Acupuncture: an Ancient Practice in the Modern Era

       Acupuncture is a method of alternative medicine originating from traditional Chinese medicine where extremely thin needles are inserted into the skin to stimulate specific points of the body. Starting with some brief history, this practice dates back to ancient China where it was first documented in the Huangdi Neijing (The Yellow Emperor’s Classic of Internal Medicine) around 100 BCE (White & Ernst, 2004). This text was an influential reference for traditional Chinese medicine for centuries and most likely acted as the foundation for modern acupuncture (Curran, 2008). This text also describes the flow of Qi (vital energy) which was believed to maintain good health when in balance. A Qi deficiency could mean that you are lacking in sleep, nutrition, or social interaction while excess Qi could mean stress, overeating, or exposure to toxins (Acupuncture & Massage College, 2017). (This idea seemed a bit silly to me as I am always stressed and lacking sleep. So, what does that mean for my Qi levels?) Acupuncture was believed to treat people by improving Qi flow and restoring balance by poking certain acupuncture points (Johns Hopkins Medicine, N.d.).

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        Acupuncture is said to treat a wide variety of illnesses: musculoskeletal pain, headaches, addiction, and anxiety to name a few (Johns Hopkins Medicine, N.d.). Ok, but how does acupuncture really work? Well, the answer is, we don’t really know. Acupuncture is thought to stimulate the nervous system (and probably your peripheral nervous system if you have a fear of needles) to cause your body to release chemicals that activates its natural healing abilities (Johns Hopkins Medicine, N.d.). It is also believed that placebo effect may play an important role in the therapeutic effects of acupuncture.  However, very little is actually known about the mechanism, and we are just beginning to understand its effects on the brain and body. In fact, according to PubMed, in the recent years there has been an increase in research studying the clinical use of acupuncture.

         It seems that society now has become more open to alternative medicines, whether it is because medicinal treatments have failed or because people are simply seeking a more natural therapy. But the biggest question with alternative medicine is, does it work? After all, even China thought it was bogus enough to completely ban the practice in 1929 along with other forms of traditional Eastern medicine and it wasn’t until 1949 that the Communist government reinstated such practices (White & Ernst, 2004). Despite the stigma we Americans may have towards traditional Chinese medicine, there are actually significant amounts of evidence showing the benefits of acupuncture therapy.

    A recent study conducted in The General Hospital of Western Theater Command, Sichuan Province assessed the effects of acupuncture of chronic lower back pain (Luo et al. 2019). In this trial, participants were randomly assigned to one of three treatment groups: hand-ear acupuncture, standard acupuncture, and usual care, which involved restorative exercise, strength training, medications, etc. (Luo et al. 2019). Ear acupuncture, or auricular acupuncture, is thought to be similar to reflexology where the ear has regional organization centers that represent different parts of the body created by pluripotent cells. When a certain region is stimulated, it can relieve pathological symptoms from other parts of the body for a period of time (Gori & Firenzuolli, 2007). The hand-ear acupuncture group were acupunctured at yaotongdian (lower back pain points) EX-UE 7 on the hand every other day for 4 weeks followed by acupuncture at yaotongdian AH 9 on the ear twice a week for the remaining 3 weeks. The standard acupuncture group received routine needle treatment curated by experts to specifically treat chronic lower back pain every other day for 4 weeks and twice a week for the remaining 3. Finally, the usual care group received usual care for the 7 weeks (Luo et al. 2019). The outcomes of this study were assessed via a series of blind interviews and measured at baseline, at 2 months after treatment, and at 6 months after. A modified Roland-Morris Disability Questionnaire (RMDQ) was used to evaluate back dysfunction and the visual analogue scale (VAS) was used to assess the severity of pain (Luo et al. 2019) This study found that both acupuncture treatments were more effective than usual care; however, the hand-ear group improved notably better in back function and lower back pain than the standard acupuncture treatment. The hand-ear group also showed better improvement over time indicating better long-term efficacy (Luo et al. 2019). This shows that acupuncture itself may have therapeutic effects and it is not dependent on placebo, as if that were the case, both acupuncture groups would have similar results.

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        As an Asian-America, I find traditional Chinese medicine really fascinating and I think there is so much potential. However, there is still a lot of doubt surrounding the practice. Now that we have been conducting more research, I believe that we are on the road to unlocking new and effective methods for treating patients. In a 2012 breakthrough documentary, Escape Fire: The Fight to Rescue American Healthcare (a fantastic film, I highly recommend), acupuncture was used as an alternative to narcotics to reduce pain in military soldiers during long and turbulent flights (Froemke & Heineman, 2012). More research is still needed to understand the underlying effects of acupuncture and there is sill much to learn from ancient medicine.

 By Emily Xu, A Bachelor's of Science Student at the University of Kentucky

 References

 Acupuncture & Massage College. (2017, August 28). What is Qi? Definition of Qi in Traditional Chinese Medicine. https://www.amcollege.edu/blog/qi-in-traditional-chinese-medicine

 A. White, E. Ernst (2004). A brief history of acupuncture, Rheumatology, Volume 43, Issue 5, Pages 662– 663, https://doi.org/10.1093/rheumatology/keg005

 Curran, J. (2008). The Yellow Emperor’s Classic of Internal Medicine. BMJ : British Medical Journal, 336(7647), 777. https://doi.org/10.1136/bmj.39527.472303.4E

 Froemke, S. & Heineman, M. (Director). (2012). Escape Fire: The Fight to Rescue American Healthcare

[Film]. Aisle C & Our Time Projects.

Small Interfering RNAs: Gene Silencing and its Applications

   

PubMed trend for published papers on siRNA

           

    Gene therapy is a hot topic in both genetics and pharmacology. It involves exploiting genetic pathways to treat disease by replacing a mutated gene, integrating a new gene, knocking a gene out, or silencing a gene. "This allows for an entirely new platform of drug targets outside of traditional small molecule targets such as enzymes and receptors.  Among the most prominent of these methods is gene silencing, a field in research and medicine that has started to come into its own and show results clinically. The method I will be discussing here - gene silencing via the use of small interfering RNA (siRNA) - requires small pieces of RNA that complement the mRNA transcript of the targeted gene in order to disable or "silence" expression of the gene.

 

Figure 1: "Gene Silencing by Design" Chemical and Engeering News, November 18, 2013 https://cen.acs.org/articles/91/i46/Gene-Silencing-Design.html

    siRNAs are administered as double-stranded RNAs, and then cleaved by endonucleases into single-stranded RNAs (Fig. 1). One of these strands is simply a "passenger" strand that is released and plays no further role. The other strand is the siRNA itself, a fragment of 21-25 nucleotides engineered to be complimentary to the messenger RNA (mRNA) of the targeted gene (Gavrilov & Saltzman, 2012). The siRNA interacts with key proteins such as DICER (an RNA-cleaving endoribonuclease) and Ago-2 (an RNA-binding protein which can mediate RNA degradation) to form a complex called the RNA-Induced Silencing Complex (RISC). When the siRNA, as part of the RISC complex, binds the target mRNA, the mRNA is cleaved. The cleaved mRNA is thus incomplete and non-functional, and will not be translated into protein (Lam, Chow, Zhang, & Leung, 2015). The transcription of the gene, therefore, does not serve its biological purpose and is functionally "silenced".

 

Figure 2.  The growth of siRNA-based therapeutics: Updated clinical studies" Biochemical Pharmacology, July 2021 (https://www.sciencedirect.com/science/article/abs/pii/S0006295221000289?via%3Dihub)

  

    The clinical applications of siRNA-based treatments are extensive. As of July of 2021, there are three siRNA-based drugs which have been approved by FDA with several being tested in clinical trials (Fig. 2). The first to be approved was Patisiran, an siRNA drug approved to treat transthyretin-mediated amyloidosis (hATTR). hATTR is caused by mutations in the gene coding for the transthyretin protein, which causes amyloid deposition in the central nervous system (CNS), heart, kidneys, and GI tract, leading to severe neuropathy, heart disease, and ulimately death. The siRNA drug disrupts expression of this protein, and significantly alleviates symptoms. The second siRNA drug approved for clinical use by the FDA was Givosiran. Givosiran is used as a treatment for acute hepatic porphyria (AHP), which causes accumulation of neurotoxic metabolites, leading to symptoms such as seizures, muscle weakness, tachycardia, and paralysis. Givosiran disrupts expression of the ALAS1 gene, reducing AHP-related "attacks" by 74% in clinical trials. Finally, the most recent FDA-approved drug was Lumasiran, which hit the market in November of 2020. Lumasiran is used to treat primary hyperoxaluria type 1 (PH1), a disease associated with hepatic enzyme deficiency and toxic metabolite accumulation. The primary symptom of the disease is excessive calcium oxalate forming kidney stones, leading to severe damage of the renal system and potential death due to systemic accumulation of oxalate. Lumasiran targets the gene transcript associated with a protein which synthesizes the precursor to oxalate, providing a 53-65% reduction in oxalate levels. Several drugs are currently being tested in clinical trials for their potential to treat a variety of diseases, including other hepatic diseases, familial hypercholesterolemia, hemophilia, kidney disease, glaucoma, and others (Zhang, Bahal, Rasmussen, Manautou, & Zhong, 2021).

 

Figure 3.  RNA Therapy: Current Status and Future Potential" Chonnam Medical Journal, May 2020
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250668/

Clearly, siRNA therapeutics are a promising avenue in pharmacological research which have begun to realize their potential after gaining the interest of the biomedical research community in the late 1990's/early 2000's (Fig. 3). The results are impressive, and even more so is the fact that many of these treatments exhibit effects lasting months following a single treatment, due to the ability of the RISC to protect siRNAs from degradation (Kim, 2020). The merits of siRNA drugs are beginning to yield great advancements in gene therapy, and the number of siRNA- based products on the market is expected to grow significantly in the next decade. Clinical use of siRNA therapeutics is still in its infancy, but its role in the future of medicine is sure to be prominent.

By Henry Snider, A Master’s of Medical Science Student at the University of Kentucky

 

References

 Borman, S. (2013). Gene Silencing by Design. Chemical & Engineering News, 91(46).

Gavrilov, K., & Saltzman, W. M. (2012). Therapeutic siRNA: principles, challenges, and strategies. Yale J Biol Med, 85(2), 187-200.

 Kim, Y. K. (2020). RNA Therapy: Current Status and Future Potential. Chonnam Med J, 56(2), 87-93. doi:10.4068/cmj.2020.56.2.87

 Lam, J. K., Chow, M. Y., Zhang, Y., & Leung, S. W. (2015). siRNA Versus miRNA as Therapeutics for Gene Silencing. Mol Ther Nucleic Acids, 4, e252. doi:10.1038/mtna.2015.23

 Zhang, M. M., Bahal, R., Rasmussen, T. P., Manautou, J. E., & Zhong, X. B. (2021). The growth of siRNA-based therapeutics: Updated clinical studies. Biochem Pharmacol, 189, 114432. doi:10.1016/j.bcp.2021.114432

CBD: an effective therapeutic for seizures?

During the past few years, cannabis has become increasingly accepted from a societal standpoint. Contrary to the overall acceptance of the public, very little funding was gathered to explore therapeutics derived from cannabinoids. The lack of funding may be attributed to psychoactive effects produced by some of the products harvested from the plant such as THC. This has limited the potential benefits that patients may be able to receive due to limited research involving of the isolation of compounds derived from cannabis. Recently, a new isolated compound from hemp, cannabidiol (CBD), looks to have potential benefits but more research still needs to be completed to understand its therapeutic applications.

Figure 1: Minimal energy conformations (A) and 2D structures of CBD and THC (B)(Burstein, 2015).

Cannabis is comprised of two main compounds, which are tetrahydrocannabinol (THC) and CBD. CBD is the main compound of cannabis that has sparked research interest due to its similar structure and nature to THC, without producing the psychoactive high that THC produces (Figure 1). CBD is a cannabinoid, so its chemical targets are the CB1 and CB2 receptors. The CB1 receptor is found on neurons and glial cells, while the CB2 receptor is primarily found throughout the immune system (Volkow, 2015). The difference in structural conformation between CBD and THC allows THC to tightly bind to the CB1 receptor while CBD binds to the CB1 receptor with low affinity. The difference in binding affinities allows CBD to act on other pathways in the brain without eliciting a psychoactive effect (Volkow, 2015). The broad range of CBD’s therapeutic effects include exerting antioxidant, neuroprotectant, anti-tumor, antipsychotic, and anti-anxiety activities. These therapeutic uses have been tested through cell culture and animal models, however, in recent years a new therapeutic benefit of CBD emerged. Emerging research has indicated that CBD may also be used to reduce seizures and act as a mild anti-convulsant and is now an FDA approved therapeutic for treating seizures within genetic diseases.

            Research completed by Patel et al. (2019) emphasized a possible clinical application of CBD. Using the TMEV-induced model of epilepsy, researchers were able to observe the role CBD plays in epileptic seizures. Here, researchers administered two different doses of TMEV to the mice; one group was administered 180 mg/kg and the other group was administered 150 mg/kg and each dose was administered twice a day. These mice were analyzed based on the number and intensity of seizures experienced daily (graded by the Racine scale). When observing the outcomes between the two populations, they observed that the population administered with the 180mg/kg dose of CBD experienced a significant decrease in the frequency and severity of seizures due to TMEV infection. While the population administered with 150 mg/kg of CBD experienced decreased frequency of seizures, they did not experience a significant decrease in the severity of seizures. These results from Patel et al. (2019) suggest that CBD displays promising characteristics as an anti-seizure therapeutic for intractable epilepsies. This evidence of therapeutic success within the TMEV model suggests that further studies should be completed to further investigate the pharmacological effects and mechanisms behind CBD.

            Following the research done by Patel et al., Anderson et al. (2019) explored the pharmacokinetics of CBD and clobazam as a therapeutic to treat Dravet’s syndrome. Dravet’s syndrome, similarly to TMEV, is an intractable childhood epilepsy. The evidence of CBD’s effects as an anti-seizure medication sparked Anderson et al.’s interest to test CBD’s pharmacokinetics as an adjunct with clobazam. Anderson et al. (2019) utilized Scn1a^+/- mice to model the effects of Dravet’s syndrome. Utilizing this mice population, they administered clobazam with various concentrations of CBD, including concentrations that were above and below the anticonvulsant dosage for CBD. Anderson et al. (2019) then subjected the Scn1a^+/- mice to hyperthermia-induced seizure experiments and measured the drug-drug interactions and overall therapeutic efficacy of the treatment. When an anticonvulsant dose of CBD was paired with clobazam, Anderson et al. observed an increased efficacy of clobazam treatment on the mice. CBD acted by extending the half-life, increasing exposure time, and increasing interactions of clobazam and its target, N-CLB. Anderson et al. also discovered a pharmacokinetic mechanism between CBD and clobazam that enhanced inhibitory GABA_A receptor activation, further contributing to its efficacy in treating intractable epilepsy.

Figure 2: U.S. funding of the various cannabis research sectors (https://www.science.org/content/article/cannabis-research-database-shows-how-us-funding-focuses-harms-drug)

The studies by Patel et al. and Anderson et al. displayed the therapeutic efficacy and the pharmacological interactions associated with the anti-seizure effects of CBD. Even with strong evidence supporting CBD’s therapeutic benefits, research is still slow to take off due in part, to cannabis being labeled as a Schedule I drug. This labelling has led to funding cannabis research that focuses on harm and abuse of cannabis, rather than the therapeutic benefits (O’Grady, 2021). This skewed distribution of funding has allowed for increased research on why cannabis is a dangerous and abusive substance, rather than the possible benefits of isolated compounds derived from cannabis. This has made introducing cannabis-derived therapeutics challenging, as it is illegal to produce so it is hard to obtain and further isolate its compounds. This negative stigma has been slowly chipped away by public opinion and cultural shifts, which can be observed by 36 states having legalized cannabis and their products for medicinal use. This rapid shifting of cultural norms and values has allowed further CBD and cannabinoid research to take place, allowing for further exploration of the therapeutic benefits that these compounds display. This increase in research has allowed the medical community to realize the therapeutic and clinical benefits of CBD use. The only question to be answered now is: when will society see CBD as a viable therapeutic, rather than simply another recreational substance?

           

By William Lathram, A Master's of Medical Science Student at the University of Kentucky            

References

Anderson, L. L., Absalom, N. L., Abelev, S. V., Low, I. K., Doohan, P. T., Martin, L. J., Chebib, M., McGregor, I. S., & Arnold, J. C. (2019). Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions. Epilepsia, 60(11), 2224–2234. https://doi.org/10.1111/epi.16355

Bissell, L. J. L., Balneaves, L. G., Oliffe, J. L., Capler, N. R., & Buxton, J. (2013). Perceptions of cannabis as a stigmatized medicine: A qualitative descriptive study. Harm Reduction Journal, 10(1), 2. https://doi.org/10.1186/1477-7517-10-2

Burstein, S. (2015). Cannabidiol (CBD) and its analogs: A review of their effects on inflammation. Bioorganic & Medicinal Chemistry, 23(7), 1377–1385. https://doi.org/10.1016/j.bmc.2015.01.059

Commissioner, O. of the. (2020, July 31). FDA approves new indication for drug containing an active ingredient derived from cannabis to treat seizures in rare genetic disease. U.S. Food and Drug Administration. Retrieved October 27, 2021, from https://www.fda.gov/news-events/press-announcements/fda-approves-new-indication-drug-containing-active-ingredient-derived-cannabis-treat-seizures-rare.

O'Grady, C. (2020, August 27). Cannabis research database shows how U.S. funding focuses on harms of the drug. Science. Retrieved October 27, 2021, from https://www.science.org/content/article/cannabis-research-database-shows-how-us-funding-focuses-harms-drug.

Patel, D. C., Wallis, G., Fujinami, R. S., Wilcox, K. S., & Smith, M. D. (2019). Cannabidiol reduces seizures following CNS infection with Theiler's murine encephalomyelitis virus. Epilepsia Open, 4(3), 431–442. https://doi.org/10.1002/epi4.12351

Volkow, N. D. (2015, June 24). The biology and potential therapeutic effects of cannabidiol. NIDA Archives. Retrieved October 17, 2021, from https://archives.drugabuse.gov/testimonies/2015/biology-potential-therapeutic-effects-cannabidiol.