HDAC/JAK dual target inhibitors of cancer-related targets: The success of nonclearable linked pharmacophore mode.

In recent years, the development of dual target drugs has become a research hotspot in cancer treatment and the reasonable design of the drugs is critical. The nonclearable linked pharmacophore mode is one of the commonly used strategies for designing dual target drugs, it can connect the pharmacophores of two synergistic target inhibitors into one molecule through the linker, which greatly improves the utilization of drugs. Epigenetic modifications as a potential treatment for multiple diseases have always been a subject of great concern, and Histone deacetylases (HDAC) plays an important role. Janus Kinase (JAK) is a family of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals through the JAK-signal transducers and the activators of transcription (STAT) pathway. Studies showed the combination of HDAC and JAK inhibitors exhibited synergistic effects in breast cancer treatment [1]. In addition, the pharmacophore models of the aforementioned two inhibitors indicate similar essential features. Further investigation on recent years' progress in the field demonstrated the nonclearable linked pharmacophore mode, using different length carbon chains as linkers to connect the pharmacophores of the two inhibitors, is the main strategy to design HDAC/JAK dual-target inhibitors which has been verified to be effective in biological activity tests. This review takes recent years' HDAC/JAK dual target inhibitors' development details as an example to summarize the general ideas behind the scene. We wish to provide the readers a theoretical basis for the development of more efficient dual-target or multi-target drugs in future.

A retrospective study of focused ultrasound versus cryotherapy in treatment of cervical squamous intraepithelial lesions.

PURPOSE: To compare the efficacy and safety of focused ultrasound (FUS) therapy and cryotherapy for cervical squamous intraepithelial lesion (SIL). METHODS: In this retrospective study, data pertaining to women treated for cervical SIL with FUS therapy or cryotherapy at the Second Affiliated Hospital of Chongqing Medical University between 21 April 2018 and 31 August 2020 were obtained. The patients were followed up after 3-6 and 6-12 months. The proportions of women with no evidence of disease, recurrent disease, clearance of the human papillomavirus (HPV) and adverse effects or complications were determined. RESULTS: Of the 250 women with complete data who were included in the study, 144 and 106 received FUS therapy and cryotherapy, respectively. Overall, FUS therapy was observed to be more effective than cryotherapy (91.7 vs. 79.2%, p = 0.005). Statistically significant differences were noted in the treatment efficacy for patients with low-grade SIL (LSIL) (92.3 vs. 80.2%, p = 0.011). However, there were no significant differences in the treatment efficacy for patients with high-grade SIL (HSIL) (88.9 vs. 75.0%, p = 0.390). The recurrence rates in patients with LSIL treated with FUS therapy or cryotherapy showed no significant differences at the 6-12-month follow-up (1.0 vs. 6.0%, p = 0.163). Furthermore, there was no recurrence in patients with HSIL, either in the FUS or cryotherapy group. FUS therapy and cryotherapy resulted in similar HPV clearance at the 3-6-month follow-up (77.1 vs. 64.8%, p = 0.057). No statistically significant differences were observed in the complication rates between the two groups (3.5 vs. 1.9%, p = 0.717). CONCLUSION: The results of this study suggest that FUS therapy is superior to cryotherapy in the treatment of cervical LSIL.

Effectiveness and immune responses of focused ultrasound ablation for cervical intraepithelial neoplasia.

PURPOSE: To investigate the safety, efficacy, and the immune responses of focused ultrasound in cervical intraepithelial neoplasia (CIN). METHODS: Patients with biopsy-confirmed CIN were recruited for focused ultrasound treatment and asked to return during 3-6 and 6-12 months post-treatment to receive cervical cytology, high-risk human papilloma virus (HPV) detection, and colposcopy. The effective rate was evaluated within 3-6 months, whereas the recurrence rate was evaluated within 6-12 months. Cervicovaginal lavage and cervical tissue were sampled before and 3-6 months after treatment. The expression of interferon gamma (IFN-γ), endoplasmic reticulum aminopeptidase 1 (ERAP1), human leucocyte antigen I (HLA-I), cluster of differentiation 4 (CD4), and cluster of differentiation 8 (CD8) in the cervical tissue were observed by immunohistochemistry. Immunoglobulin A (IgA) and interleukin 10 (IL-10) levels in the cervicovaginal lavage were detected by enzyme-linked immunosorbent assay. Comparisons were made in immune analyte levels before and after treatment. RESULTS: We analyzed the results of 154 patients. The effective rate at 3-6 months was 96.8%. The recurrence rate at 6-12 months was 2.0%. The eradication rate of HPV was 72.4% at 3-6 months and 81.0% at 6-12 months. No serious adverse reactions and complications were observed. After treatment, a higher expression of ERAP1 was observed (p < 0.05). Significant down-regulation of IgA and IL-10 were detected (each p < 0.05). However, the expression of CD4, CD8, HLA-I, as well as the release of IFN-γ, did not reach statistical significance (each p > 0.05). CONCLUSIONS: Focused ultrasound is an effective and safe therapy for treating CIN, which could improve the local immune milieu of the cervix to some extent.

Unleashing the Potential of Camptothecin: Exploring Innovative Strategies for Structural Modification and Therapeutic Advancements.

Camptothecin (CPT) is a potent anti-cancer agent targeting topoisomerase I (TOP1). However, CPT has poor pharmacokinetic properties, causes toxicities, and leads to drug resistance, which limit its clinical use. In this paper, to review the current state of CPT research. We first briefly explain CPT's TOP1 inhibition mechanism and the key hurdles in CPT drug development. Then we examine strategies to overcome CPT's limitations through structural modifications and advanced delivery systems. Though modifications alone seem insufficient to fully enhance CPT's therapeutic potential, structure-activity relationship analysis provides insights to guide optimization of CPT analogs. In comparison, advanced delivery systems integrating controlled release, imaging capabilities, and combination therapies via stimulus-responsive linkers and targeting moieties show great promise for improving CPT's pharmacological profile. Looking forward, multifaceted approaches combining selective CPT derivatives with advanced delivery systems, informed by emerging biological insights, hold promise for fully unleashing CPT's anti-cancer potential.

Bacteroides ovatus alleviates high-fat and high-cholesterol -induced nonalcoholic fatty liver disease via gut-liver axis.

Gut microbiota acts as a critical regulator in the development of nonalcoholic fatty liver disease (NAFLD), making probiotics a promise therapeutic strategy. Studies are needed to identify beneficial Bacteroides strains against NAFLD. Bacteroides ovatus (B. ovatus) may also exhibit therapy effect on NAFLD. The aim of this work was to evaluate the effect of B. ovatus on NAFLD and examine the mechanism. C57BL/6 J male mice were randomly divided into three groups: a control group (NCD) that received control standard diet, a model group (M) with high-fat and high-cholesterol (HFHC) diet, and M_Bo group that was fed HFFC supplemented with B. ovatus. Treatment with B. ovatus could reduce body weight, prevent hepatic steatohepatitis and liver injury. Mechanistically, B. ovatus induced changes of gut microbial diversity and composition, characterized by a decreased Firmicutes/Bacteroidetes (F/B) ratio in M_Bo group mice, a lower abundance of Proteobacteria, Verrucomicrobiota at phylum level and Ruminococcus_torques_group, Ruminococcus_gauvreauii_group, Erysipelatoclostridium at genus level, simultaneously a remarkablely higher fecal abundance of Lachnospiraceae_NK4A136_group, norank_f__Oscillospiraceae, Colidextribacter. Compared with M group, mice treated with B. ovatus showed an markedly altered fecal short chain fatty acids (SCFAs), a decline in serum levels of lipopolysaccharide (LPS), CD163, IL-1ß, TNF-α, reduced macrophages in livers. Additionally, B. ovatus treatment caused downregulation of genes involved in denovo lipogenesis (such as Srebfl, Acaca, Scd1, Fasn), which was accompanied by the upregulation of genes related with fatty acid oxidation (such as Ppara). In conclusion, this study provides evidence that B. ovatus could ameliorate NAFLD by modulating the gut-liver axis.

The effect of systemic lupus erythematosus on sexual function in women: an updated meta-analysis based on cross-sectional studies.

BACKGROUND: Systemic lupus erythematosus (SLE), a chronic systemic autoimmune disease, often affects different organs and tissues. It can be effectively managed using drugs; however, attention should be paid to the patient's quality of life. This study aimed to evaluate the effect of SLE on female sexual function based on current literature. METHODS: The PubMed, Embase, and Cochrane Library databases were searched for eligible studies published up to November 9, 2021. This review included all English studies that compared the sexual function between women with SLE and healthy women. A meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: A total of 367 records were retrieved from 3 electronic databases. Five studies that involved 710 women with SLE and 2059 healthy women were finally included in this meta-analysis. The result indicated a significant decrease (mean difference = - 1.74, 95% confidence interval - 3.14 to - 0.34, p = 0.02) in the total scores of the Female Sexual Function Index in women with SLE, implying that healthy women had better sexual function than those with SLE. CONCLUSION: The results of our study indicated that SLE could negatively affect the quality of sexual life in terms of desire, arousal, and pain. Thus, close attention should be paid to the sexual function of women with SLE. TRIAL REGISTRATION: This study was registered in the International Prospective Register of Systematic Reviews (registration number: CRD42021290439).

NAE modulators: A potential therapy for gastric carcinoma.

Neural precursor cell expressed developmentally downregulated protein-8 (NEDD8) is a ubiquitin-like protein, which activates an important post-translational modification process: neddylation, thereby regulating the stability and degradation of various proteins related to multiple physiological processes. And the abnormal activation of NEDD8 (overexpression or underexpression) is related to the occurrence of multiple cancers including gastric carcinoma. NEDD8 activating enzyme (NAE), a key enzyme for the activation of NEDD8, controls the initiation of the NEDD8 transfer cascade, which is an important target for anti-tumor drugs. With the disclosure of the anti-tumor mechanism, NAE modulators (inhibitors and agonists) have gradually become a research hotspot in the development of anti-tumor drugs. And the application of NAE modulators has also been further expanded, not only limited to certain hematological tumors, its therapeutic potential in multiple solid tumors, especially gastric carcinoma, has been gradually uncovered. This paper mainly explains the structural characteristics, catalytic sites, and mechanism of NAE. And the relationships between neddylation and tumors are also elaborated from the perspective of NAE regulating the downstream pathways. In addition, the NAE modulators reported in recent years were reviewed, mainly focusing on their discovery processes, structure-activity relationships, inhibitory efficacy, pharmacological mechanism, and clinical research. And we reasonably predict the application of NAE modulators in gastric carcinoma, according to its relationship with neddylation. We summarize the issues in NAE modulator development and discuss the possible development directions.

Advances in RIPK1 kinase inhibitors.

Programmed necrosis is a new modulated cell death mode with necrotizing morphological characteristics. Receptor interacting protein 1 (RIPK1) is a critical mediator of the programmed necrosis pathway that is involved in stroke, myocardial infarction, fatal systemic inflammatory response syndrome, Alzheimer's disease, and malignancy. At present, the reported inhibitors are divided into four categories. The first category is the type I ATP-competitive kinase inhibitors that targets the area occupied by the ATP adenylate ring; The second category is type Ⅱ ATP competitive kinase inhibitors targeting the DLG-out conformation of RIPK1; The third category is type Ⅲ kinase inhibitors that compete for binding to allosteric sites near ATP pockets; The last category is others. This paper reviews the structure, biological function, and recent research progress of receptor interaction protein-1 kinase inhibitors.

SPARC in hematologic malignancies and novel technique for hematological disease with its abnormal expression.

Secreted protein acidic and rich in cysteine (SPARC), also known as osteonectin or BM-40, is a matricellular protein involved in several biological processes including cell adhesion, growth factor availability, extracellular matrix remodeling and immune-regulation. SPARC has also been associated with a variety of diseases including diabetes, colon cancer, and leukemia. The expression of SPARC in different diseases exhibits some degree of ambiguity, especially in hemopathies. Herein, we review the current expression and effects of SPARC in various hematologic disorders with respect to nanoparticle albumin bound innovative therapies and related diagnostic research, providing a clinical perspective on the use of NAB technology in the frontier treatment of hematologic diseases.

Drugs for the treatment of glaucoma: Targets, structure-activity relationships and clinical research.

Glaucoma is the third leading cause of blindness and impairment of vision worldwide, after refractive errors and cataracts. According to the survey, the number of people with glaucoma is more than 76 million, with projections increasing to 112 million by 2040. With the coming of an aging society, the number of people suffering from glaucoma will increase day by day. Glaucoma is a heterogeneous disease characterized by damage to the head of the optic nerve and visual field. High intraocular pressure is a major risk and cause of glaucoma optic neuropathy. Therefore, drug lowering intraocular pressure therapy is still the first-line therapy in clinical practice. Here, the targets, structure-activity relationship, and clinical progress of drugs for the treatment of glaucoma are reviewed.

Effect of Bariatric Surgery on Urinary Incontinence in Obese Women: A Meta-analysis and Systematic Review.

OBJECTIVES: The aim of this study was to explore the effectiveness of bariatric surgery in obese women with urinary incontinence (UI) through meta-analysis. METHODS: Searches of PubMed, the Cochrane Library, and EMBASE databases were performed using "weight loss surgery/bariatric surgery/gastric bypass surgery" and "incontinentia urinae/uracratia/urinary incontinence/uroclepsia" in the title/abstract before January 2018. Then, meta-analysis was analyzed by Review Manager 5.3 (Cochrane Collaboration, Oxford, United Kingdom). The standardized mean difference (SMD) and odds ratio (OR) were used to describe results of continuous variables and dichotomous variables, respectively. RESULTS: Pooled data showed that bariatric surgery reduced the incidence of UI in obese women at the follow-up of 6 months (OR, 3.27; 95% confidence interval [CI], 2.55-4.21; P < 0.00001) and 12 months (OR, 4.04; 95% CI, 2.62-6.22; P < 0.00001) and significantly reduced the body mass index at 6 months (SMD, 1.86; 95% CI, 1.19-2.53; P < 0.00001) and 12 months (SMD, 2.04; 95% CI, 1.44-2.64; P < 0.00001). In addition, bariatric surgery could also significantly increase the quality of life (SMD, 0.53; 95% CI, 0.27-0.80; P < 0.00001) and improve the function of pelvic floor disorders (SMD, 0.55; 95% CI, 0.38-0.72; P < 0.00001) based on quality-of-life questionnaires and Pelvic Floor Distress Inventory 20, respectively. CONCLUSIONS: This meta-analysis demonstrated that bariatric surgery is an effective choice for obese women with UI. However, more randomized controlled trials are required to confirm this result.

Recent researches for dual Aurora target inhibitors in antitumor field.

Non-infectious and chronic diseases such as malignant tumors are now one of the main causes of human death. Its occurrence is a multi-factor, multi-step complex process with biological characteristics such as cell differentiation, abnormal proliferation, uncontrolled growth, and metastasis. It has been found that a variety of human malignant tumors are accompanied by over-expression and proliferation of Aurora kinase, which causes abnormalities in the mitotic process and is related to the instability of the genome that causes tumors. Therefore, the use of Aurora kinase inhibitors to target tumors is becoming a research hotspot. However, in cancer, because of the complexity of signal transduction system and the participation of different proteins and enzymes, the anticancer effect of selective single-target drugs is limited. After inhibiting one pathway, signal molecules can be conducted through other pathways, resulting in poor therapeutic effect of single-target drug treatment. Multi-target drugs can solve this problem very well. It can regulate the various links that cause disease at the same time without completely eliminating the relationship between the signal transmission systems, and it is not easy to cause drug resistance. Currently, studies have shown that Aurora dual-target inhibitors generated with the co-inhibition of Aurora and another target (such as CDK, PLK, JAK2, etc.) have better therapeutic effects on tumors. In this paper, we reviewed the studies of dual Aurora inhibitors that have been discovered in recent years.

The effect of systemic lupus erythematosus on sexual function in women: an updated meta-analysis based on cross-sectional studies

Abstract Background: Systemic lupus erythematosus (SLE), a chronic systemic autoimmune disease, often affects different organs and tissues. It can be effectively managed using drugs; however, attention should be paid to the patient's quality of life. This study aimed to evaluate the effect of SLE on female sexual function based on current literature. Methods: The PubMed, Embase, and Cochrane Library databases were searched for eligible studies published up to November 9, 2021. This review included all English studies that compared the sexual function between women with SLE and healthy women. A meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: A total of 367 records were retrieved from 3 electronic databases. Five studies that involved 710 women with SLE and 2059 healthy women were finally included in this meta-analysis. The result indicated a significant decrease (mean difference =−1.74, 95% confidence interval −3.14 to −0.34, p =0.02) in the total scores of the Female Sexual Function Index in women with SLE, implying that healthy women had better sexual function than those with SLE. Conclusion: The results of our study indicated that SLE could negatively affect the quality of sexual life in terms of desire, arousal, and pain. Thus, close attention should be paid to the sexual function of women with SLE. Trial registration: This study was registered in the International Prospective Register of Systematic Reviews (registration number: CRD42021290439).