Lanrong Bi - Academia.edu (original) (raw)

Papers by Lanrong Bi

Bioorganic & Medicinal Chemistry, Feb 15, 2008

A new series of optically pure 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes were designed an... more A new series of optically pure 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes were designed and synthesized via a chemo-enzymatic combined method to develop new chemoprevention agents. Twenty-four of newly synthesized compounds significantly inhibited xylene-induced rat ear edema and exhibited comparable or better anti-inflammatory activities than the reference drug aspirin. Treatment of these anti-inflammatory agents did not prolong the tail bleeding time in rat. In addition, 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes exhibited good membrane permeability based on in vitro Caco-2 cell monolayer permeability assay. Furthermore, some preliminary structure-activity relationships were further analyzed among these compounds. Taken together, 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes may represent a new class of anti-inflammatory drugs with safer pharmacological profile.

HAL (Le Centre pour la Communication Scientifique Directe), Oct 15, 2006

Beta-carboline represents a class of compounds with potent anti-tumor activity by intercalating w... more Beta-carboline represents a class of compounds with potent anti-tumor activity by intercalating with DNA. To further enhance the cytotoxic potency and bioavailability of beta-carboline, a series of novel beta-carboline amino acid ester conjugates were designed and synthesized, and the cytotoxic activities of these compounds were tested using a panel of human tumor cell lines. In addition, the membrane permeability of these compounds was evaluated in vitro using a Caco-2 cell monolayer model. The beta-carboline amino acid ester conjugates demonstrated improved cytotoxic activity compared to the parental beta-carbolines. In particular, the Lys/Arg conjugates were the most potent analogs with an IC(50) value of 4 and 1 microM against human cervical carcinoma cells. The low interaction energy of Arg conjugate based on molecular modeling may contribute to its enhanced cytotoxicity. Taken together, this study provided new insights into structure-activity relationships in the beta-carboline amino acid ester conjugates and identified the beta-carboline Lys/Arg conjugates as promising lead compounds for further in vivo biological and molecular evaluation.

La presente invention concerne un procede permettant le sequencage d'ADN simple brin au moyen... more La presente invention concerne un procede permettant le sequencage d'ADN simple brin au moyen d'un nanopore et de nucleotides modifies.

Proceedings of the National Academy of Sciences, 2007

Pyrosequencing is a method used to sequence DNA by detecting the pyrophosphate (PPi) group that i... more Pyrosequencing is a method used to sequence DNA by detecting the pyrophosphate (PPi) group that is generated when a nucleotide is incorporated into the growing DNA strand in polymerase reaction. However, this method has an inherent difficulty in accurately deciphering the homopolymeric regions of the DNA templates. We report here the development of a method to solve this problem by using nucleotide reversible terminators. These nucleotide analogues are modified with a reversible chemical moiety capping the 3′-OH group to temporarily terminate the polymerase reaction. In this way, only one nucleotide is incorporated into the growing DNA strand even in homopolymeric regions. After detection of the PPi for sequence determination, the 3′-OH of the primer extension products is regenerated through different deprotection methods. Using an allyl or a 2-nitrobenzyl group as the reversible moiety to cap the 3′-OH of the four nucleotides, we have synthesized two sets of 3′- O -modified nucleot...

Physiology, May 1, 2023

It has been reported that small extracellular vesicles (sEVs ≤ 200 nm) are implicated in the path... more It has been reported that small extracellular vesicles (sEVs ≤ 200 nm) are implicated in the pathogenesis of multiple diseases including hypertension. However, the role of brain-derived sEVs in the development of salt sensitive hypertension (SSHTN) remains unclear. We hypothesize that brain-derived sEVs from high salt diet-treated rats can induce inflammation and oxidative stress in the central nervous system (CNS). To test this hypothesis, brain-derived sEVs of Dahl salt-sensitive rats with high salt (HS) diet (Dahl-HS-sEV) were used to treat primary brain neuronal cultures and microinjected into brain lateral ventricles, respectively, proinflammatory cytokines, chemokines, and oxidative stress markers were measured through real-time PCR or fluorescent probes. sEVs isolated from Sprague Dawley (SD) rats with normal salt (NS) diet (SD-NS-sEV) were used as a control. Briefly, we isolated sEVs from brain tissues using ultracentrifugation and identified sEVs with scanning electron microscopy, dynamic light scattering and western blots. Primary neurons derived from neonatal SD rats were incubated with either Dahl-HS-sEV (4μg/mL), or SD-NS-sEV (4μg/mL) for 24 h. The mRNA levels of inflammatory factors, neuronal activity indicator (c-Fos) and NADPH oxidase subunits (CYBA and CYBB) were tested by real-time PCR. Results showed that Dahl-HS-sEV incubation increased mRNA levels of inflammatory cytokines including TNFα (2.3-fold) and IL1β (3.7-fold) with statistical significance (P<0.05). It also significantly increased (P<0.05) mRNA levels of chemokines including CCL2 (2.4-fold), CCL5 (2.1-fold), and CCL12 (4.2-fold). In addition, Dahl-HS-sEV treatment increased mRNA levels of transcription regulator, NF-κB (1.4-fold), and neuronal activation marker, c-FOS (1.3-fold), as well as CYBA (1.7-fold), in primary neurons, compared to SD-NS-sEV-treated cells (P<0.05). We further tested mitochondrial reactive oxygen species (ROS) levels using fluorescent probes in primary neurons. Confocal images showed that Dahl-HS sEV significantly increased mitochondrial ROS levels, with total fluorescence intensity increased 1.6-fold relative to SD-NS-sEV treatment (P<0.01). Subsequently, we tested the effect of sEVs on the inflammatory cytokine marker expression in the brain. SD-NS rats received intracerebroventricular injection of either Dahl-HS-sEV (5.5 μg /rat, n=4) or SD-NS-sEV (5.5 μg/rat, n=4) and euthanized 6 h after injection. Their brains were removed and paraventricular nucleus (PVN) were punched out. RNAs were isolated from PVN tissues and used for real-time PCR assessment. Results showed that Dahl-HS-sEV significantly increased (P<0.05) PVN mRNA levels of IL1β (4.3-fold), CCL5 (2.6-fold), IL-6 (3.4-fold) and NOS2 (5.2-fold) in SD-NS rats 6 h after injection. These results suggested that in SSHTN, brain-derived sEVs may induce central inflammation and oxidative stress, which in turn results in an elevation of arterial blood pressure. This work was supported by NIH grant R01HL 163159 (Shan) and R15HL 150703 (Shan), and Portage Health Foundation Mid-Career Award (Shan). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Bioorganic & Medicinal Chemistry Letters, Apr 1, 2016

Mitochondrial oxidative damage contributes to a wide range of pathologies, including ischemia/rep... more Mitochondrial oxidative damage contributes to a wide range of pathologies, including ischemia/reperfusion (I/R) injury, cardiovascular disorders and neurodegenerative diseases. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel kyotorphinnitroxide hybrid molecules, and examined their free radical scavenging activities, in addition to their anti-inflammatory and analgesic activities. We have further characterized these compounds in a simulated I/R cellular model. Our findings suggest that the protective effects of kyotorphinnitroxides partially reside in maintaining optimal mitochondrial function.

bioRxiv (Cold Spring Harbor Laboratory), Nov 3, 2022

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting from the prog... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting from the progressive loss of both upper and lower motor neurons in the cerebral cortex, brainstem, and spinal cord. Currently, there are only two drugs, Riluzole (Rilutek) and Edaravone (Radicava), approved by FDA for ALS treatment. These two drugs are very expensive with only a few months of life extension. So far, there is no cure for ALS. Aberrant protein aggregation in motor neurons is an intracellular hallmark of ALS. The disturbance in protein homeostasis may contribute to the onset and progression of ALS. Autophagy plays an important role in degrading misfolded proteins, thereby preventing their aggregation. Pharmacological manipulation of autophagy has been proposed as a new therapeutic approach for treating ALS. IADB, a novel indole alkaloid derivative, has been reported to exert mitochondrial protection and cardioprotection through its autophagy-modulating potential. Our present study attempted to examine whether IADB has therapeutic potential in SOD1 G93A-associated experimental models of ALS. We found that IADB could promote the clearance of SOD1 G93A aggregates and reduce the overproduction of mitochondrial reactive oxygen species (mtROS) in motor neuron-like NSC-34 cells transfected with SOD1 G93A. We further examined the IADB in a SOD1-G93A mouse model of ALS. Administration of IADB started at the age of 55 days until the end stage of the disease. IADB treatment significantly increased LC3-II levels and decreased human SOD1 levels and p62 expression in the spinal cords of SOD1 G93A mice, suggesting that IADB treatment could induce autophagy activation and promote clearance of mutant SOD1 aggregates in this mouse model of ALS. Moreover, IADB treatment could alleviate the activation of microglia and astrocytes and reduce mitochondrial oxidative damage in the spinal cord of SOD1 G93A mice. Finally, we demonstrated that IADB treatment could improve motor performance and delay the onset and progression of the disease in a mouse model of ALS. The neuroprotective effects of IADB may mainly originate from its autophagy-promoting property.

Bioorganic & Medicinal Chemistry Letters, Aug 1, 2016

Pharmacological protection of mitochondrial function mitigates acute limb ischemia/reperfusion in... more Pharmacological protection of mitochondrial function mitigates acute limb ischemia/reperfusion injury

bioRxiv (Cold Spring Harbor Laboratory), Jul 4, 2023

Mitochondrial dysfunction is implicated in both brain tumors and neurodegenerative diseases, lead... more Mitochondrial dysfunction is implicated in both brain tumors and neurodegenerative diseases, leading to various cellular abnormalities that can promote tumor growth and resistance to therapies, as well as impaired energy production and compromised neuronal function. Developing targeted therapies aimed at restoring mitochondrial function and improving overall cellular health could potentially be a promising approach to treating these conditions. Brain-derived exosomes (BR-EVs) have emerged as potential drug delivery vessels for neurological conditions. Herein, we report a new method for creating mitochondria-targeting exosomes and test its application in vitro and in vivo.

Ischemia/reperfusion (I/R) injury results in cell death by inducing apoptosis. During I/R, early ... more Ischemia/reperfusion (I/R) injury results in cell death by inducing apoptosis. During I/R, early generation of mitochondrial reactive oxygen species (mtROS) can induce neighboring mitochondria to release additional ROS, a toxic cycle resulting in significant mitochondrial and cellular injury. Oxidative damage in the mitochondria contributes to various pathologies, including I/R injury. Accordingly, preventing mitochondrial oxidative damage should be therapeutically relevant for many disorders, including cardiovascular diseases. We recently discovered an Indole-Peptide-Tempo Conjugate (IPTC) that served as a novel bifunctional agent with both antioxidant and autophagy-modulating capacity. Here, we demonstrate that IPTC can protect H9C2 cardiomyocytes from hypoxia/reoxygenation (H/R) injury that results from mtROS overproduction due to impaired mitophagy and resultant mitochondrial dysfunction. We hypothesize that the mechanism of action of IPTC involves the capacity to decrease mtROS combined with induction of mitophagy.

ACS Omega, 2018

Clinically approved therapeutics that mitigate chemotherapy-induced cardiotoxicity, a serious adv... more Clinically approved therapeutics that mitigate chemotherapy-induced cardiotoxicity, a serious adverse effect of chemotherapy, are lacking. The aim of this study was to determine the putative protective capacity of a novel indole alkaloid derivative B (IADB) against 5-fluorouracil (5-FU)-induced cardiotoxicity. To assess the free-radical scavenging activities of IADB, the acetylcholine-induced relaxation assay in rat thoracic aorta was used. Further, IADB was tested in normal and cancer cell lines with assays gauging autophagy induction. We further examined whether IADB could attenuate cardiotoxicity in 5-FU-treated male ICR mice. We found that IADB could serve as a novel bifunctional agent (displaying both antioxidant and autophagy-modulating activities). Further, we demonstrated that IADB induced production of cytosolic autophagy-associated structures in both cancer and normal cell lines. We observed that IADB cytotoxicity was much lower in normal versus cancer cell lines, suggesting an enhanced potency toward cancer cells. The cardiotoxicity induced by 5-FU was significantly relieved in animals pretreated with IADB. Taken together, IADB treatment, in combination with chemotherapy, may lead to reduced cardiotoxicity, as well as the reduction of anticancer drug dosages that may further improve chemotherapeutic efficacy with decreased off-target effects. Our data suggest that the use of IADB may be therapeutically beneficial in minimizing cardiotoxicity associated with high-dose chemotherapy. On the basis of the redox status difference between normal and tumor cells, IADB selectively induces autophagic cell death, mediated by reactive oxygen species overproduction, in cancer cells. This novel mechanism could reveal novel therapeutic targets in chemotherapy-induced cardiotoxicity.

ACS Omega, 2021

Many organelles, such as lysosomes and mitochondria, maintain a pH that is different from the cyt... more Many organelles, such as lysosomes and mitochondria, maintain a pH that is different from the cytoplasmic pH. These pH differences have important functional ramifications for those organelles. Many cellular events depend upon a well-compartmentalized distribution of H + ions spanning the membrane for the optimal function. Cells have developed a variety of mechanisms that enable the regulation of organelle pH. However, the measurement of organellar acidity/alkalinity in living cells has remained a challenge. Currently, most existing probes for the estimation of intracellular pH show a single-organelle targeting capacity. Such probes provide data that fails to comprehensively reveal the pathological and physiological roles and connections between mitochondria and lysosomes in different species. Mitochondrial and lysosomal functions are closely related and important for regulating cellular homeostasis. Accordingly, the design of a single fluorescent probe that can simultaneously target mitochondria and lysosomes is highly desirable, enabling a better understanding of the crosstalk between these organelles. We report the development of a novel fluorescent sensor, rhodamine−coumarin pH probe (RCPP), for detection of organellar acidity/alkalinity. RCPP simultaneously moves between mitochondrion and lysosome subcellular locations, facilitating the simultaneous monitoring of pH alterations in mitochondria and lysosomes.

ACS Omega

We recently designed and synthesized a series of novel levodopa− peptide−TEMPO conjugates (LPTCs)... more We recently designed and synthesized a series of novel levodopa− peptide−TEMPO conjugates (LPTCs). Among these compounds, LPTC-5 possesses both free-radical scavenging potential and mitochondrial fusionpromoting activity. The free-radical scavenging capacity of LPTC-5 was confirmed using a PC12 cell survival assay. LPTC-5 could restore the mitochondrial tubular network following genetically induced fragmentation. The therapeutic efficacy of LPTC-5 was then examined employing in vitro and in vivo ischemia/reperfusion (I/R) models. LPTC-5 protected cells from mitochondrial reactive oxygen species overproduction and inhibited cytochrome c release in a simulated I/R cellular model. Additionally, LPTC-5 attenuated organ damage in a cardiac I/R animal model. The data suggest that LPTC-5 exerts cardioprotection via modulation of mitochondrial fission/fusion dynamics, ultimately improving mitochondrial function and cardiac function.

Bioorganic & medicinal chemistry, May 1, 2017

Mitochondrial oxidative damage contributes to a wide range of pathologies including ischemia/repe... more Mitochondrial oxidative damage contributes to a wide range of pathologies including ischemia/reperfusion injury. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel indole-TEMPO conjugates that manifested good anti-inflammatory properties in a murine model of xylene-induced ear edema. We have demonstrated that these compounds can protect cells from simulated ischemia/reperfusion (s-I/R)-induced reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Furthermore, we have demonstrated that indole-TEMPO conjugates can attenuate organ damage induced in rodents via intestinal I/R injury. We therefore propose that the pharmacological profile and mechanism of action of these indole-TEMPO conjugates involve convergent roles, including the ability to decrease free radical production via lipid peroxidation which couples to an associated decrease in ROS-medi...

Bioorganic & medicinal chemistry letters, 2015

Mitochondrial oxidative stress has been implicated in aging, neurodegenerative diseases, diabetes... more Mitochondrial oxidative stress has been implicated in aging, neurodegenerative diseases, diabetes, stroke, ischemia/reperfusion injury, age-related macular degeneration (AMD) and cancer. Recently, we developed two new mitochondria-targeting fluorescent probes, MitoProbes I/II, which specifically localize in mitochondria and employed both in vivo and in vitro for detection of mitochondrial oxidative stress. Here, we report the design and synthesis of these agents, as well as their utility for real-time imaging of mitochondrial oxidative stress in cells.

Scientific reports, Jan 11, 2015

Intracellular pH plays an important role in the response to cancer invasion. We have designed and... more Intracellular pH plays an important role in the response to cancer invasion. We have designed and synthesized a series of new fluorescent probes (Superior LysoProbes) with the capacity to label acidic organelles and monitor lysosomal pH. Unlike commercially available fluorescent dyes, Superior LysoProbes are lysosome-specific and are highly stable. The use of Superior LysoProbes facilitates the direct visualization of the lysosomal response to lobaplatin elicited in human chloangiocarcinoma (CCA) RBE cells, using confocal laser scanning microscopy. Additionally, we have characterized the role of lysosomes in autophagy, the correlation between lysosome function and microtubule strength, and the alteration of lysosomal morphology during apoptosis. Our findings indicate that Superior LysoProbes offer numerous advantages over previous reagents to examine the intracellular activities of lysosomes.

Scientific reports, Jan 26, 2015

We report the design, synthesis and application of several new fluorescent probes (LysoProbes I-V... more We report the design, synthesis and application of several new fluorescent probes (LysoProbes I-VI) that facilitate lysosomal pH monitoring and characterization of lysosome-dependent apoptosis. LysoProbes are superior to commercially available lysosome markers since the fluorescent signals are both stable and highly selective, and they will aid in characterization of lysosome morphology and trafficking. We predict that labeling of cancer cells and solid tumor tissues with LysoProbes will provide an important new tool for monitoring the role of lysosome trafficking in cancer invasion and metastasis.