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Urolithin A is a microbial metabolite produced by the gut microbiota. Many studies provide evidence that it may have potential use against CNS disorders. It is known to be able to cross the blood-brain barrier and maintain a favorable safety profile. CNS disorders are a growing concern due to the global aging population.

Where does it come from?

The precursors to urolithin production are found in many foods including pomegranates, various berries, nuts, tropical fruits, and tea. However, because urolithin itself is produced in the gut, and gut microbiota can vary across different populations, everyone may not get the all benefits of urolithin, even while consuming the same foods. Therefore, direct supplementation could allow all populations to gain the benefits provided by urolithin. Safety studies have shown a high limit of tolerability and the US FDA has granted ‘generally recognized as safe’ status to this compound to be used as a food additive.

Potential Benefits

Many benefits of urolithin have been uncovered so far. These include regulating mitochondrial function, modulating immunometabolism, and reducing DNA damage-induced senescence. This molecule has shown protective effects across many disease models including Alzheimer’s, Parkinson’s, diabetes-associated cognitive impairment, stroke, and traumatic CNS injury. In addition, it shows positive effects against several cancer models, radiation brain injury, multiple sclerosis, amyotrophic lateral sclerosis, and spinal muscular atrophy.

Knowledge Gaps

All in all, a lot of research has shown positive effects of urolithin A. However, the molecular mechanisms responsible are not yet completely understood. Most of the research so far has focused on cellular and animal models, and the same effects may or may not be observed in human subjects. In addition, there remain gaps in knowledge regarding side-effects, long-term safety profile and drug interactions. While many studies have shown an abundance of positive results for this chemical, there is still quite a bit of additional information to be filled in. Further research is certainly warranted for this chemical. Not only for urolithin A, but for other urolithins as well.

Urolithins available at LKT Labs include:

Urolithin A

Urolithin B

Urolithin C

Zhang Q, Zhang W, Yuan X, et al. Urolithin A in central nervous system disorders: therapeutic applications and challenges. Biomedicines. 2025 Jun 25;13(7):1553. PMID: 40722629

 

Pancreatic ductal adenocarcinoma is a highly malignant form of cancer and the most common form of pancreatic cancer. It most often is only diagnosed at advanced stages, leaving dismal outlooks. Chemotherapy for this cancer has centered around gemcitabine for several decades. Unfortunately, the cancer is quick to develop resistance to gemcitabine and then the drug fails to remain effective.

To improve treatment efficacy, combination therapy is often the next step. However, combination therapies are often even more toxic overall. Because of increased toxicity, another desired improvement is the ability to deliver the chemical directly to the tumor, with less impact on the healthy cells and tissues. Unfortunately, conventional nanocarrier systems tend to result in severe hepatotoxicity and inadequate delivery to the tumor site.

Recently, researchers at Zhejiang University School of Medicine attempted to treat pancreatic cancer by targeted delivery using vesicles containing combination treatment of gemcitabine and RP-6306. Working with a mouse model they found that this method of drug delivery was effective. The drugs were delivered to the tumor microenvironment as intended, while successfully avoiding inducing cytotoxic effects.

While gemcitabine disrupts DNA synthesis, RP-6306 disrupts the G2/M checkpoint by silencing PKMYT1, thereby inducing PANoptosis. This combination effectively targeted the cancer cells without inducing organ damage. The use of vesicles showed superior biocompatibility and minimal toxicity. Further studies of this combination are warranted as the current work shows great promise.

Chen J, Ren J, Zhang C, et al. Targeted delivery of the PKMYT1 inhibitor RP-6306 mediates PANoptosis in pancreatic cancer via mitotic catastrophe. Cell Death Dis. 2025 Jul 15;16(1):526. PMID: 40664640

 

Thapsigargin is a natural chemical found in the plant Thapsia garganica, a flowering perennial in the carrot family. One response to the COVID-19 pandemic was intense exploration for new antivirals. The antiviral activity of thapsigargin was consequently reassessed and demonstrated broad-spectrum antiviral effects.

While it did not become one of the go-to drugs for COVID infections, the global pig industry also suffers the effects of several coronaviruses, so it could have potential use there. In addition to the loss of marketable animals and financial hardships, there is always the risk of cross-species transmission leading to human infection. The unceasing emergence of mutant strains puts limitations on the effectiveness of the available vaccines. Therefore, the use of antiviral drugs in combination with vaccinations has become the go-to strategy to increase the survival rate of the animals.

To assess the effect of thapsigargin for the pig industry, the porcine coronavirus known as transmissible gastroenteritis virus (TGEV) was chosen. Piglets were first orally infected with the TGEV virus, then given thapsigargin at 1 hour and 12 hours post-infection. The animals were checked at 0, 12, and 24 hours post-infection for viral shedding. After 24 hours, the animals were euthanized and the intestinal tissues were collected and evaluated.

The results of the tissue tests showed that the infection was suppressed by the thapsigargin treatment. However, there were also concerning signs of the impact of side effects on the gastrointestinal mucosa. While this compound certainly shows potential for controlling viral infections, further evaluation should be undertaken to improve our understanding.

Li Y, Liu Y, Zhang Y, et al. In vitro and in vivo evaluation of thapsigargin as an antiviral agent against transmissible gastroenteritis virus. Vet Res. 2024 Aug 2;55(1):97. PMID: 39095890

Ochratoxin A is a mycotoxin that is possibly toxic to humans. Unfortunately, it is also found as a contaminant in many food items, including coffee. A mycotoxin is a metabolite produced by mold spores that may be present in the processing of many grains, fruits, and nuts. Exposure to ochratoxin A (OTA) by consumption of contaminated foods may cause direct damage to DNA. In addition, it is carcinogenic to the kidney. Therefore, it is beneficial to find methods to prevent or remove this contaminant from coffee and other foods.

Recently, a research team in Taiwan evaluated the plausibility of using wild yeasts to inhibit the germination of molds during the fermentation processing of coffee. Preventing the mold from forming and growing would prevent the metabolites from being produced. This would mean the finished coffee products would be free of OTA.

Yeast Conquer Mold

Coffee pulp is the primary bi-product of coffee processing and was selected as a substrate to simulate the fermentation process. The pulp was inoculated with various wild yeasts prior to fermentation. The idea is that metabolites of these yeasts may inhibit the germination of the mold spores. The various yeasts that were used also contributed to different scent profiles in the finished products. The optimum yeast will exhibit a high growth rate, so that the metabolite concentration produced will be enough to keep the mold in check, while at the same time also contributing to a pleasant aroma.

2 Strategies to Consider

It is noted that it is the metabolites, not the yeasts themselves, that are responsible for the inhibition of the mold. So there are 2 options apparent: addition of the live yeast to the fermentation, or simply addition of the metabolites to the fermentation. If the metabolites themselves can be added, then the selection of which yeast to use to ferment the coffee can be chosen for other factors such as taste and scent optimization.

Research into food processing and handling is important to prevent illnesses and long-term health effects caused by various contaminants. Because OTA is found as a contaminant in many foods, the metabolites discovered in this research may also find a use in the processing strategies for some other foods too.

Liu T, Hsu W, Lee B. Evaluation of the application of wild yeasts in inhibiting germination of ochratoxin-producing fungi during coffee fermentation process. Food Chem X. 2024 Dec 9:25:102077. PMID: 39758057

Gastric cancer is one of the leading causes of cancer deaths worldwide. It is known to be an aggressive type of cancer and unfortunately, is often undiagnosed until already reaching an advanced stage. One of the main treatments for gastric cancer is radiation therapy, however, the cancer cells are sometimes quick to develop radioresistance, creating another obstacle to overcome.

New research recently completed at Nantong University investigated a method to treat radioresistant gastric cancer cells. A well-known natural product, β-elemene, stood out as having potential to act as a radiosensitizer. β-Elemene is found in the plant Curcuma zedoaria, which has been used as a spice similar to ginger. Previous studies have suggested that it may act as a radiosensitizer against cancer cells.

For this study, 2 human gastric cancer cell lines, known to have different characteristics and behaviors, were used. These cell lines were radiated and then the surviving cells propagated several times, resulting in radioresistant populations.

Next, the radioresistant cancer cells were subcutaneously injected into a mouse model. The growth of the tumor was monitored until the size was appropriate, approximately 2 weeks. Then the treatment with β-elemene, radiation, or combination was begun. The treatments were administered for 20 days, and then finally the mice were sacrificed, and the tissues analyzed.

The results of this study showed that the combination of β-elemene together with radiation was the most effective option. With either chemical or radiation alone, the tumor growth was slowed, however, the combination treatment was even more effective. It is thought that the β-elemene is responsible for modulating ferroptosis, which strongly impacts some of the tumor-associated proteins.

Further structural and biochemical analysis should be done which will help develop the targeted therapy. Perhaps the reliance of the radioresistant cancer cells on ferroptosis can be successfully exploited so that the cancer cells can be finally destroyed.

He J, Li M, Bao J, et al. β-Elemene promotes ferroptosis and reverses radioresistance in gastric cancer by inhibiting the OTUB1-GPX4 interaction. Front Pharmacol. 2024 Oct 17:15:1469180. PMID: 39484165 

Combination treatment for the prevention or delay of brain aging is a compelling area of research. Age-related cognitive decline may be influenced by multiple factors and impact various biological processes in the brain. Learning to manipulate key factors will allow for control over major pathways of aging and prevention of severe degenerative conditions such as Alzheimer’s disease.

A recent study completed at the University of Washington investigated the impact of a 3-chemical cocktail on aging brain biology. This specific cocktail has already demonstrated cognitive protection in a previous study. This new study aimed to understand the transcriptomic and molecular changes caused by these chemicals.

Experimental:

In this study, an aged mouse model was treated with either an individual chemical or the combination of all 3: rapamycin, acarbose, and phenylbutyrate. The treatments were begun when the mice reached ‘old age’ at 20 months old. The mice were provided with medicated diets for the following 3 months. After this, the mice were euthanized and the brain tissues collected.

Data Analysis:

The brain tissues were then analyzed using RNA-seq, q-PCR, IHC, and QuPath. These analyses showed that rapamycin intake led to decreased mTOR1 signaling, which decreases nutrient signaling and extends longevity. They also showed that acarbose intake led to improved insulin sensitivity and decreased insulin signaling, which may prevent or reverse some of the effects of aging. In addition, phenylbutyrate intake was shown to downregulate histone deacetylation, which impacts the downstream cellular function.

Most interestingly, receiving the 3-chemical cocktail was shown to produce a synergistic interaction with the collective action producing even more positive results. The cocktail treatment produced lower levels of DNA damage than otherwise found, in addition to lower levels of biomarkers for senescence. The biomarkers for autophagy were increased, while the biomarkers for inflammation were decreased. Altogether, these brain tissues showed much improvement with greatly reduced characteristics of aging.

This study is an encouraging step toward the design of a combination treatment to decrease the risk of severe cognitive degeneration.

Jiang Z, He Q, Wezeman J, et al. A cocktail of rapamycin, acarbose, and phenylbutyrate prevents age-related cognitive decline in mice by targeting multiple aging pathways. Geroscience. 2024 Oct;46(5):4855-4868. PMID: 38755466

Drug repurposing for viral variants may prove to be an efficient means to combat the mutating of COVID-19. As vaccine-resistant variants emerge, many patients with comorbidities require hospitalization due to sever complications. The fastest and cheapest route to discovering a new treatment is to check if any of the existing approved drugs are effective against COVID.

The search begins…

Recently, the FDA-approved drugs library was used for this purpose. To begin, first a simulation of each drug molecule docking with SARS-CoV-2 spike receptor-binding domain was run. The database contained around 2,500 drugs.

The spike receptor-binding domain was chosen for the simulation because it is already known that this domain plays a significant role in the entry of the virus into the host cell. The primary goal of this study is to find a drug that can impede the entry point, and thereby prevent infection from even beginning.

From the library of 2,500 drugs, 20 showed good results with the simulation and relatively high safety profiles. These 20 were carried on for further validation in the lab using a binding assay kit. The assay kit was also specific for the SARS-CoV-2 spike binding.

From the binding assay, 5 of the molecules continued to show promise as they consistently and significantly inhibit the binding of SARS-CoV-2 and the receptor. These 5 were carried on with in vitro work using Vero E6 cells. Each molecule was assessed for the required concentration and toxic concentration.

And then there were 3…

From the 5 molecules, 3 of them continued to show promise against SARS-CoV-2. These 3: argatroban, ranolazine, and glimepiride had a high selectivity index, and most interestingly, they each impacted different stages of the viral life cycle. Argatroban induced a direct virucidal effect; glimepiride inhibited viral replication; ranolazine inhibited viral adsorption onto the host cell.

This project has successfully identified 3 high-potential candidates for drug repurposing by weeding through the library of 2,500 already approved drugs. Further testing must also be done to develop the most safe and effective dosing, formulation, and potentially combination therapies to continue combating the new COVID variants.

Sobky S, Fawzy I, Ahmed M, et al. Drug repurposing of argatroban, glimepiride, and ranolazine shows anti-SARS-CoV-2 activity via diverse mechanisms. Heliyon. 2025 Jan 10;11(3):e41894. PMID: 39968139

Canagliflozin and dapagliflozin are sodium-glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 is the membrane protein in the kidney which is responsible for reabsorption of glucose. The capability of inhibiting these proteins has proven to effectively control blood sugar, cholesterol, and triglycerides. This type of compound has become the go-to method in the treatment of type 2 diabetes. However, there are also concerns about possible unfavorable side-effects that must be addressed.

A recent study at the Medical University of Silesia looked into the effects that canagliflozin and dapagliflozin may have on bones. The experiment used Wistar rats and induced type 2 diabetes by use of high-fat diet followed by an injection of streptozocin. The chemicals were then administered to the animals once a day by oral gavage for a total of 4 weeks of treatment. During this time, the blood glucose and grip strength were measured weekly. 4 weeks of treatment in the life of a rat is comparable to approximately 2.5 years for a human.

At the end of the treatment, the animals were sacrificed, and the organs, bones, and blood serum were collected and analyzed. Biochemical concentrations in the serum were measured, as well as mechanical properties and mineral composition of the bones.

The results showed that both canagliflozin and dapagliflozin effectively normalized several biochemical metabolic parameters in this diabetic model. However, they were found to also unfavorably affect the skeletal system. Moreover, these SGLT2 inhibitors were not equivalent in regards to their impact on bones. Therefore, each SGLT2 inhibitor ought to be individually assessed for its impact on the skeletal system. In a situation involving both diabetes and high risk of bone fracture, the choice of SGLT2 inhibitor presents a serious concern. Further evaluation of these inhibitors should be continued.

Londzin P, Zych M, Janas A, et al. Effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors, dapagliflozin and canagliflozin, on the musculoskeletal system in an experimental model of diabetes induced by high-fat diet and streptozocin in rats. Biomed Pharmacother. 2025 Mar:184:117912. PMID: 39955854

Sertraline is a selective serotonin reuptake inhibitor that is well-known for its use in treating various psychiatric disorders. It is certainly involved in serotonin regulation. However, its impact may also extend beyond that and into the expression of genes tied to neurobiology. Recent studies have also investigated the role of sertraline in other pathologies including cancer pathways and neurochemistry stress response.

In a new study at the National Autonomous University of Mexico, the impact of sertraline on fruit flies was investigated. The fruit fly larvae were submitted to a single exposure of sertraline during their third instar larval stage. Amazingly, the effects of a single 24 hour exposure in early-life stage caused notable changes that were observable in the grown adult flies. These changed included significant effects on alternative splicing of genes that deal with neuronal function and structure.

The most remarkable finding of this study was the lasting impact of the single pharmacological exposure early in life. The single exposure was sufficient to modulate gene expression through the lifetime of the fly. In this case, the impact of sertraline seemed to be positive. It enhanced the autophagy machinery, resulting in a persistent neuroprotective effect.

Further studies using vertebrate models are needed to further assess the full potential of sertraline to modulate key genes involved in neuronal function.

Santos-Cruz L, Campos-Aguilar M, Castañeda-Partida L, et al. Impact of larval sertraline exposure on alternative splicing in neural tissue of adult Drosophila melanogaster. Int J Mol Sci. 2025 Jan 10;26(2):563. PMID: 39859278

Acepromazine is a derivative of chlorpromazine which is useful as a veterinary research tool. It has been shown to decrease packed cell volume, a.k.a. hematocrit, a measurement of the proportion of blood that is made up of cells.

Coagulopathy is a common issue in equine illness and requires proper attention and management. Recognizing, predicting, and treating abnormal coagulation is essential. Recently, an equine study made use of acepromazine as a research tool in a study of coagulopathy.

The study involved eight healthy horses and intravenous administration of acepromazine to induce anemia. Several viscoelastic parameters were then evaluated in order to establish the relationship between blood cell mass, hypercoagulability, and hypocoagulability. Understanding these relationship dynamics is essential to correctly interpreting and test results that are produced by an anemic subject.

The results showed acepromazine to be successful in inducing anemia in this model, and showed a connection between red blood cell mass and hypercoagulability. Although this study was limited in size, it does confirm the very different testing profiles found in anemic versus polycythemic subjects. Further studies could increase the understanding and develop appropriate reference ranges expected under these conditions.

Mersich I, Bishop R, Yucupicio S, et al. Decreased circulating red blood cell mass induced by intravenous acepromazine administration alters viscoelastic and traditional plasma coagulation testing results in healthy horses. Animals (Basel). 2024 Oct 28;14(21):3102. PMID: 39518825

 

Hydroxytyrosol is a naturally occurring polyphenol with remarkable antioxidant activity. Its precursor oleuropein is present in olive fruits but also in all parts of the olive tree. While oleuropein has several known biological activities, the activity of hydroxytyrosol may be even greater. Therefore, obtaining as much as possible hydroxytyrosol, rather than oleuropein, from the plant is desirable.

The agricultural waste produced from annual pruning of olive trees is normally disposed of by burning. However, these leaves and small branches also contain oleuropein. Here there is an opportunity to extract a high-value product from what is generally thought to be a waste material.

Recently, researchers have attempted to develop and optimize just such a process. Enzymatic reactions were developed to convert the original oleuropein into the desired hydroxytyrosol. Enzymes with varied characteristics such as molecular size, isoelectric point, and hydrophobic domains, were tested.

With a two-step reaction strategy, first the glucosidic bond was broken, followed by hydrolysis of the aglycon. They found that the first step alone required 7 days, at low concentration, and the second step did not work as expected, but seemed to also require enzyme action. The outcome was only 5% transformation.

They also examined a one-step reaction scheme using a different type of enzyme, and this process allowed for a higher concentration and obtained 30% transformation in 12 days. This process was much more effective than the two-step strategy.

However, with only 30% transformation, it may be possible to further optimize the process to obtain even better yield of hydroxytyrosol. On the whole, using a waste material to create a valuable product is bound to be a worthwhile endeaver.

Garcia-Molina G, Peters E, Palmeri R, et al. Enzymatic synthesis of hydroxytyrosol from oleuropein for valorization of an agricultural waste. Bioengineered. 2024 Dec;15(1):2396647. PMID: 39235136

Betulinic acid is a natural product found in several plant sources including white birch bark. Interestingly, this molecule has several biological activities, notably antioxidant properties. Studies indicate that the antioxidant activity of this molecule is mediated through the Nrf2/Keap1 signaling pathway, which defends against oxidative stress.

Oxidative stress is one of the major causes of in vitro oocyte maturation defects. Therefore, optimizing the in vitro conditions will lead to more successful outcomes. Undeniably, this is an important step in the process of assisted reproductive technology.

Recently, a study looked at the impact of betulinic acid on the maturation of porcine oocytes. First, the cumulus-oocyte complexes (COCs) were extracted from porcine ovaries. The the COCs were allowed to mature in vitro in the presence or absence of various concentrations of betulinic acid. Next, the matured oocytes were parthenogenetically activated, followed by incubation for 6 days.

As it turns out, the COCs treated with betulinic acid showed enhanced meiotic progression leading to more successful outcomes. Anaylsis indicates that the treatment regulated antioxidant genes, thereby reducing the intracellular oxidative stress level.

Now that these positive in vitro results have been observed, it will be necessary to further evaluate for any long-term effects on the embryonic development. This research is important for the improvement of in vitro maturation systems.

Additionally, related compounds are also available from LKT Labs:

Betulin

Betulin-3-Acetate

Kim MJ, Kang HG, Jeon SB, et al. The antioxidant betulinic acid enhances porcine oocyte maturation through Nrf2/Keap1 signaling pathway modulation. PLoS One. 2024 Oct 10;19(10):e0311819. PMID: 39388445

 

Benfotiamine is a synthetic derivative of the B vitamin thiamine. There are 8 types of vitamin B ! This derivative contains an open thiazole ring allowing it to cross the blood-brain barrier. The ability to cross the blood-brain barrier gives it significantly increased bioavailability. This may prove to be useful in controlling diseases involving thiamine deficiency, such as Parkinson’s disease.

Thiamine and Dopamine

Parkinson’s disease is noted to have decreased levels of dopamine in the brain. Thiamine is involved in the synthesis and release of dopamine, an important relationship to note. Studies have shown that the level of free thiamine found in cerebrospinal fluid is lowered in Parkinson’s patients compared to healthy patients. Therefore, it may be possible that adding thiamine may result in a normal level of dopamine synthesis and decelerate or treat Parkinson’s.

Experimental Modelling

Recently, a study using a mouse model of the disease explored that possibility. The toxin MPTP is known to selectively damage dopaminergic neurons in the substantia nigra. This tool is often used to replicate the characteristics of Parkinson’s disease. In the study, the mice were treated with MPTP by intraperitoneal  injections for 5 days to develop the disease characteristics. Some of the groups were also given benfotiamine by oral administration for 28 days.

Testing and Results

Next, the mice were subjected to behavioral tests including the pole test, hang test, step distance experiment, and open field test. The mice that received treatment of benfotiamine showed improved performance of several motor functions.

Finally, brain tissues were collected and analyzed. These results showed that the treatment increased the number of dopaminergic neurons and partially replenished dopamine and its metabolites. Overall, benfotiamine was credited with the neuroprotective effect.

This study gave some very positive results that should be further investigated. Additional models of Parkinson’s disease are available and should also be used. Testing with an increased sample size and possibly some forms of combination therapies should also be considered.

Wang K, Han C, Yang J, et al. Benfotiamine protects MPTP-induced Parkinson’s disease mouse model via activating Nrf2 signaling pathway. PLoS One. 2024 Jul 23;19(7):e0307012. PMID: 39042624

Ginsenosides are the naturally occurring steroid compounds found in ginseng. Approximately 100 different ginsenosides have been identified so far and most of these have some biological activity including anti-tumor effects.

Recently, the effects of ginsenoside Rg1 against the malignant tumors of multiple myeloma were observed. Multiple myeloma is generally treated with bortezomib, however, the emergence of drug resistance against this treatment has increased in recent years. There is need for a new treatment or combination treatment to battle this cancer.

In a new study at Ningbo University, a drug-resistant cell line RMPI8226R was constructed. Next, a four-week-old nude mouse model was subcutaneously inoculated with either the ‘normal’ cancer cells or these drug-resistant cancer cells. All of the mice developed tumors, which were then allowed to grow to a predetermined size. Once the tumors were well-developed, treatments were begun.

The treatments involved intraperitoneal injections of either bortezomib, or ginsenoside Rg1, or a combination of bortezomib + ginsenoside Rg1. Injections were continued every 3 days for 15 days. After that time, the tumors were collected and analyzed.

The results showed that treatment with ginsenoside Rg1 was able to inhibit the development of multiple myeloma tumors. It was also found that the addition of ginsenoside Rg1 to bortezomib treatment was able to overcome the drug resistance. This proved the anti-tumor effect of ginsenoside Rg1, however, only one multiple myeloma cell line RMPI8226 was investigated so far. Further research including additional cell lines is needed.

Ginsenoside Rg1 as well as several other ginsenosides are available from LKT Labs: see all

Lin L, Chen D, Li S, et al. Ginsenoside Rg1 inhibits multiple myeloma and overcomes bortezomib resistance through AMPK-mTOR pathway. Heliyon. 2024 Jul 1;10(13):e33935. PMID: 39071579

PF-07321332 is an active ingredient in Paxlovid, which is a treatment for COVID-19. This molecule inhibits the activity of the main protease of the virus SARS-CoV-2. This main protease is responsible for producing 12 functional proteins which are highly conserved across several coronaviruses. This includes several of the well-known COVID-19 variants.

Finding a treatment that can remain effective against various mutant varieties as well as the wild-type is key to combating this virus. Recently, the D48N mutant was investigated in comparison to the wild-type for effectiveness of the treatment. The D48N mutant contains a single amino acid substitution near the main protease active site. This substitution has already been confirmed to exist in several COVID-19 variants.

To begin the study, first the D48N mutant was cultured and purified. The next step was to run enzymatic inhibition assays to test the inhibitory activities of both shikonin and PF-07321332. Shikonin was also included in the test because the research team’s previous work shows that it also appears to be promising for main protease inhibition.

Next, the purified D48N was mixed together with either of these molecules and allowed time to bond, resulting in the formation of a complex. The complex was then crystallized and the crystals collected for examination. By this method the structures of the complexes can be determined and the interaction of the molecule with D48N confirmed.

The results showed that both PF-07321332 and shikonin have potent inhibitory effects against both D48N mutant and wild-type main protease. Interestingly, shikonin demonstrated non-covalent binding while PF-07321332 demonstrated covalent binding. The data from this study may be useful in further work to develop additional treatments for COVID-19.

Zhao Z, Zhu Q, Zhou X, et al. Structural basis for the inhibition of SARS-CoV-2 Mpro D48N mutant by shikonin and PF-07321332. Viruses. 2023 Dec 30;16(1):65. PMID: 38257765

Levosimendan is a calcium sensitizer that produces a potent effect on the heart muscle. Acting as a positive inotrope, it strengthens the heart’s contractions, making it pump more efficiently. In comparison with other inotropes, levosimendan does not cause unwanted arrythmogenic effects.

In an aging population, chronic diseases are expected to have increasing prevalence. One such disease is heart failure with preserved ejection fraction (HFpEF).

Recently, an animal study was completed to investigate the possibility that HFpEF may be controlled using this inodilator. ZSF1 obese rats were used as a preclinical surrogate model for HFpEF. The animals were treated for 6 weeks with 1 mg/kg/day levosimendan in drinking water. Another group was submitted to i.v. levosimendan infusion to determine the acute effects.

Both types of treatment seemed to show beneficial haemodynamic effects in this study. However, as with many animal models of human diseases, this model has some limitations. Further research should carefully appraise the effectiveness of this treatment on an aging population of HFpEF.

Moreira-Costa L, Tavares-Silva M, Almeida-Coelho J, et al. Acute and chronic effects of levosimendan in the ZSF1 obese rat model of heart failure with preserved ejection fraction. Eur J Pharmacol. 2024 Mar 5:966:176336. PMID: 38272343

Caerulomycin A is a microbial metabolite isolated from marine actinomycetes. The chemical structure consists of a 2,2′-bypyridine core, which is similar to a biphenyl core. Because of this similarity, it is thought that it may bind well to tubulins and DNA topoisomerase, and thereby provide a potent anti-cancer affect.

In vitro and in vivo studies have shown caerulomycin A to be effective against paclitaxel-resistant cancer. In a study at Ohio University, several types of human tumor cell lines were prepared in vitro and treated with caerulomycin A and in combination with paclitaxel. The melanoma cells were also injected subcutaneously into a mouse model for in vivo study. The mice were then administered caerulomycin A by intraperitoneal injections.

The in vitro studies showed the growth of all cancer types was inhibited, including the paclitaxel-resistant cancer cells. The animal model was also effective and confirmed a significant reduction in tumor size.

The results of this study suggest a synergistic effect when used in combination with paclitaxel against several cancer types. Further work with caerulomycin A and related compounds may offer a new strategy for cancer treatment.

Tong L, Sun W, Wu S, et al. Characterization of caerulomycin A as a dual-targeting anticancer agent. Eur J Pharmacol. 2022 May 5:922:174914. PMID: 35337812

 

Virginiamycin is commonly used in livestock as a growth promoter. In the final stage of cattle farming, the dietary components of the feedlot are adjusted to produce the best quality meat. This generally involves increasing the amount of fat in the animal. In most cases, the final stage diet is grain-based, rather than grass. During this stage, additives such as virginiamycin are also introduced.

Virginiamycin is a macrolide antibiotic which has repeatedly been shown to improve animal performance. However, it is unclear whether it works by protecting the liver, or impacting the short-chain fatty acid profile in the rumen, or improving the protein flow to the small intestine.

Recently, a study at Texas A&M evaluated the effects of this additive in an attempt to understand exactly how it works. The animals were treated with 3 different dosage levels for comparison. After treatment, samples of rumen fluid, feces, and urine were collected and analyzed.

The results from this study found that virginiamycin supplementation did not effect nutrient digestibility but did increase ruminal pH and impacted the rumen dynamics. It also seemed to improve the protein flow to the small intestine.

Additional research should be done to further understand the impact of virginiamycin supplementation on the bacteria population and fermentation in the rumen. Laboratory reference standards for specific virginiamycins are available at LKT Labs:

Virginiamycin M1

Virginiamycin S1

Virginiamycin Mixture (M1 & S1)

Batista L, Rivera M, Fonseca M, et al. The influence of virginiamycin on digestion and ruminal parameters under feedlot conditions. Transl Anim Sci. 2024 Feb 14:8:txae019. PMID: 38406320

Capsaicin has been identified as the primary component that contributes to the hotness of chili peppers. Around the world, chili peppers are a popular ingredient used in many kinds of food. There are many varieties of chili pepper and each offers a slightly different flavor and level of heat. In some communities they are even used as a food staple.

Over time, this ingredient and its possible role in cancer has become a subject of controversy. While some studies with capsaicin have shown that it can inhibit cancer cell growth and metastasis, other studies have shown the opposite result.

Recently, a study at Nanjing University focused specifically on a diet with high level of capsaicin and its impact on gastric cancer. This study used a xenograft mouse model of gastric cancer fed with a diet of either 50 mg/kg or 100 mg/kg capsaicin. This is the equivalent of a human consuming 90-250 mg capsaicin each day. The results showed that this type of diet led to increased metastasis rates and increased number of cancer nodules. Interestingly, the size of the tumors did not increase.

While other experiments have given evidence of capsaicin having anticancer properties, this study gives evidence of its cancer promoting properties. One key difference between studies is likely to be the concentration or intensity of the application. Perhaps at lower concentration and frequency of consumption, there is a beneficial effect, but with continual high concentration intake as in this study, the effects become detrimental. It seems chili peppers provide yet another example of ‘moderation is key’.

Deng R, Yu S, Ruan X, et al. Capsaicin orchestrates metastasis in gastric cancer via modulating expression of TRPV1 channels and driving gut microbiota disorder. Cell Commun Signal. 2023 Dec 21;21(1):364. PMID: 38129926

Acetylcholine neurotransmission is thought to be important in combating Alzheimer’s disease. When acetylcholine transmission is reduced, cognitive impairment as seen in Alzheimer’s patients is observed. Therefore, maintaining or increasing the level of acetylcholine in the brain is the strategy to treat this disease.

There are two known enzymes that catalytically hydrolyze acetylcholine in the brain. These are acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). AChE is the predominant enzyme, while BChE is thought to have a supportive role. Because of that, AChE inhibition has traditionally been the goal to set. However, as the disease progresses, it is noted that AChE levels progressively decrease while BChE levels increase. Eventually BChE becomes the more abundant enzyme. As such, at later stages of the disease, the more effective battle may be against BChE.

Another strategy is to use a molecule that acts as inhibitor for both AChE and BChE. Rivastigmine is such a dual inhibitor and is currently used in treatment of dementia. However, rivastigmine is more selective for AChE than BChE. Another molecule, bambuterol, is more selective for BChE than AChE. Therefore, a hybrid analogue molecule of rivastigmine and bambuterol may have improved potency and selectivity than either molecule alone.

To test this idea, 15 hybrids were synthesized and evaluated in vitro for their capability as AChE and BChE inhibitors. As it turns out, each of these hybrids is a stronger inhibitor of BChE than bambuterol. One of them also had longer-lasting inhibition. These hybrids are a good starting point in searching for new candidates for Alzheimer’s research.

Wu J, Tan Z, Pistolozzi M, et al. Rivastigmine-bambuterol hybrids as selective butyrylcholinesterase inhibitors. Molecules. 2023 Dec 22;29(1). doi: 10.3390/molecules29010072. PMID: 38202655