, and the distal part mainly focuses on immune response. This distribution ensures the unity of the duodenal absorption and immune defence, and also significantly increases the efficiency of the entire small intestine, which is why the number of FcµR positive cells decreases in the order of duodenal lymph nodes, jejunal lymph nodes and ileal lymph nodes.