Design, synthesis and biological evaluation of nitrofuran-1,3,4-oxadiazole hybrids as new antitubercular agents.

Three series of novel nitrofuran-1,3,4-oxadiazole hybrids were designed and synthesized as new anti-TB agents. The structure activity relationship study indicated that the linkers and the substituents on the oxadiazole moiety greatly influence the activity, and the substituted benzenes are more favoured than the cycloalkyl or heterocyclic groups. Besides, the optimal compound in series 2 was active against both MTB H37Rv strain and MDR-MTB 16883 clinical isolate and also displayed low cytotoxicity, low inhibition of hERG and good oral PK, indicating its promising potential to be a lead for further structural modifications.

Different roles of the RAAS affect bone metabolism in patients with primary aldosteronism, Gitelman syndrome and Bartter syndrome.

BACKGROUND: Components of the RAAS may influence bone metabolism. Different roles of the RAAS are found in patients with primary aldosteronism (PA), Gitelman syndrome (GS) and Bartter syndrome (BS). We collected inpatient medical records including 20 patients with Gitelman syndrome (GS group), 17 patients with Bartter syndrome (BS group) and 20 age-matched patients with primary aldosteronism (PA group). We found the following results. (1) PA patients had significantly higher serum magnesium, potassium, plasma aldosterone, serum parathyroid hormone, urinary calcium and BMI (p<0.05) while significantly lower serum calcium and phosphorus (P < 0.05) than GS and BS patients. (2) Total hip and femoral neck bone mineral density (BMD) in PA patients were significantly lower than those in GS and BS patients (P<0.05). (3) GS patients had lower serum magnesium and urinary calcium than BS patients (P < 0.05). (4) Compared with BS patients, the vertebral BMD in GS patients were significantly higher (P < 0.05). So we believe higher aldosterone and PTH levels may be the reason that PA patients have lower hip BMD. Lower urinary calcium and inactivation of the NCC gene (Na-Cl cotransporter) in GS patients may have protective effects on vertebral bone mineral density. CONCLUSIONS: With persistence disordered RAAS, PA patients have lower BMD, especially hip BMD as compared with GS and BS patients. We presumed the lower renin and higher aldosterone level may be the reason. With the same level of renin and aldosterone, BS patients have lower vertebrate BMD than GS patients. Decreased urinary calcium excretion may be the reason.

Median nerve block increases the success rate of radial artery cannulation in women with gestational hypertension undergoing cesarean section.

BACKGROUND: The radial artery cannulation helps to maintain the stability of maternal hemodynamics and reduce complications, however, it is difficult for women with gestational hypertension. Ultrasound-guided median nerve block can cause arterial vasodilation, which may improve the success rate of radial artery cannulation. METHODS: Ninety-two women with gestational hypertension and risks of intra-operative bleeding undergoing cesarean section following failed ultrasound-guided cannulation were identified and randomized into the median nerve block group and control group. Median nerve block was performed under the guidance of ultrasound in the middle forearm and 5 ml of 0.5% lidocaine was injected. Subcutaneous local block was administered in the control group. The ultrasound-guided radial artery cannulation was performed ten minutes after blocking. Baseline measurements (T1) were performed after 10 minutes of rest. All variables were measured again at 10 (T2) and 30 (T3) minutes after median nerve block or local block. The primary outcome was the success rate of radial artery cannulation within 10 minutes after blocking. The puncture time, number of attempts, the overall complications, and ultrasonographic measurements including radial artery diameter and cross-sectional area were recorded before (T1), 10 minutes (T2) after, and 30 minutes (T3) after block. RESULTS: A total of 92 pregnant women were identified and completed the follow-up. As compared to control group, the first-attempt success rate of radial artery cannulation was significantly higher (95.7% vs78.3%, p = 0.027) and procedure time to success was significantly shorter (118 ± 19 s vs 172 ± 66 s, p < 0.001) in median nerve group. Median nerve group also had a significantly less overall number of attempts (p = 0.024). Compared with control group, the diameter and cross-sectional area of radial artery increased significantly at the T2 and T3 points in median nerve group (p < 0.001), as well as percentage change of radial artery diameter and CSA. No difference was observed in the overall complication at chosen radial artery, which including vasospasm (21.7% vs 28.3%; p = 0.470) and hematoma (4.3% vs 8.7%; p = 0.677). CONCLUSIONS: Ultrasound-guided median nerve block can increase the first-attempt success rate of chosen radial artery cannulation in women with gestational hypertension and risks of intra-operative bleeding undergoing cesarean section following failed radial artery cannulation, and especially for those anesthesiologists with less experienced in radial artery cannulation. TRIAL REGISTRATION: ChiCTR2100052862; http://www.chictr.org.cn , Principal investigator: MEN, Date of registration: 06/11/2021.

Association of neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, mean platelet volume with the risk of gestational diabetes mellitus.

OBJECTIVE: In the present study, we aimed to investigate the correlation of neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, mean platelet volume with the risk of gestational diabetes mellitus. METHODS: The study enrolled 120 pregnant women who were the 24th and 28th weeks of gestation, including GDM group (n = 58), the control group (n = 62). The NLR, PLR and MPV levels were measured. RESULTS: NLR, PLR and MPV were significantly higher in GDM compared with control group. Logistic regression analysis showed that elevated WBC, NLR, PLR and MPV was an independent variable for predicting GDM in pregnancy. The OR and 95% CI was (OR: 1.6, 95% CI: 1.2-2.5), (OR: 4.1, 95% CI: 1.3-13.1), (OR: 5.5, 95% CI: 1.5-20.0), (OR: 4.0, 95% CI: 1.2-12.0), respectively. CONCLUSION: Increased WBC, PLR, NLR, MPV were independent predictors of GDM.

Evaluating distal renal tubular acidification function in primary hyperparathyroidism and its effects on bone mineral density.

BACKGROUND: Primary hyperparathyroidism (PHPT) is a common endocrinopathy that may increase fracture risk and decrease bone mineral density (BMD). Some patients develop distal renal tubular acidification dysfunction under conditions of hyperchloraemia or hyperchloraemic acidosis. To examine whether this dysfunction influences the clinical outcome, we explored the distal renal tubular acidification function in patients with PHPT and its effects on the clinical manifestations of the disease. METHODS: We retrospectively analysed 75 PHPT patients with regard to renal tubular acidification and blood gas analysis. The patients were divided into two groups, the renal tubular acidification dysfunction group and normal function group. RESULTS: Serum phosphate level and total hip bone density were significantly decreased and 25OHD level was significantly increased in the renal tubular acidification dysfunction group in comparison to the normal function group. Female patients in the renal tubular acidification dysfunction group showed significantly decreased femoral neck and total hip BMD and increased susceptibility to fracture. However, there were no such differences in male patients between the two groups. CONCLUSIONS: About 54.6 % of PHPT patients in our study population had abnormal distal renal tubular acidification. PHPT patients with abnormal distal renal tubular acidification may have lower hip bone density. Female PHPT patients with abnormal distal renal tubular acidification showed increased susceptibility to fractures and the development of osteoporosis.

Switchable Synthesis of Arylalkynes and Phthalides via Controllable Palladium-Catalyzed Alkynylation and Alkynylation-Annulation of Benzoic Acids with Bromoalkynes.

A ligand-promoted palladium(II)-catalyzed synthesis of arylalkynes and phthalides from benzoic acids and bromoalkynes via carboxylate-assisted ortho-C-H activation is reported. A series of phthalides with various functional groups are prepared via ortho-alkynylation and alkynylation-annulation. Moreover, the key ortho-alkynylated products are also obtained by controlling the reaction conditions. In addition, heteroaryl acids could react smoothly to form the corresponding alkynylation and cyclization products.

A near-infrared fluorescent probe for monitoring leucine aminopeptidase in living cells.

Leucine aminopeptidase (LAP), one of the important cancer-related biomarkers, is significantly over-expressed in many malignant tumor cells. Developing an effective fluorescent probe for high-specificity and in situ trapping of endogenous LAP in living samples is still challenging. In this project, we report a water-soluble near-infrared (NIR) fluorescent probe (CHMC-M-Leu) for specific monitoring of LAP in vitro and in vivo. The novel fluorescent probe (CHMC-M-Leu) contains a NIR-emitting fluorophore (CHMC-M) as the reporter and l-leucine as the enzyme-active trigger moiety which are linked together by a p-aminobenzyl alcohol (PABA) section. Upon exposure to LAP, the fluorescence at 625 nm gets impressively enhanced, which belongs to the near-infrared region and is beneficial for imaging in vivo. Furthermore, the novel fluorescent probe exhibits fast response and highly chemoselective detection of LAP in various bio-related species. In addition, CHMC-M-Leu shows favourable cellular uptake and was successfully used to monitor endogenous LAP in living cells.

Imino proton NMR guides the reprogramming of A•T specific minor groove binders for mixed base pair recognition.

Sequence-specific binding to DNA is crucial for targeting transcription factor-DNA complexes to modulate gene expression. The heterocyclic diamidine, DB2277, specifically recognizes a single G•C base pair in the minor groove of mixed base pair sequences of the type AAAGTTT. NMR spectroscopy reveals the presence of major and minor species of the bound compound. To understand the principles that determine the binding affinity and orientation in mixed sequences of DNA, over thirty DNA hairpin substrates were examined by NMR and thermal melting. The NMR exchange dynamics between major and minor species shows that the exchange is much faster than compound dissociation determined from biosensor-surface plasmon resonance. Extensive modifications of DNA sequences resulted in a unique DNA sequence with binding site AAGATA that binds DB2277 in a single orientation. A molecular docking result agrees with the model representing rapid flipping of DB2277 between major and minor species. Imino spectral analysis of a (15)N-labeled central G clearly shows the crucial role of the exocyclic amino group of G in sequence-specific recognition. Our results suggest that this approach can be expanded to additional modules for recognition of more sequence-specific DNA complexes. This approach provides substantial information about the sequence-specific, highly efficient, dynamic nature of minor groove binding agents.

Synthesis and In Vitro Antimycobacterial and Antibacterial Activity of 8-OMe Ciprofloxacin-Hydrozone/Azole Hybrids.

A series of novel 8-OMe ciprofloxacin (CPFX)-hydrazone/azole hybrids were designed, synthesized, and evaluated for their in vitro biological activities. Our results reveal that all of the hydrozone-containing hybrids (except for 7) show potency against Mycobacterium tuberculosis (MTB) H37Rv (minimum inhibitory concentration (MIC): <0.5 µM), which is better than the parent drug CPFX, and comparable to moxifloxacin and isoniazid, some of the tested Gram-positive strains (MIC: 0.06-4 µg/mL), and most Gram-negative strains (MIC: ≤0.03-4 µg/mL).

Synthesis and antitumor activity of ATB-429 derivatives containing a nitric oxide-releasing moiety.

A series of novel ATB-429 (an anti-inflammatory candidate) derivatives containing a nitric oxide (NO)-releasing moiety were designed, synthesized and evaluated for their in vitro activity against six human cancer cell lines. Our results reveal that phenylsulfonylfuroxan-based derivatives have considerable antitumor activity, and compounds 7-9 (IC50s: 0.256-3.024 µM) against HT-29 and PANC-1, 8a,b (IC50s: 2.677-3.051 µM) against MCF-7 and 8a (IC50: 1.270 µM) against DU145 are more active than Vandetanib (IC50s: 1.925-4.107 µM).

Synthesis and Antitumor Activity of 5-Bromo-7-azaindolin-2-one Derivatives Containing a 2,4-Dimethyl-1H-pyrrole-3-carboxamide Moiety.

We report herein the design and synthesis of a series of novel 5-bromo-7-azaindolin-2-one derivatives containing a 2,4-dimethyl-1H-pyrrole-3-carboxamide moiety. These newly synthesized derivatives were evaluated for in vitro activity against selected cancer cell lines by MTT assay. Results revealed that some compounds exhibit broad-spectrum antitumor potency, and the most active compound 23p (IC50: 2.357-3.012 µM) was found more potent than Sunitinib (IC50: 31.594-49.036 µM) against HepG2, A549 and Skov-3, respectively.

Understanding mixed sequence DNA recognition by novel designed compounds: the kinetic and thermodynamic behavior of azabenzimidazole diamidines.

Sequence-specific recognition of DNA by small organic molecules offers a potentially effective approach for the external regulation of gene expression and is an important goal in cell biochemistry. Rational design of compounds from established modules can potentially yield compounds that bind strongly and selectively with specific DNA sequences. An initial approach is to start with common A·T bp recognition molecules and build in G·C recognition units. Here we report on the DNA interaction of a synthetic compound that specifically binds to a G·C bp in the minor groove of DNA by using an azabenzimidazole moiety. The detailed interactions were evaluated with biosensor-surface plasmon resonance (SPR), isothermal calorimetric (ITC), and mass spectrometry (ESI-MS) methods. The compound, DB2277, binds with single G·C bp containing sequences with sub-nanomolar potency and displays slow dissociation kinetics and high selectivity. A detailed thermodynamic and kinetic study at different experimental salt concentrations and temperatures shows that the binding free energy is salt concentration dependent but essentially temperature independent under our experimental conditions, and binding enthalpy is temperature dependent but salt concentration independent. The results show that in the proper compound structural context novel heterocyclic cations can be designed to strongly recognize complex DNA sequences.

Mixed up minor groove binders: Convincing A·T specific compounds to recognize a G·C base pair.

DNA minor-groove-binding compounds have limited biological applications, in part due to problems with sequence specificity that cause off-target effects. A model to enhance specificity has been developed with the goal of preparing compounds that bind to two AT sites separated by G·C base pairs. Compounds of interest were probed using thermal melting, circular dichroism, mass spectrometry, biosensor-SPR, and molecular modeling methods. A new minor groove binder that can strongly and specifically recognize a single G·C base pair with flanking AT sequences has been prepared. This multi-site DNA recognition mode offers novel design principles to recognize entirely new DNA motifs.

Two histopathologically different diseases: hormone receptor-positive and hormone receptor-negative tumors in HER2-positive breast cancer.

The clinical behavior of human epidermal growth factor 2 (HER2)-positive breast cancer, including pathologic complete response rate and pattern of relapse and metastasis, differs substantially according to hormone receptor (HR) status. We investigated various histopathologic features of HER2-positive breast cancer and their correlation with HR status. We retrospectively analyzed tumors of 450 HER2-positive breast cancer patients treated with chemotherapy and 1 year of trastuzumab. HR-/HER2+ tumors showed higher nuclear grade, less tubule formation, higher histologic grade, frequent apocrine features, diffuse and abundant lymphocytic infiltration, strong HER2 immunohistochemical staining (3+), higher average HER2 copy number and HER2/CEP17 ratio, the absence of HER2 genetic heterogeneity, and greater p53 expression than HR+/HER2+ tumors. An inverse correlation was observed between estrogen receptor or progesterone receptor Allred score and average HER2 copy number or HER2/CEP17 ratio. The percentage of ductal carcinoma in situ (DCIS) within the tumor was negatively correlated with ER Allred score, but positively correlated with average HER2 copy number and HER2/CEP17 ratio. Pathologic tumor size and DCIS percentage also showed a significant inverse correlation. Ratio of metastatic to total examined lymph node number was significantly correlated with average HER2 copy number and HER2/CEP17 ratio. High pT stage (hazard ratio, 2.370; p = 0.027), the presence of lymphovascular invasion (hazard ratio, 2.806; p = 0.005), and HR negativity (hazard ratio, 2.202; 1.074-4.513; p = 0.031) were found to be independent prognostic indicators of poor disease-free survival. In conclusion, HR+/HER2+ and HR-/HER2+ breast cancer showed distinct histopathologic features that may be relevant to their distinct clinical behavior.

Structure-dependent binding of arylimidamides to the DNA minor groove.

Heterocyclic diamidines are strong DNA minor-groove binders and have excellent antiparasitic activity. To extend the biological activity of these compounds, a series of arylimidamides (AIAs) analogues, which have better uptake properties in Leishmania and Trypanosoma cruizi than diamidines, was prepared. The binding of the AIAs to DNA was investigated by Tm , fluorescence displacement titration, circular dichroism, DNase I footprinting, biosensor surface plasmon resonance, X-ray crystallography and molecular modeling. These compounds form 1:1 complexes with AT sequences in the DNA minor groove, and the binding strength varies with substituent size, charge and polarity. These substituent-dependent structure and properties provide a SAR that can be used to estimate K values for binding to DNA in this series. The structural results and molecular modeling studies provide an explanation for the differences in binding affinities for AIAs.

Design and synthesis of heterocyclic cations for specific DNA recognition: from AT-rich to mixed-base-pair DNA sequences.

The compounds synthesized in this research were designed with the goal of establishing a new paradigm for mixed-base-pair DNA sequence-specific recognition. The design scheme starts with a cell-permeable heterocyclic cation that binds to AT base pair sites in the DNA minor groove. Modifications were introduced in the original compound to include an H-bond accepting group to specifically recognize the G-NH that projects into the minor groove. Therefore, a series of heterocyclic cations substituted with an azabenzimidazole ring has been designed and synthesized for mixed-base-pair DNA recognition. The most successful compound, 12a, had an azabenzimidazole to recognize G and additional modifications for general minor groove interactions. It binds to the DNA site -AAAGTTT- more strongly than the -AAATTT- site without GC and indicates the design success. Structural modifications of 12a generally weakened binding. The interactions of the new compound with a variety of DNA sequences with and without GC base pairs were evaluated by thermal melting analysis, circular dichroism, fluorescence emission spectroscopy, surface plasmon resonance, and molecular modeling.

Near Infrared Light-Activatable Platelet-Mimicking NIR-II NO Nano-Prodrug for Precise Atherosclerosis Theranostics.

Atherosclerosis is a chronic inflammatory disease that affects arteries and is the main cause of cardiovascular disease. Atherosclerotic plaque formation is usually asymptomatic and does not manifest until the occurrence of clinical events. Therefore, early diagnosis and treatment of atherosclerotic plaques is particularly important. Here, a series of NIR-II fluorescent dyes (RBT-NH) are developed for three photoresponsive NO prodrugs (RBT-NO), which can be controllably triggered by 808 nm laser to release NO and turn on the NIR-II emission in the clinical medicine "therapeutic window". Notably, RBT3-NO is selected for its exhibited high NO releasing efficiency and superior fluorescence signal enhancement. Subsequently, a platelet-mimicking nano-prodrug system (RBT3-NO-PEG@PM) is constructed by DSPE-mPEG5k and platelet membrane (PM) for effectively targeted diagnosis and therapy of atherosclerosis in mice. The results indicate that this platelet-mimicking NO nano-prodrug system can reduce the accumulation of lipids at the sites of atherosclerotic plaques, improve the inflammatory response at the lesion sites, and promote endothelial cell migration, thereby slowing the progression of plaques.

The pathological mechanisms and potential therapeutic drugs for myocardial ischemia reperfusion injury.

BACKGROUND: Cardiovascular disease is the main cause of death and disability, with myocardial ischemia being the predominant type that poses a significant threat to humans. Reperfusion, an essential therapeutic approach, promptly reinstates blood circulation to the ischemic myocardium and stands as the most efficacious clinical method for myocardial preservation. Nevertheless, the restoration of blood flow associated with this process can potentially induce myocardial ischemia-reperfusion injury (MIRI), thereby diminishing the effectiveness of reperfusion and impacting patient prognosis. Therefore, it is of great significance to prevent and treat MIRI. PURPOSE: MIRI is an important factor affecting the prognosis of patients, and there is no specific in-clinic treatment plan. In this review, we have endeavored to summarize its pathological mechanisms and therapeutic drugs to provide more powerful evidence for clinical application. METHODS: A comprehensive literature review was conducted using PubMed, Web of Science, Embase, Medline and Google Scholar with a core focus on the pathological mechanisms and potential therapeutic drugs of MIRI. RESULTS: Accumulated evidence revealed that oxidative stress, calcium overload, mitochondrial dysfunction, energy metabolism disorder, ferroptosis, inflammatory reaction, endoplasmic reticulum stress, pyroptosis and autophagy regulation have been shown to participate in the process, and that the occurrence and development of MIRI are related to plenty of signaling pathways. Currently, a range of chemical drugs, natural products, and traditional Chinese medicine (TCM) preparations have demonstrated the ability to mitigate MIRI by targeting various mechanisms. CONCLUSIONS: At present, most of the research focuses on animal and cell experiments, and the regulatory mechanisms of each signaling pathway are still unclear. The translation of experimental findings into clinical practice remains incomplete, necessitating further exploration through large-scale, multi-center randomized controlled trials. Given the absence of a specific drug for MIRI, the identification of therapeutic agents to reduce myocardial ischemia is of utmost significance. For the future, it is imperative to enhance our understanding of the pathological mechanism underlying MIRI, continuously investigate and develop novel pharmaceutical agents, expedite the clinical translation of these drugs, and foster innovative approaches that integrate TCM with Western medicine. These efforts will facilitate the emergence of fresh perspectives for the clinical management of MIRI.

Reversible pH-switchable NIR-II nano-photosensitizer for precise imaging and photodynamic therapy of tumors.

Photodynamic therapy (PDT) has attracted widespread attention from researchers as an emerging cancer treatment method. There have been many reports on various types of NIR-II photosensitizers for imaging and treatment of tumor sites. However, there are few reports on the development of NIR-II organic small molecule photosensitizers that have intelligent response to the tumor microenvironment, precise imaging, real-time treatment, and high biocompatibility. In this work, we developed a series of NIR-II photosensitizers (RBTs) with near-infrared excitation, good photostability, and large Stokes shift. Among them, RBT-Br exhibited higher reactive oxygen species (ROS) generation efficiency due to the introduction of halogen heavy atoms to enhance intersystem crossing (ISC). It is noteworthy that RBT-Br can generate singlet oxygen (1O2) and superoxide anion radicals (•O2-) simultaneously under 730 nm laser. Subsequently, we used molecular engineering technology to construct three pH-responsive NIR-II photosensitizers (RBT-pHs) by utilizing the closure of the lactam ring, among which RBT-pH-1 (pKa = 6.78) is able to be directionally activated under the stimulation of tumor micro-acid environment, with its fluorescence emission window reaching 933 nm. Subsequently, RBT-pH-1 NPs encapsulated in DSPE-mPEG5k were applied for PDT treatment of mouse tumors. The results showed that RBT-pH-1 NPs were activated by the acidic tumor microenvironment and generated ROS under laser excitation, exhibiting precise tumor imaging and significant tumor growth inhibition. We look forward to these multifunctional NIR-II organic small molecule photosensitizers providing a more efficient approach for clinical treatment of tumors. STATEMENT OF SIGNIFICANCE: A reversible pH-switchable NIR-II nano-photosensitizer RBT-pH-1 NPs (pKa = 6.76) is developed for precise imaging and PDT therapy of mouse tumors, which can be effectively used for targeted enrichment and activation of tumor micro-acid environments. The results show that this NIR-II photosensitizer generates ROS through tumor micro-acid environment stimulation and laser triggering, showing precise tumor imaging guidance and significant tumor growth inhibition.