Chronic visceral pain is a persistent and debilitating condition arising from dysfunction or sensitization of the visceral organs and their associated nervous pathways. Increasing evidence suggests that imbalances in central nervous system function play an essential role in the progression of visceral pain, but the exact mechanisms underlying the neural circuitry and molecular targets remain largely unexplored. In the present study, the ventral tegmental area (VTA) was shown to mediate visceral pain in mice. Visceral pain stimulation increased c-Fos expression and Ca²⁺ activity of glutamatergic VTA neurons, and optogenetic modulation of glutamatergic VTA neurons altered visceral pain. In particular, the upregulation of NMDA receptor 2A (NR2A) subunits within the VTA resulted in visceral pain in mice. Administration of a selective NR2A inhibitor decreased the number of visceral pain-induced c-Fos positive neurons and attenuated visceral pain. Pharmacology combined with chemogenetics further demonstrated that glutamatergic VTA neurons regulated visceral pain behaviors based on NR2A. In summary, our findings demonstrated that the upregulation of NR2A in glutamatergic VTA neurons plays a critical role in visceral pain. These insights provide a foundation for further comprehension of the neural circuits and molecular targets involved in chronic visceral pain and may pave the way for targeted therapies in chronic visceral pain.
Animals ; Male ; Visceral Pain/metabolism* ; Up-Regulation/physiology* ; Ventral Tegmental Area/metabolism* ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors* ; Neurons/drug effects* ; Mice, Inbred C57BL ; Mice ; Proto-Oncogene Proteins c-fos/metabolism* ; Chronic Pain/metabolism* ; Glutamic Acid/metabolism*

ObjectiveTo explore the molecular mechanism of modified Shengjiangsan in alleviating endoplasmic reticulum （ER） stress and reducing urinary protein in the rat model of diabetic nephropathy （DN）. MethodSeventy-five SD rats were randomized into normal， model， low-， medium-， and high-dose （4.37， 8.73， 17.46 g·kg^-1， respectively） modified Shengjiangsan， and irbesartan （0.014 g·kg^-1） groups， with 10 rats in each group. Rats were administrated with corresponding doses of medications or distilled water by gavage， once a day， for 8 consecutive weeks. After the last administration， the levels of glucose （GLU） in the blood， 24-hour urinary protein （24 h-UTP）， and superoxide dismutase （SOD）， malondialdehyde （MDA）， and glutathione peroxidase （GSH-Px） in the renal tissue were measured. Hematoxylin-eosin staining， periodic acid-Schiff staining， and transmission electron microscopy were employed to observe the pathological changes in rat kidneys. Immunohistochemistry was employed to measure the expression levels of nephrin， podocin， glucose-regulated protein 78 （GRP78）， C/EBP homologous protein （CHOP）， and activating transcription factor 4 （ATF4） in the kidneys of rats. Western blot was employed to measure the protein levels of silent information regulator 1 （Sirt1）， phosphorylated （p）-protein kinase RNA-like endoplasmic reticulum kinase （PERK）， and p-eukaryotic translation initiation factor 2 alpha （eIF2α） in rat kidneys. ResultCompared with the normal group， the modeling caused pathological damage to the kidneys， elevated the levels of GLU and 24 h-UTP （P<0.05）， up-regulated the protein levels of GRP78， CHOP， ATF4， p-PERK， and p-eIF2α （P<0.05）， and down-regulated the protein level of Sirt1 （P<0.05） in rat kidneys. Compared with the model group， modified Shengjiangsan and irbesartan lowered the GLU and 24 h-UTP levels （P<0.05）， alleviated the pathological damage in the renal tissue， down-regulated the protein levels of GRP78， CHOP， ATF4， p-PERK， and p-eIF2α （P<0.05）， and up-regulated the protein level of Sirt1 （P<0.05）. ConclusionModified Shengjiangsan up-regulates Sirt1 expression and inhibits phosphorylation of proteins in the PERK/eIF2α pathway to reduce ER stress and oxidative stress in the renal tissue， thus alleviating the pathological damage in the renal tissue and reducing urinary protein in DN rats.

Objective To investigate the efficacy and complications of one-step and two-step ultrasound-guided percutaneous transhepatic hepatic duct drainage(PTHD)in the treatment of advanced low-level biliary obstruction.Methods A total of 112 patients with advanced low-level biliary obstruction who underwent palliative surgery for reducing jaundice in the hospital from January 2019 to July 2023 were selected,and divided into the one-step group and the two-step group according to the principle of complete randomization(grouped by random number table method).The one-step group(n=56)underwent one-step PTHD,while the two-step group(n=56)underwent two-step PTHD.Surgery related indicators,serum total bilirubin(TBIL),alkaline phosphatase(ALP),alanine transaminase(ALT),the incidence of postoperative complications,and satisfaction were compared between the two groups.Results There was no difference in intraoperative blood loss[(2.96±0.50)ml vs.(3.02±0.53)ml],drainage volume in 48 hours after surgery[(555.84±90.51)ml vs.(560.52±104.23)ml]between the two groups(P＞0.05).Operation time and postoperative VAS score of the one-step group were significantly shorter/lower than those of the two-step group[(32.50±4.26)min vs.(36.43±3.58)min,(3.72±1.57)points vs.(4.53±1.34)points],and the success rate of puncture was significantly higher than that in the two-step group(96.43％vs.76.69％),with statistically significant differences(P＜0.05).After treatment,the levels of TBIL,ALP and ALT in the two groups were significantly reduced(P＜0.05),but there was no statistically significant difference between the groups(P＞0.05).There was no statistically significant difference in the incidence of complications between the two groups(3.57％vs.7.14％,Fisher's exact probability=0.679).The satisfaction rate in the one-step group was significantly higher than that in the two-step group(94.64％vs.75.00％),with a statistically significant difference(P＜0.05).ConclusionThe operation time of one-step PTHD is shorter and the success rate of puncture is higher.In addition,patients undergoing one-step PTHD have milder pain,and are more satisfied.

Objective To investigate the correlation between the imaging manifestations and pathological classification of congeni-tal cystic adenomatoid malformation of the lung(CCAM).Methods A retrospective analysis was conducted on the clinical and radiologic data of nine patients with pathologically confirmed CCAM,and all data were compared with Stocker pathological classification,respec-tively.Results The CT images of all nine patients demonstrated cysts filled with either gas or fluid,which corresponded exactly with their gross pathological outcomes.Four cases of large cystic CCAM(cyst diameter exceeding 2 cm)were consistent with Stocker type Ⅰ.CT findings showed single or multiple capsular cavities occupying the thoracic cavity,with gas or fluid mainly in the cyst.Two cases exhibited mass effect and expansion of the involved lung lobes,while two cases showed localized decreased density around the lesion.The pathological features of these large cystic CCAM included single or multiple thick-walled cysts,with pseudostratified ciliated colum-nar epithelium lining the cyst lumen observed under microscopy.The other five cases of small cystic CCAM(cyst diameter less than 2 cm)matched Stocker type Ⅱ.CT findings showed multiple thin-walled cellular cysts confined to a single lung lobe,and none of these patients had significant mass effect or expansion of the involved lung lobes.Pathologically,these cases were characterized by multiple small cysts with septa,and the cysts were primarily lined with ciliated columnar or cuboidal epithelium upon microscopy.Conclusion CT imaging of CCAM has specific manifestations,with accurately displaying the distribution range and morphological characteristics of the lesions and reflecting the internal histological characteristics.There is a significant correlation between the CT manifestations of CCAM and their pathological classification.

The etiology of congenital biliary dilatation(CBD)is still unclear.Currently,abnormal pancreatico-bile duct confluence is the mainstream theory.In terms of classification,Todani classification is the most widely used.On the other hand,Dong′s classification which proposed by Dong Jiahong and his colleagues has guiding significance for the selection of surgical methods.CBD is difficult to detect and diagnose because of the poor specificity of clinical symptoms,and it is often necessary to make a preliminary diagnosis based on the medical history,and it is also quite dependent on the assistance of imaging.Serological examination also plays a key role in the diagnosis of CBD because of its convenience and high acceptance.This article reviewed the etiology,classification and diagnosis of CBD.

ObjectiveTo observe the intervention effect of Dahuang Xiezhuo prescription （DHXZ） on inflammation and suppressor of cytokine signaling 3 （SOCS3）/Toll-like receptor 4 （TLR4） pathway in rats with chronic renal failure （CRF）， and to explore its molecular mechanism in alleviating renal inflammatory response. MethodThe 90 male SD rats， 15 were randomly selected as sham group， and the remaining 75 were used as modeling group to replicate CRF rat model by 5/6 nephrectomy. After successful modeling， the rats were randomly divided into model group， DHXZ low-， medium-， high-dose groups （6.825， 13.65， 27.3 g·kg^-1） and Niaoduqing Granules group （2.6 g·kg^-1）. The drug intervention groups received corresponding drugs by gavage for 8 consecutive weeks. After administration， hematoxylin-eosin （HE） staining and Masson staining were used to observe the morphological changes of rat renal tissue， and blood creatinine （SCr）， blood urea nitrogen （BUN） and blood uric acid （UA） were tested. Enzyme-linked immunosorbent assay （ELISA） was performed to detect the serum contents of interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α） and C-reactive protein （CRP）. The mRNA expressions of SOCS3 and TLR4 in renal tissue were detected by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）， and the protein expressions of SOCS3， TLR4， nuclear transcription factor （NF-κB） and myeloid differentiation factor （MyD88） were detected by Western blot. Immunohistochemistry was used to determine the protein expressions of NF-κB， MyD88， NOD-like receptor protein 3 （NLRP3） and melanoma deficiency factor 2 （AIM2）. ResultCompared with the sham group， the model group had a significant inflammatory response in renal tissue， and an increase in blood SCr， BUN， UTP， IL-6， TNF-α and CRP （P<0.05）. The protein and mRNA expressions of SOCS3 in renal tissue of rats in the model group were lower while the protein expressions of TLR4， NF-κB， MyD88， NLRP3 and AIM2 and the mRNA expression of TLR4 were higher than those in the sham group （P<0.05）. Compared with the model group， DHXZ and Niaoduqing granules groups presented markedly reduced inflammatory response in renal tissue and decreased blood SCr， BUN， UTP， IL-6， TNF-α and CRP （P<0.05）. Additionally， DHXZ and Niaoduqing granules up-regulated the protein and mRNA expressions of SOCS3 in renal tissue while down-regulated the protein expressions of TLR4， NF-κB， MyD88， NLRP3 and AIM2 and the mRNA expression of TLR4 （P<0.05）. ConclusionDHXZ can reduce the release and expression of inflammatory factors， inhibit the inflammatory response and improve renal function， and the mechanism may be related to the regulation of SOCS3/TLR4 signaling pathway.

Female pelvic organ prolapse (POP) is caused by damage or loss of pelvic floor support, resulting in displacement of the pelvic organs, which leads to abnormalities in the position and function of the organs, mainly due to damage to the pelvic floor mechanical support structures caused by transvaginal birth, loss of elasticity of the pelvic floor mechanical support structures in old women, and loss of the ability to maintain the pelvic floor. The key to POP surgery is the repair of the apical vagina, but treatment based on this theory has failed to achieve satisfactory clinical outcomes. This article will analyze the common procedures of apical suspension in the treatment of mid-pelvic prolapse from the perspective of pelvic floor morphological features and pelvic floor biomechanics axially.

Interleukin (IL)-17A, a pro-inflammatory cytokine, is a fundamental function in the onset and advancement of multiple immune diseases. To uncover the primary compounds with IL-17A inhibitory activity, a large-scale screening of the library of traditional Chinese medicine constituents and microbial secondary metabolites was conducted using splenic cells from IL-17A-GFP reporter mice cultured under Th17-priming conditions. Our results indicated that some aureane-type sesquiterpene tetraketides isolated from a wetland mud-derived fungus, Myrothecium gramineum, showed remarkable IL-17A inhibitory activity. Nine new aureane-type sesquiterpene tetraketides, myrogramins A-I ( 1, 4- 11), and two known ones ( 2 and 3) were isolated and identified from the strain. Compounds 1, 3, 4, 10, and 11 exhibited significant IL-17A inhibitory activity. Among them, compound 3, with a high fermentation yield dose-dependently inhibited the generation of IL-17A and suppressed glycolysis in splenic cells under Th17-priming conditions. Strikingly, compound 3 suppressed immunopathology in both IL-17A-mediated animal models of experimental autoimmune encephalomyelitis and pulmonary hypertension. Our results revealed that aureane-type sesquiterpene tetraketides are a novel class of immunomodulators with IL-17A inhibitory activity, and hold great promise applications in treating IL-17A-mediated immune diseases.

OBJECTIVE: To explore the genetic basis for a girl with distinctive facial features, epilepsy, intellectual disability, chronic constipation and hypopigmentation of neck and upper extremities. METHODS: Whole exome sequencing was carried out for the proband. Candidate variant was verified by Sanger sequencing. RESULTS: The proband was found to harbor a heterozygous nonsense c.586G>T (p.Glu196*) variant of the ZEB2 gene, which was unreported previously. The variant was not detected in either parent. CONCLUSION The ZEB2 gene c.586G>T (p.Glu196*) variant probably underlay the Mowat-Wilson syndrome in this patient. Hypopigmentation in the neck and upper extremities may be related to Mowat-Wilson syndrome. Prenatal diagnosis was recommended for subsequent pregnancies.
Facies ; Female ; Hirschsprung Disease ; Humans ; Hypopigmentation ; Intellectual Disability/genetics* ; Microcephaly ; Pregnancy ; Zinc Finger E-box Binding Homeobox 2/genetics*

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic lipids and metabolic stress-induced liver injury. There are currently no approved effective pharmacological treatments for NAFLD. Traditional Chinese medicine (TCM) has been used for centuries to treat patients with chronic liver diseases without clear disease types and mechanisms. More recently, TCM has been shown to have unique advantages in the treatment of NAFLD. We performed a systematic review of the medical literature published over the last two decades and found that many TCM formulas have been reported to be beneficial for the treatment of metabolic dysfunctions, including Potentilla discolor Bunge (PDB). PDB has a variety of active compounds, including flavonoids, terpenoids, organic acids, steroids and tannins. Many compounds have been shown to exhibit a series of beneficial effects for the treatment of NAFLD, including anti-oxidative and anti-inflammatory functions, improvement of lipid metabolism and reversal of insulin resistance. In this review, we summarize potential therapeutic effects of TCM formulas for the treatment of NAFLD, focusing on the medicinal properties of natural active compounds from PDB and their underlying mechanisms. We point out that PDB can be classified as a novel candidate for the treatment and prevention of NAFLD.